ACTIVITY-DEPENDENT GENE THERAPY FOR NEUROLOGICAL DISORDERS

Abstract

The invention provides expression vectors or vector systems comprising a polynucleotide sequence encoding a polypeptide, wherein the gene is operably linked to a neuronal activity-dependent promoter suitable to drive expression of the gene product in a subject’s neural cells. The features of the expression vectors combine to advantageously improve the treatment of a neurological disorder associated with neuronal hyperexcitability in a subject. The invention also provides the expression vectors or vector systems for use in related methods of treatment, as well as viral particles, cells, kits and methods using the expression vectors or vector systems.

Claims

1. An expression vector for use in a method of treatment of a neurological disorder associated with neuronal hyperexcitability in a subject, the vector comprising: (a) (i) a polynucleotide sequence (“gene”) encoding a polypeptide (“gene product”) which ameliorates said disorder when expressed in the subject’s neural cells, wherein the gene is operably linked to (ii) a neuronal activity-dependent promoter suitable to drive expression of the gene product in the subject’s neural cells; or (b) (i) an intermediate polynucleotide sequence (“intermediate gene”) encoding an intermediate polypeptide (“intermediate gene product”) which alters expression of a further polynucleotide sequence (“further gene”), the further gene encoding a further polypeptide (“further gene product”) which ameliorates said disorder when expressed in the subject’s neural cells, wherein the intermediate gene is operably linked to: (ii) a neuronal activity-dependent promoter suitable to drive expression of the intermediate gene product in the subject’s neural cells.

2. The expression vector for use of claim 1, wherein the level of expression of the gene product or intermediate gene product or further gene product increases when the neuron becomes more excited and decreases when the neuron becomes less excited.

3. The expression vector for use according to any one of the above claims, wherein the promoter is a pyramidal neuronal activity-dependent promoter.

4. The expression vector for use according to any one of the above claims, wherein the promoter is an immediate early gene (IEG) promoter.

5. The expression vector for use according to any one of the above claims, wherein the promoter is c-Fos.

6. The expression vector for use according to any one of the above claims, wherein the promoter has a nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 3 or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 3.

7. The expression vector for use according to any one of claims 1-4, wherein the promoter is Arc, or wherein the promoter comprises a nucleotide sequences that comprises part of the Arc nucleotide sequence.

8. The expression vector for use according to any one of claims 1-4, wherein the promoter is mArc (“minimal Arc”).

9. The expression vector for use according to claim 7 or claim 8, wherein the promoter has a nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 15 or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 15.

10. The expression vector for use according to any one of claims 1-4, wherein the promoter is ESARE (“enhanced synaptic activity-responsive element”).

11. The expression vector for use according to claim 9, wherein the promoter has a nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 16 or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 16.

12. The expression vector for use according to any one of claims 1-4, wherein the promoter is NRAM (“Npas4-specific Robust Activity Marker”).

13. The expression vector for use according to claim 11, wherein the promoter has a nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 17 or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 17.

14. The expression vector for use according to any one of claims 1-4, wherein the promoter is Egr1.

15. The expression vector for use according to claim 13, wherein the promoter has a nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 18 or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 18.

16. The expression vector for use according to any one of the above claims, wherein the gene or further gene is an ion channel gene, and the gene product or further gene product is an ion channel.

17. The expression vector for use according to any one of the above claims, wherein the gene or further gene is a potassium ion channel gene, and the gene product or further gene product is a potassium ion channel.

18. The expression vector for use according to any one of the above claims, wherein the gene or further gene is a KCNA1 gene, and the gene product or further gene product is a Kv1.1 potassium channel.

19. The expression vector for use according to any one of the above claims, wherein the gene or further gene is an engineered KCNA1 gene, and the gene product or further gene product is an edited Kv1.1 potassium channel.

20. The expression vector for use according to claim 19, wherein the engineered KCNA1 gene has a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence shown in SEQ ID NO: 1, and wherein the edited Kv1.1 potassium channel has an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 2 and comprises a valine amino acid residue at a position corresponding to amino acid residue 400 shown in SEQ ID NO: 2.

21. The expression vector for use according to any one of claims 1-16, wherein the gene or further gene is a KNCJ2 gene, and the gene product or further gene product is a Kir2.1 potassium channel.

22. The expression vector for use according to claim 21, wherein the KNCJ2 gene has a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence shown in SEQ ID NO: 13, and wherein the Kir2.1 potassium channel has an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 14.

23. The expression vector for use according to any one of the above claims, wherein the further gene is an endogenous gene and the further gene product is an endogenous gene product.

24. The expression vector for use according to claim 23, wherein the endogenous gene is KCNA1 or KCNJ2.

25. The expression vector for use according to any one of the above claims, wherein the intermediate gene is endonuclease deficient cas (“dcas”), such as dcas9, spCas9 or saCas9.

26. The expression vector for use according to claim 25, further comprising: (a) RNA polymerase III, optionally wherein the polymerase III is U6; and (b) an sgRNA (“single guide RNA”) that targets the further gene.

27. The expression vector for use according to any one of the above claims, wherein the intermediate gene product increases expression of the further gene via an intermediate expression system, optionally an intermediate inducible expression system.

28. The expression vector for use according to claim 27, wherein the intermediate inducible expression system is a Tet-On expression system.

29. An expression vector system for use in a method of treatment of a neurological disorder associated with neuron hyperexcitability in a subject, comprising: (a) a first nucleotide sequence comprising a neuronal activity-dependent promoter suitable to drive expression of reverse tetracycline-controlled transactivator (“rtTA”) in the subject’s neural cells; and (b) a second nucleotide sequence comprising a Tet-On promoter suitable to drive expression of an intermediate gene or further gene according to any one of the above claims, wherein either the first nucleotide, second nucleotide, or expression system optionally further comprises: (c) an RNA polymerase, optionally wherein the RNA polymerase is RNA polymerase II or RNA polymerase III, further optionally wherein the RNA polymerase III is U6; and (d) an sgRNA (“single guide RNA”) that targets the further gene. and/or (e) a tetracycline, preferably doxycycline.

30. An expression vector system for use according to claim 29, comprising: (a) a first nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 37 or 39, or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 37 or 39; and (b) a second nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 35 or 36, or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 35 or 36.

31. The expression vector or vector system for use according to any one of the above claims,wherein the vector or vector system can cause a reduction in the spike frequency of a neuron of the subject by more than 5%, or more than 10%, or more than 20%, or more than 30%, or more than 40%, or more than 50%, or more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 91%, or more than 92%, or more than 93%, or more than 94%, or more than 95%, or more than 96%, or more than 97%, or more than 98%, or more than 99%, or 100%.

32. The expression vector or vector system for use according to claim 31, wherein the vector or vector system can cause a reduction in the spike frequency of a neuron of the subject by more than 75%.

33. The expression vector or vector system for use according to claim 32 or claim 31, wherein the reduction in the spike frequency of the neuron is measured using multi-electrode arrays on or after 21 DIV (days in vitro).

34. The expression vector or vector system for use according to any one of claims 31-33, wherein the reduction in the spike frequency of the neuron is measured relative to a vector comprising SEQ ID NO: 6.

35. The expression vector or vector system for use according to any one of claims 31-34, wherein the neuron is a primary cortical neuron.

36. The expression vector or vector system for use according to any one of the above claims, wherein the vector or vector system can cause fewer than 10 action potentials per second, or fewer than 5 action potentials per second, or fewer than 4 action potentials per second, or fewer than 3 action potentials per second, or fewer than 2 action potentials per second, or no action potentials per second, in a neuron.

37. The expression vector or vector system for use according to any one of the above claims, wherein the vector or vector system can cause a resting membrane potential in a neuron of less than -50 mV, or less than -60 mV, or less than -70 mV, or less than -80 mV, or less than -90 mV, or less than -100 mV.

38. The expression vector or vector system for use according to any of the above claims, wherein the vector or vector system can increase the threshold for action potentials in a neuron to more than 50 pA, or more than 75 pA, or more than 100 pA, or more than 150 pA, or more than 200 pA, or more than 250 pA, or more than 300 pA, or more than 350 pA, or more than 400 pA, or more than 450 pA, or more than 500 pA, or more than 550 pA, or more than 600 pA, or more than 700 pA, or more than 800 pA, or more than 900 pA, or more than 1000 pA, wherein the threshold is the sum of current threshold and holding current.

39. The expression vector or vector system for use according to any one of claims 36-38, wherein the number of action potentials, resting membrane potential, or threshold for action potentials is measured in an acute hippocampal slice from a subject.

40. The expression vector or vector system for use according to any one of claims 36-39, wherein the number of action potentials, resting membrane potential, or threshold for action potentials is measured using acute hippocampal slice electrophysiology and/or patch clamp electrophysiology.

41. The expression vector or vector system for use according to any one of claims 36-40, wherein the neuron is capable of driving a seizure and/or when the neuron generates sustained firing and/or when the neuron becomes over-depolarised.

42. The expression vector or vector system for use according to any one of the above claims, wherein the vector or vector system can cause a greater anti-epileptic effect in a neuron driving a second seizure in a subject, than the anti-epileptic effect in the neuron driving the first seizure in the subject, wherein the second seizure is subsequent to the first seizure.

43. The expression vector or vector system for use according to claim 42, wherein anti-epileptic effect is measured using any of the methods described in claims 23-33.

44. The expression vector or vector system for use according to any one of the above claims, wherein the vector or vector system can prevent a second seizure in a subject, wherein the second seizure is subsequent to a first seizure in the subject.

45. The expression vector or vector system for use of any of the above claims, wherein the method of treatment is close-loop therapy.

46. The expression vector or vector system for use according to any one of the above claims, wherein the neurological disorder is a seizure disorder.

47. The expression vector or vector system for use according to claim 46, wherein the seizure disorder is epilepsy, optionally neocortical epilepsy, temporal lobe epilepsy or refractory epilepsy.

48. The expression vector or vector system for use according to any one of claims 1-45, wherein the neurological disorder is Parkinson’s disease, chronic pain, sudden unexpected death in epilepsy (SUDEP), migraine, cluster headache, trigeminal neuralgia, post-herpetic neuralgia, paroxysmal movement disorders, uni-or bipolar affective disorders, anxiety, or phobias.

49. The expression vector or vector system for use according to any one of the above claims, wherein the vector or vector system is a viral vector or vector system.

50. The expression vector or vector system for use according to claim 49, wherein the viral vector or vector system is a recombinant adeno-associated virus (AAV) vector or vector system, or a lentiviral vector or vector system, optionally wherein the lentiviral vector or vector system is a non-integrating lentiviral vector or vector system.

51. The expression vector or vector system for use according to claim 49, wherein the vector or vector system comprises a nucleotide sequence having at least 95% identity to the nucleotide sequence of SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10.

52. The expression vector or vector system for use according to claim 49, wherein the vector or vector system comprises a nucleotide sequence having at least 95% identity to any one of SEQ ID NOs: 20-34.

53. An expression vector comprising: (a) an engineered KCNA1 gene having a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence shown in SEQ ID NO: 1, encoding an edited Kv1.1 potassium channel having an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 2 and comprises a valine amino acid residue at a position corresponding to amino acid residue 400 shown in SEQ ID NO: 2; and (b) an activity-dependent promoter having a nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 3 or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 3, wherein the gene is operably linked to the promoter.

54. An expression vector system comprising: (a) (i) an engineered KCNA1 gene having a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence shown in SEQ ID NO: 1, encoding an edited Kv1.1 potassium channel having an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 2 and comprises a valine amino acid residue at a position corresponding to amino acid residue 400 shown in SEQ ID NO: 2; or (ii) a KCNJ2 gene having a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence shown in SEQ ID NO: 13, encoding a Kir2.1 potassium channel having an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 14; and (b) an activity-dependent promoter having a nucleotide sequence comprising or consisting of the nucleotide sequence shown in any one of SEQ ID NOs: 3 and 13-18, or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in any one of SEQ ID NOs: 3 and 13-18, wherein (c) the KCNA1 or KCNJ 2 gene is operably linked to the promoter; or (d) the KCNA1 or KCNJ 2 gene’s expression can be altered by an intermediate gene as defined in any one of the above claims, wherein the intermediate gene is operably linked to the activity-dependent promoter.

55. An in vitro method of making viral particles comprising: transducing mammalian cells with a vector or vector system according to any one of the above claims and expressing viral packaging and envelope proteins necessary for particle formation in the cells; and culturing the transduced cells in a culture medium, such that the cells produce viral particles that are released into the medium.

56. An in vitro method of claim 55, wherein the method comprises transducing the mammalian cells with one or more viral packaging and envelope expression vectors that encode the viral packaging and envelope proteins necessary for particle formation.

57. An in vitro method of claim 55 or claim 56, wherein the one or more packaging proteins includes a non-functional integrase enzyme such that the vector or vector system is unable to incorporate its viral genome into the genome of the cell.

58. An in vitro method of any one of claims 55-57, further comprising separating the viral particles from the culture medium and optionally concentrating the viral particles.

59. A viral particle produced by the method of any one of claims 55-58, the viral particle optionally comprising an RNA molecule or DNA molecule transcribed from the expression vector or vector system of any of the above claims.

60. A viral particle comprising a single stranded RNA molecule or DNA molecule encoding a gene, and/or intermediate gene, and/or further gene as described in any one of the above claims, wherein the gene, and/or intermediate gene, and/or further gene encodes a gene product, and/or intermediate gene product, and/or further gene product as defined in any one of the above claims, wherein the promoter is optionally as defined in any one of the above claims, and wherein the viral particle is optionally an AAV.

61. A kit comprising an expression vector or vector system of any one of the above claims and one or more viral packaging and envelope expression vectors that encode viral packaging and envelope proteins necessary for particle formation when expressed in a cell.

62. A kit of claim 61, wherein the viral packaging expression vector is an integrase-deficient viral packaging expression vector.

63. A viral particle of claim 59 or claim 60 for use in a method of treatment, wherein the method of treatment is defined in any one of claims 45-48.

64. A method of treatment of a neurological disorder as defined in any one of claims 1 and 45-48, comprising administering to an individual with the neurological disorder the expression vector or vector system as defined in any one of the above claims, or the viral particle of claim 59 or 60.

65. A method of confirming the presence of a gene product and/or intermediate gene product, and/or further gene product as defined in any one of the above claims, the method comprising: transducing a cell with an expression vector of any one of the above claims or administering a viral particle of claim 59 or 60 to a cell under conditions that permit expression of the gene product and/or intermediate gene product, and/or further gene product; and detecting the presence of the gene product and/or intermediate gene product, and/or further gene product in the cell using a hybridisation assay.

66. An in vitro or ex vivo method of confirming the presence of a gene product and/or intermediate gene product, and/or further gene product as defined in any one of the above claims that has been obtained from a subject administered with a viral particle of claim 59 or 60, the method comprising: detecting the presence of the gene product and/or intermediate gene product, and/or further gene product in the cell using a hybridisation assay.

67. A method of claim 65 or claim 66, wherein the hybridisation assay is an in situ hybridisation assay using a labelled RNA probe, optionally wherein the labelled RNA probe is fluorescently labelled.

68. A cell comprising the expression vector or vector system of any one of the above claims.

Description

FIGURES

[0146] FIG. 1 is a schematic representation of certain aspects of the invention. FIG. 1A (upper) represents neurons with normal activity levels. FIG. 1A (lower) represents hyperexcited neurons with high activity (darker shading) driving a seizure. FIG. 1B represents current gene-therapy approaches, wherein all neurons are permanently modified in order to modulate neuron excitability and treat a seizure. FIG. 1C represents certain aspects of the present invention, wherein only hyperexcited neurons are modified in order to modulate neuron excitability and treat a seizure. FIG. 1D shows a hypothesized molecular mechanism of c-Fos-KCNA1 action, and an exemplary vector of the disclosure. Hyperactivity (strong increase in neuronal excitability) / epileptic activity or seizures will induce c-fos or other activity-dependent promoter activation that in turns will activate KCNA1 or other transgenes able to reduce neuronal excitability (Kv1.1 channel HL = 12 d). Activity-dependent promoter activation may lead to KCNA1 overexpression. The activation of the promoter is transient but the protein expressed will be expressed in the neuron for longer time (e.g. days) i.e. sustained anti-epileptic effect. Once the pathological state is corrected the tool is switched off (and will be reactivated if necessary) FIG. 1E shows an overview of activity-dependent genes suitable for use in the invention. FIG. 1F shows an example of c-fos activation induced by hyperactivity in rodents and human. FIG. 1G shows different combinations of activity-dependent promoters and transgenes suitable for use in this invention. Other transgenes as shown may also be suitable for use with the invention. The transgenes have different properties and functional effects on neuronal excitability. The promoters have different properties in terms of timing of activation, cell specificity and deactivation. FIG. 1 is described further in Example 1.

[0147] FIG. 2 shows the results of a c-Fos immunostaining experiment (FIG. 2A and FIG. 2B). Seizure-like activity (induced by 4-aminopyridine + Picrotoxin) leads to a rapid but transient increase in endogenous c-Fos expression. FIG. 2 is described further in Example 2.

[0148] FIG. 3 shows the results of a Lentivirus c-Fos-dsGFP (FIG. 3A) fluorescence imaging experiments (FIG. 3B and FIG. 3C). FIG. 3D shows the results of AAV9 cfos-dsGFP-KCNJ2 (middle) and mArc-dsGFP-KCNJ2 (right) fluorescence imaging experiments. These show that the promoters follow neuronal activity. FIG. 3 is described further in Example 3.

[0149] FIG. 4 shows that AAV c-Fos-dsGFP-KCNA1 reduced neuronal network excitability in cortical neurons, compared to AAV c-Fos-dsGFP, as measured by spikes/second, bursts/min, and mean number of spikes per burst (see lower panel). An example recording from the EEG experiment is shown in the upper panel (vertical scale bar corresponds to 20 .Math.V; horizontal scale bar corresponds to 1 s). FIG. 4 is described further in Example 4.

[0150] FIG. 5 shows that AAV c-Fos-dsGFP-KCNA1 reduced neuronal network excitability in vitro over 48 hours, compared to AAV c-Fos-dsGFP, as measured by spikes/second (FIG. 4A), bursts/min (FIG. 4B), burst duration (msec) (FIG. 4C) and mean number of spikes per burst (FIG. 4D). PTX is a proconvulsant agent (picrotoxin). FIG. 5E shows that AAV c-Fos-dsGFP-KCNA1, cfos-dsGFP-KCNJ2, mArc-dsGFP-KCNA1, mArc-dsGFP-KCNJ2, and ESARE-dsGFP-KCNA1 reduced neuronal network excitability in cortical neurons, compared to AAV c-Fos-dsGFP, as measured by firing rate spikes/second. FIG. 5 is described further in Examples 4 and 5.

[0151] FIG. 6 shows the results of an in vivo fluorescence experiment demonstrating that, compared with cell-dependent gene-expression (FIG. 6A), activity-dependent gene expression (FIG. 6B) is specific for seizure focus. The scale bar for FIG. 6A is 500 .Math.m; the scale bar for FIG. 6B is 50 .Math.m. A schematic of the experimental procedure is shown in FIG. 6C. FIG. 6 is described further in Example 6.

[0152] FIG. 7 shows the results of an activity-dependent gene therapy preclinical trial performed in a rat epilepsy model. FIG. 7 is described further in Example 7. The horizontal scale car corresponds to 500 .Math.m. “CA1” refers to the Cornu ammonis 1 sub-field of the hippocampus, and “DG” refers to dentate gyrus.

[0153] FIG. 8 shows a map of vector pX552-c-FosP-dscGFP-T2A-KCNA1co.1400V, which was used in Examples 4-11.

[0154] FIG. 9 shows a map of vector pX552-c-FosP-KCNA1co.1400V. FIG. 9 is described further in Example 7. FIG. 9 is also described further in Example 11.

[0155] FIG. 10 shows the experimental plan of an ex vivo hippocampal slice electrophysiology experiment to demonstrate the activation of activity-dependent promoters following a seizure and the effect on neuronal excitability when they drive either KCNA1 or KCNJ2. PTZ is an acute chemoconvulsant (pentylenetrazole). FIG. 10 is described further in Example 8.

[0156] FIGS. 11 and 12 show the results of an ex vivo electrophysiology experiment in acute hippocampal neurons demonstrating that activity-dependent KCNA1 expression activated by a seizure is enough to decrease neuronal excitability. FIG. 11 shows representative traces for neuronal firing. FIG. 12 is a graph showing number of action potential elicited with different current injections, demonstrating the efficiency of the activity-dependent gene therapy in selectively decreasing neuronal excitability. FIGS. 11 and 12 are described further in Example 8.

[0157] FIG. 13 shows the results of an ex vivo electrophysiology experiment demonstrating that either activity-dependent KCNA1or KCNJ2 expression activated by a seizure is enough to decrease neuronal excitability. On the left: KCNJ2 hyperpolarizes neurons (RMP: resting membrane potential). On the right: Activity-dependent promoter-driven KCNA1 or KCNJ2 expression increases the current required to elicit action potentials. FIG. 14 is described further in Example 8.

[0158] FIGS. 14 and 15 show the fluorescence of the slices after an ex vivo electrophysiology experiment demonstrating that activity-dependent promoters activated by a seizure selectively activated only some neurons. FIGS. 14 and 15 are described further in Example 8.

[0159] FIGS. 16 and 17 show the results of in vivo experiments showing the protective effect against repetitive seizures. Activity-dependent gene therapy is activated by a first seizures and when a second seizure is induced it showed an anti-epileptic effect. This experiment has been performed using c-Fos-dsGFP-KCNJ2 as an example. FIGS. 16 and 17 are described further in Example 9.

[0160] FIGS. 18, 19 and 20 show the results of an activity-dependent gene therapy preclinical trial performed in a mouse epilepsy model. These data show that activity-dependent gene therapy rescues the epileptic phenotype in a severe model of chronic intractable epilepsy. FIGS. 18, 19 and 20 are described further in Example 10.

[0161] FIG. 21 shows the results of an activity-dependent gene therapy preclinical trial performed in a mouse epilepsy model. These data show that activity-dependent gene therapy protect epileptic animals against a further severe insult that leads to death epileptic animals injected with a control virus. FIG. 21 is described further in Example 10.

[0162] FIG. 22 shows the results of an activity-dependent gene therapy preclinical trial performed in a mouse epilepsy model. These data show that activity-dependent gene therapy is self-regulated (closed-loop). Animals treated with the activity-dependent gene therapy do not exhibit seizures and do not show detectable fluorescence, meaning that the activity-dependent approach (and expression) is switched off because the animal was cured. FIG. 22 is described further in Example 10.

[0163] FIG. 23 summarizes the tests used to test the effect of activity-dependent gene therapy on behaviour. The data show that activity-dependent gene therapy has no effect on spontaneous locomotion, anxiety and memory. Open field, Object localisation Test and T-Maze were used to screen for effects of the activity-dependent gene therapy in healthy animals. FIG. 23 is described further in Example 11.

[0164] FIG. 24 shows further results of an activity-dependent gene therapy preclinical trial performed in a rat epilepsy model. The horizontal scale bar in B corresponds to 500 .Math.m. FIG. 21 is described further in Example 7.

[0165] FIG. 25 shows that AAV c-Fos-dCas9-VP64-eGFP-Kcna1 (2 AAVs), reduced neuronal network excitability in cortical neurons exposed to PTX (proconvulsant agent), compared to AAV c-Fos-dCas9-VP64-eGFP (2 AWs), as measured by spikes/second over 48 hours. Doxycycline has been used to activate the inducible promoter driving the dCAS9-VP64. All the tool is controlled by the c-Fos promoter driving the transactivator of the inducible promoter. FIG. 25 is described further in Example 5.

[0166] FIG. 26 shows a map of vector pX552-c-FosP-dscGFP-T2A-KCNJ2. FIG. 26 is described further in Examples 4,8,and 9.

[0167] FIG. 27 shows a map of vector pX552-miniARC-dscGFP-T2A-KCNA1co.I400V. FIG. 27 is described further in Example 4 and 8.

[0168] FIG. 28 shows a map of vector pX552-miniARC-dscGFP-T2A-KCNJ2. FIG. 28 is described further in Example 4 and 8.

[0169] FIG. 29 shows a map of vector pX552-ESARE-dscGFP-T2A- KCNA1co.I400V. FIG. 29 is described further in Example 4 and 8.

[0170] FIG. 30 shows a map of vector pX552-ESARE-dscGFP-T2A-KCNJ2. FIG. 30 is described further in Example 8.

[0171] FIG. 31 shows a map of vector pX552-NRAM-hcfos-dscGFP-T2A- KCNA1co.I400V. FIG. 31 is described further in Example 8.

[0172] FIG. 32 shows a map of vector pX552-NRAM-hcfos-dscGFP-T2A-KCNJ2.

[0173] FIG. 32 shows a map of vector pX552-Egr1-dscGFP-T2A- KCNA1co.I400V.

[0174] FIG. 33 shows a map of vector pX552-Egr1-dscGFP-T2A-KCNJ2.

[0175] FIG. 34 shows maps of the CRISPRa vectors pAAV-TetO-dCAS9VP64 and pAAV-U6-sgRNA_Kcna1-cFos-rtTA-T2A-EGFP. FIG. 34 is described further in Example 5.

EXAMPLES

Example 1 - Illustration of Activity-Dependent Therapy and Hypothesized Molecular Mechanism of c-Fos-KCNA1 Action

[0176] One aspect of the invention is a method to treat epilepsy using activity-dependent promoters in order to selectively target the neurons driving seizures, or contributing to propagating seizures, (darker shading in FIG. 1A) which in turn will alter the expression of genes that affect neuronal properties, compared to neurons that are not driving seizures (lighter shading in FIG. 1A).

[0177] Some current experimental gene therapies rely on permanent modification of neuronal excitability, for example using a Kv1.1 ion channel under the control of a cell-specific promoter, and which may not discriminate between neurons involved in seizure and healthy neurons (FIG. 1B).

[0178] Neuronal excitation elicits the rapid induction of a set of genes called immediate early genes (IEGs) such as c-Fos and Arc. c-Fos may discriminate between those neurons involved or not in the seizures, as increased expression of c-Fos in specific neurons after seizures has been observed in mouse models, and in human epileptic brains, where c-Fos has a transient expression.

[0179] Using a c-Fos promoter in an adeno-associated viral vector enables up-regulation of expression of the effector gene (KCN1A) encoding the potassium channel Kv1.1, which in turn reduces neuronal firing. The increased expression of KCNA1 is predicted to restore normal neuronal behaviour in the epileptic focus. After the circuit activity returns to near-normal levels, the promoter activity decreases and the expression of the potassium channel returns to baseline (FIG. 1D).

[0180] The c-Fos promoter will be activated by a seizure and then switch on immediately, staying on for 6-12 hours. In this lag of time the therapeutic gene will be express and protein transcribed. The protein will stay stable for longer time (KCNA1 is supposed to be stable in the membrane for >96 hrs).

[0181] In this case the patients are “protected” from seizures for days, and as many patients experience seizures in clusters, the treatment should reduce the number of seizures experienced within a cluster. Furthermore, a rescue of clustered seizures may lead to a restoration of a physiological state that can result in no more seizures at all.

[0182] If other seizures occur later, the system will be switched on again.

[0183] FIG. 1E shows an overview of activity-dependent genes suitable for use in the invention. FIG. 1F shows an example of c-fos activation induced by hyperactivity in rodents and human. FIG. 1G shows different combinations of activity-dependent promoters and transgenes suitable for use in this invention. Other transgenes such as other potassium channels (right) may also be suitable for use with the invention. The transgenes have different properties and functional effects on neuronal excitability. The promoters have different properties in terms of timing of activation, cell specificity and deactivation

Example 2 - Seizure-Like Activity Increases IEG Expression

Materials and Methods

[0184] Primary mature cortical neurons were stimulated with pro-convulsant drugs and c-fos expression was assessed by immunofluorescence at different time points (2, 6, 24 and 48) after fixation.

Results and Discussion

[0185] FIG. 2 shows that seizure-like activity (induced by 4-aminopyridine (“4AP”) + Picrotoxin (“PTX”)) leads to a rapid but transient increase in endogenous c-Fos expression.

Example 3 - c-Fos Promoter Can Drive GFP Expression, and Arc Promoter Can Drive GFP Expression

Materials and Methods

[0186] A minimal promoter of c-Fos with a part of the 5′UTR and a chimeric intron to boost the expression of the transgene was used. The promoter was then inserted into an AAV backbone with the dsGFP and KCNA1 codon optimised.

[0187] Also, a minimal promoter for Arc was used to boost the expression of the transgene. The promoter was inserted into an AAV backbone with KCNJ2.

Results and Discussion

[0188] FIG. 3 shows that c-Fos promoter can drive GFP expression when seizure-like activity is induced in neural cells by 4AP and PTX.

[0189] Also, FIG. 3D shows that Arc can drive GFP expression when seizure-like activity is induced in neural cells with 4AP and PTX.

Example 4 - Activity-Dependent Dampening of Excitability

Materials and Methods

[0190] Primary cortical neurons were grown on multi-electrode arrays (MEAs) for 21 DIV and transduced at 7 DIV with either AAV c-Fos-dsGFP or AAV c-Fos-dsGFP-KCNA1. Network activity was assessed at 21 DIV. Repeats were n=6 (C-Fos-dsGFP) and n=7 (C-Fos-KCNA1).

[0191] Also, primary cortical neurons were grown on multi-electrode arrays (MEAs) for 21 DIV (days in vitro) and transduced at 7 DIV with either AAV c-Fos-dsGFP or AAV c-Fos-dsGFP-KCNA1 or c-Fos-dsGFP-KCNJ2 or mArc-dsGFP-KCNA1 or mArc-dsGFP-KCNJ2 or ESARE-dsGFP-KCNA1. Network activity was assessed at 21 DIV. Repeats were n=6 (C-Fos-dsGFP), n=7 (C-Fos-KCNA1), n=16 (c-Fos-dsGFP-KCNJ2), n=6 (mArc-dsGFP-KCNA1), n=5 (mArc-dsGFP-KCNJ2), and n= 5 (ESARE-dsGFP-KCNA1).

Results and Discussion

[0192] FIG. 4 shows that AAV c-Fos-dsGFP-KCNA1 reduced neuronal network excitability in cortical neurons, compared to AAV c-Fos-dsGFP, as measured by spikes/second (FIG. 4A), bursts/min (FIG. 4B), burst duration (msec) (FIG. 4C), and mean number of spikes per burst (FIG. 4C). An example recording from the MEA experiment is shown in in the upper panel.

[0193] Also, FIG. 5E shows that AAV c-Fos-dsGFP-KCNA1, c-Fos-dsGFP-KCNJ2, mArc-dsGFP-KCNA1, mArc-dsGFP-KCNJ2 or ESARE-dsGFP-KCNA1 reduced neuronal network excitability in cortical neurons, compared to AAV c-Fos-dsGFP, as measured by spikes/second.

[0194] As discussed in example 5, FIG. 5 shows that AAV c-Fos-dsGFP-KCNA1 reduced neuronal network excitability in cortical neurons, compared to AAV c-Fos-dsGFP, as measured by spikes/second, bursts/min, burst duration (msec), and mean number of spikes per burst.

Example 5 - Time-Course for Activity-Dependent Dampening of Excitability

Materials and Methods

[0195] Primary cortical neurons were grown on multi-electrode arrays (MEAs) for 21 DIV and transduced at 7 DIV with either AAV c-Fos-dsGFP or AAV c-Fos-dsGFP-KCNA1. Network activity was assessed at 21 DIV, and at different time points (2, 6, 24, 48 hrs) after addition of 30 .Math.M picrotoxin (baseline/ 0 hr). Repeats were n=6 (c-Fos-dsGFP) and n=7 (c-Fos-dsKCNA1).

[0196] Also, primary cortical neurons were grown on multi-electrode arrays (MEAs) for 21 DIV and transduced at 7 DIV with either c-Fos-dCAS9-VP64-GFP or c-Fos-dCAS9-VP64-GFP-KCNA1 (2 AAVs). Network activity was assessed at 21 DIV, and at different time points (2, 6, 24,48 hrs) after addition of 30 .Math.M picrotoxin (baseline/ 0 hr). Repeats were n=16 (c-Fos-dCAS9-VP64-GFP) and n=10 (c-Fos-dCAS9-VP64-GFP-KCNA1).

Results and Discussion

[0197] FIG. 5 shows that AAV c-Fos-dsGFP-KCNA1 slows down the increase neuronal network excitability induced by PTX, compared to AAV c-Fos-GFP, as clearly shown by burst duration (msec).

[0198] Also, FIG. 25 shows that c-Fos-dCAS9-VP64-GFP-KCNA1 slows down the increase neuronal network excitability induced by PTX, compared to c-Fos-dCAS9-VP64-GFP, as clearly shown by burst duration (msec) or spikes/seconds. Gene therapy delivered with two AAVs allows Doxycycline to switch it on using the TeT-On system.

Example 6 - Activity-Dependent Gene Therapy Affects Fewer Neurons Than Conventional Over-Expression

Materials and Methods

[0199] Acute pilocarpine injections in the visual cortex were performed after viral injection of either AAV Camk2a-GFP or AAV cfos-GFP. Acute pilocarpine injections lead to focal seizures. The spread of the virus and the number of neurons positive for GFP were evaluated.

Results and Discussion

[0200] FIG. 6 shows that In vivo activity-dependent gene expression is specific for seizure focus, compared to constitutive gene expression. In contrast to conventional gene therapy (FIG. 6A), only a small number of neurons are targeted and the GFP reporter only lights up after a seizure (FIG. 6B) using activity-dependent gene expression.

[0201] Because the virus serotype used is the same (AAV9), the spread of transduction is comparable and this provides direct evidence that the treatment will not affect bystander neurons that do not participate in the seizure. Thus, the therapeutic effect is specifically targeted to neurons that become over-activated.

[0202] A schematic of the experimental procedure is shown in FIG. 6C.

Example 7 - Preclinical Epilepsy Model

Materials and Methods

[0203] A chronic rat model of temporal lobe epilepsy (TLE) was created using intraperitoneal (IP) injection of kainic acid (KA). After 12 weeks EEG transmitters and cannulas were implanted and the rats were recorded continuously for 5 weeks (Baseline). Then, AAV-cfos-dsGFP or AAV-cfos-dsGFP-KCNA1 (as shown in FIG. 8) were injected through the cannulas and animals were recorded for a further 8 weeks.

Results and Discussion

[0204] FIG. 7 demonstrates in vivo activity-dependent gene therapy in a rat epilepsy model, using the construct of FIG. 8. A decrease in number of seizures was observed in rats injected with AAV-cfos-dsGFP-KCNA1 compared to AAV-cfos-dsGFP (FIG. 7A). In some cases, the construct of FIG. 8 will lack a sequence encoding a reporter protein, as shown in FIG. 9, and in SEQ ID NO: 10. This may be preferred for regulatory reasons, for example.

[0205] FIG. 24 provides further data to also demonstrate in vivo activity-dependent gene therapy in a rat epilepsy model, using the construct of FIG. 8. A decrease in number of seizures was observed in rats injected with AAV-cfos-dsGFP-KCNA1 compared to AAV-cfos-dsGFP (FIG. 24 C, D). In some cases, the construct of FIG. 8 will lack a sequence encoding a reporter protein, as shown in FIG. 9, and in SEQ ID NO: 10. This may be preferred for regulatory reasons, for example.

Example 8 - Activity-Dependent Gene Therapy Is Activated by a Single Seizure and Selectively Damps Neuronal Excitability in Hyperactive Neurons

Materials and Methods

[0206] Acute intraperitoneal Pentylenetetrazole (PTZ) injections were performed after viral injection of either AAV cfos-GFP or c-Fos-dsGFP-KCNJ2 or mArc-dsGFP-KCNA1, mArc-dsGFP-KCNJ2 or ESARE-dsGFP-KCNA1, or ESARE-dsGFP-KCNA1 or NRAM-dsGFP-KCNA1. Acute PTZ injections lead to a single tonic-clonic generalised seizure. The effect on fluorescent cells (activated by the seizure) after >2 hours was evaluated with single cell patch clamp. The experimental setup is shown in FIG. 10.

Results and Discussion

[0207] FIGS. 11 to 15 show that, in vivo, activity-dependent gene expression is specific for seizures, and is able to damp neuronal excitability with different promoters and transgenes. The strength of the promoters differed (FIGS. 12, 14 and 15). Expression was observed in Hippocampal CA3 dentate gyrus (granule cells and mossy cells), subiculum and deep hippocampal CA1 neurons. ESARE appears strongest, especially in CA1.The effect of either KCNA1 or KCNJ2 on neurons also differed (FIG. 13), but all permutations of promoter and transgene lead to a profound decrease in neuronal excitability. KCNA1 decreases the firing frequency while KCNJ2 hyperpolarizes the membrane resting potential to make neurons less excitable (FIGS. 11 to 13).

[0208] Because the fluorescence is selective to a small subset of neurons, this provides direct evidence that the treatment will not affect bystander neurons that do not participate in the seizure. Thus, the therapeutic effect is specifically targeted to neurons that become over-activated. The transient expression of either KCNA1 or KCNJ2 is enough to reduce neuronal excitability. This provides direct evidence that the treatment selectively decreases the activity of hyperexcitable neurons participating in the seizure.

Example 9 - Activity-Dependent Gene Therapy Is Activated by a Single Seizure and Is Anti-Epileptic

Materials and Methods

[0209] Two consecutive acute intraperitoneal Pentylenetetrazole (PTZ) injections were performed after viral injection of either AAV cfos-GFP or c-Fos-dsGFP-KCNJ2. Each PTZ injection normally leads to a single tonic-clonic generalised seizure allowing the protective effect of the activity-dependent therapy to be evaluated with the second injection. The experimental set up is shown in FIG. 16.

Results and Discussion

[0210] FIG. 17 shows a protective effect against the chemoconvulsant injection. Activity-dependent gene therapy is activated by the first seizure, and prevents the second chemoconvulsant injection from eliciting a seizure. This result provides direct evidence that the treatment will protect from repetitive seizures.

Example 10 - Activity-Dependent Gene Therapy Suppresses Seizures in a Preclinical Epilepsy Model

Materials and Methods

[0211] A chronic mouse model of temporal lobe epilepsy (TLE) was created using intra-amygdala injection of kainic acid (KA). After 2 weeks EEG transmitters and cannulas were implanted and the mice were recorded continuously for 2 weeks (Baseline). Then, AAV-cfos-dsGFP or AAV-cfos-dsGFP-KCNA1 (as shown in FIGS. 18-20) were injected through the cannulas and, after waiting 2 weeks for virus expression, animals were recorded for a further 2 weeks. After the recordings some animals were used to analyse fluorescence expression (FIG. 22) or to receive an acute PTZ injection (FIG. 21).

Results and Discussion

[0212] FIGS. 18-20 demonstrates in vivo activity-dependent gene therapy in a mouse epilepsy model. A strong decrease in number of seizures was observed in mice injected with AAV-cfos-dsGFP-KCNA1 compared to AAV-cfos-dsGFP (FIGS. 19 and 20). Animals injected with AAV-cfos-dsGFP-KCNA1 receiving a further PTZ injection showed a higher survival compared to the animals injected with AAV-cfos-dsGFP (FIG. 21). Furthermore, animals treated with AAV-cfos-dsGFP-KCNA1 in whom seizures were suppressed did not exhibit fluorescence, indicating that the therapy was switched off after successful treatment (FIG. 22). N=6 (AAV-cfos-dsGFP) and n=5 (AAV-cfos-dsGFP-KCNA1).

[0213] These data confirm the self-regulated anti-epileptic effect of the activity-dependent gene therapy.

[0214] In some cases, the construct of FIG. 8 will lack a sequence encoding a reporter protein, as shown in FIG. 9, and in SEQ ID NO: 10. This may be preferred for regulatory reasons, for example.

Example 11 - Activity-Dependent Gene Therapy Has No Effect on Physiological Behaviour (Spontaneous Locomotion, Anxiety and Memory)

Materials and Methods

[0215] Mice were tested for different behaviour using open field, Object Location Test and T-Maze Spontaneous Alternation before and after injection with either AAV-cfos-dsGFP or AAV-cfos-dsGFP-KCNA1.

Results and Discussion

[0216] FIG. 23 summarizes the tests used to show that treatment with AAV-cfos-dsGFP-KCNA1 had no deleterious effects on physiological behaviour including spontaneous locomotion, and tests of anxiety and memory. N=5 (AAV-cfos-dsGFP) and n=3 (AAV-cfos-dsGFP-KCNA1).

[0217] These data confirm that activity-dependent gene therapy well tolerated.

FURTHER EMBODIMENTS OF THE INVENTION

[0218] The following embodiments E1 to E33 also form part of the invention:

[0219] E1. An expression vector for use in a method of treatment of a neurological disorder associated with neuronal hyperexcitability in a subject, the vector comprising: [0220] (i) a polynucleotide sequence (“gene”) encoding a polypeptide (“gene product”) which ameliorates said disorder when expressed in the subject’s neural cells, wherein the gene is operably linked to [0221] (ii) a neuronal activity-dependent promoter suitable to drive expression of the gene product in the subject’s neural cells.

[0222] E2. The expression vector for use of E1, wherein the level of expression of the gene product increases when the neuron becomes more excited and decreases when the neuron becomes less excited.

[0223] E3. The expression vector for use according to any one of the above embodiments, wherein the promoter is a pyramidal neuronal activity-dependent promoter.

[0224] E4. The expression vector for use according to any one of the above embodiments, wherein the promoter is an immediate early gene (IEG) promoter.

[0225] E5. The expression vector for use according to any one of the above embodiments, wherein the promoter is c-Fos, Arc, or Egr1.

[0226] E6. The expression vector for use according to any one of the above embodiments, wherein the promoter has a nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 3 or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 3.

[0227] E7. The expression vector for use according to any one of the above embodiments, wherein the gene is an ion channel gene, and the gene product is an ion channel.

[0228] E8. The expression vector for use according to any one of the above embodiments, wherein the gene is a potassium ion channel gene, and the gene product is a potassium ion channel.

[0229] E9. The expression vector for use according to any one of the above embodiments, wherein the gene is a KCNA1 gene, and the gene product is a Kv1.1 potassium channel.

[0230] E10. The expression vector for use according to any one of the above embodiments, wherein the gene is an engineered KCNA1 gene, and the gene product is an edited Kv1.1 potassium channel.

[0231] E11. The expression vector for use according to any one of the above embodiments, wherein the engineered KCNA1 gene has a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence shown in SEQ ID NO: 1, and

[0232] wherein the edited Kv1.1 potassium channel has an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 2 and comprises a valine amino acid residue at a position corresponding to amino acid residue 400 shown in SEQ ID NO: 2.

[0233] E12. The expression vector for use of any of the above embodiments, wherein the method of treatment is close-loop therapy.

[0234] E13. The expression vector for use according to any one of the above embodiments, wherein the neurological disorder is a seizure disorder.

[0235] E14. The expression vector for use according to E13, wherein the seizure disorder is epilepsy, optionally neocortical epilepsy, temporal lobe epilepsy or refractory epilepsy.

[0236] E15. The expression vector for use according to any one of E1-12, wherein the neurological disorder is Parkinson’s disease, chronic pain, sudden unexpected death in epilepsy (SUDEP), migraine, cluster headache, trigeminal neuralgia, post-herpetic neuralgia, paroxysmal movement disorders, uni- or bipolar affective disorders, anxiety, or phobias.

[0237] E16. The expression vector for use according to any one of the above embodiments, wherein the vector is a viral vector.

[0238] E17. The expression vector for use according to E16, wherein the viral vector is a recombinant adeno-associated virus (AAV) vector, or a lentiviral vector, optionally wherein the lentiviral vector is a non-integrating lentiviral vector.

[0239] E18. The expression vector for use according to E16, wherein the vector comprises a nucleotide sequence having at least 95% identity to the nucleotide sequence of SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10.

[0240] E19. An expression vector comprising: [0241] (a) an engineered KCNA1 gene having a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence shown in SEQ ID NO: 1, encoding an edited Kv1.1 potassium channel having an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 2 and comprises a valine amino acid residue at a position corresponding to amino acid residue 400 shown in SEQ ID NO: 2; and [0242] (b) an activity-dependent promoter having a nucleotide sequence comprising or consisting of the nucleotide sequence shown in SEQ ID NO: 3 or a nucleotide sequence having at least 80% identity to the nucleotide sequence shown in SEQ ID NO: 3, wherein the gene is operably linked to the promoter.

[0243] E20 An in vitro method of making viral particles comprising: [0244] transducing mammalian cells with a vector according to any one of E1-19 and expressing viral packaging and envelope proteins necessary for particle formation in the cells; and [0245] culturing the transduced cells in a culture medium, such that the cells produce viral particles that are released into the medium.

[0246] E21. An in vitro method of E20, wherein the method comprises transducing the mammalian cells with one or more viral packaging and envelope expression vectors that encode the viral packaging and envelope proteins necessary for particle formation.

[0247] E22. An in vitro method of E20 or E21, wherein the one or more packaging proteins includes a non-functional integrase enzyme such that the vector is unable to incorporate its viral genome into the genome of the cell.

[0248] E23. An in vitro method of any one of E20-22, further comprising separating the viral particles from the culture medium and optionally concentrating the viral particles.

[0249] E24. A viral particle produced by the method of any one of E20-23, the viral particle optionally comprising an RNA molecule or DNA molecule transcribed from the expression vector of any of E1-19.

[0250] E25. A viral particle comprising a single stranded RNA molecule or DNA molecule encoding a gene as described in any one of E1-19, [0251] wherein the gene encodes a gene product as defined in any one of E1-19, [0252] wherein the promoter is optionally as defined in any one of E1-19, and [0253] wherein the viral particle is optionally an AAV.

[0254] E26. A kit comprising an expression vector of any one of E1-19 and one or more viral packaging and envelope expression vectors that encode viral packaging and envelope proteins necessary for particle formation when expressed in a cell.

[0255] E27. A kit of E26, wherein the viral packaging expression vector is an integrase-deficient viral packaging expression vector.

[0256] E28. A viral particle of E24 or E25 for use in a method of treatment, wherein the method of treatment is defined in any one of E12-15.

[0257] E29. A method of treatment of a neurological disorder as defined in any one of E1 and 12-15, comprising administering to an individual with the neurological disorder the expression vector as defined in any one of E1-19, or the viral particle of E24 or E25.

[0258] E30. A method of confirming the presence of a gene product as defined in any one of E1-19, the method comprising: [0259] transducing a cell with an expression vector of any one of E1-19 or administering a viral particle of E24 or E25 to a cell under conditions that permit expression of the gene product; and [0260] detecting the presence of the gene product in the cell using a hybridisation assay.

[0261] E31. An in vitro or ex vivo method of confirming the presence of a gene product as defined in any one of E1-19 that has been obtained from a subject administered with a viral particle of E24 or E25, the method comprising:

[0262] detecting the presence of the gene product in the cell using a hybridisation assay.

[0263] E32. A method of E29 or E30, wherein the hybridisation assay is an in situ hybridisation assay using a labelled RNA probe, optionally wherein the labelled RNA probe is fluorescently labelled.

[0264] E33. A cell comprising the expression vector of any one of E1-19.

Sequence Annex

[0265] TABLE-US-00001 Nucleotide sequence of an exemplary engineered hum an KCNA1 gene (SEQ ID NO: 1) ATGACCGTGATGAGCGGCGAG AACGTGGACGAGGCCTCTGCCGCTCCTGGACACCCTCAGGATGGCAGCTA TCCCAGACAGGCCGACCACGACGATCACGAGTGCTGCGAGCGGGTCGTGA TCAACATCAGCGGCCTGAGATTCGAGACACAGCTGAAAACCCTGGCCCAG TTCCCCAACACCCTGCTGGGCAACCCCAAGAAACGGATGCGGTACTTCGA CCCCCTGCGGAACGAGTACTTCTTCGACCGGAACCGGCCCAGCTTCGACG CCATCCTGTACTACTACCAGAGCGGCGGCAGACTGCGGAGGCCCGTGAAT GTGCCCCTGGACATGTTCAGCGAGGAAATCAAGTTCTACGAGCTGGGCGA GGAAGCCATGGAAAAGTTCAGAGAGGACGAGGGCTTCATCAAAGAGGAAG AGAGGCCCCTGCCCGAGAAAGAATACCAGAGACAAGTGTGGCTGCTGTTC GAGTACCCCGAGTCTAGCGGCCCTGCCAGAGTGATCGCCATCGTGTCCGT GATGGTCATCCTGATCTCTATCGTGATCTTCTGCCTGGAAACCCTGCCTG AGCTGAAGGACGACAAGGACTTCACCGGCACCGTGCACCGGATCGACAAC ACCACCGTGATCTACAACAGCAATATCTTCACCGACCCATTCTTCATCGT GGAAACACTGTGCATCATCTGGTTCAGCTTCGAGCTGGTCGTGCGGTTCT TCGCCTGCCCCAGCAAGACCGACTTCTTCAAGAACATCATGAACTTCATT GATATCGTGGCCATCATCCCCTACTTCATCACCCTGGGCACCGAGATCGC CGAGCAGGAAGGCAATCAGAAGGGCGAGCAGGCCACCAGCCTGGCCATTC TGAGAGTGATCAGACTCGTGCGGGTGTTCCGGATCTTCAAGCTGAGCCGG CACAGCAAGGGCCTGCAGATCCTGGGCCAGACACTGAAGGCCAGCATGAG AGAGCTGGGCCTGCTGATCTTCTTTCTGTTCATCGGCGTGATCCTGTTCA GCAGCGCCGTGTACTTCGCCGAGGCCGAAGAAGCCGAGAGCCACTTCAGC TCTATCCCCGACGCCTTTTGGTGGGCCGTGGTGTCCATGACCACAGTGGG CTACGGCGACATGTAnCCCGTGACAATCGGCGGCAAGATCGTGGGCAGCC TGTGTGCCATTGCCGGCGTGCTGACAGTCGCCCTGCCTGTGCCTGTGATC GTGTCCAACTTCAACTACTTCTACCACCGGGAAACCGAGGGGGAGGAACA GGCTCAGCTGCTGCACGTGTCCAGCCCCAATCTGGCCAGCGACAGCGACC TGAGCAGACGGTCTAGCAGCACCATGAGCAAGAGCGAGTACATGGAAATC GAAGAGGACATGAACAACTCTATCGCCCACTACCGCCAAGTGAACATCCG GACCGCCAACTGCACCACCGCCAACCAGAACTGCGTGAACAAGAGCAAGC TGCTGACCGATGTCTGA

wherein n is T or C

TABLE-US-00002 Amino acid sequence of an edited human Kv1.1 compr ising a valine at position 400 (underlined) (SEQ I D NO: 2) MTVMSGENVDEASAAPGHPQDGSYPRQADHDDHECCERWIN ISGLRFETQLKTLAQFPNTLLGNPKKRMRYFDPLRNEYFFDRNRPSFDAI LYYYQSGGRLRRPVNVPLDMFSEEIKFYELGEEAMEKFREDEGFIKEEER PLPEKEYQRQVWLLFEYPESSGPARVIAIVSVMVILISIVIFCLETLPEL KDDKDFTGTVHRIDNTTVIYNSNIFTDPFFIVETLCIIWFSFELWRFFAC PSKTDFFKNIMNFIDIVAIIPYFITLGTEIAEQEGNQKGEQATSLAILRV IRLVRVFRIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGVILFSSA VYFAEAEEAESHFSSIPDAFWWAWSMTTVGYGDMYPVTIGGKIVGSLCAI AGVLTVALPVPVIVSNFNYFYHRETEGEEQAQLLHVSSPNLASDSDLSRR SSSTMSKSEYMEIEEDMNNSIAHYRQVNIRTANCTTANQNCVNKSKLLTD V

TABLE-US-00003 Nucleotide sequence of the cfos promoter (SEQ ID N O: 3) GCGGCCGCAGCTTTCCTTTAGGAACAGAGGCTTCGAGCCTTTAA GGCTGCGTACTTGCTTCTCCTAATACCAGAGACTCAAAAAAAAAAAAAAA GTTCCAGATTGCTGGACAATGACCCGGGTCTCATCCCTTGACCCTGGGAA CCGGGTCCACATTGAATCAGGTGCGAATGTTCGCTCGCCTTCTCTGCCTT TCCCGCCTCCCCTCCCCCGGCCGCGGCCCCGGTTCCCCCCCTGCGCTGCA CCCTCAGAGTTGGCTGCAGCCGGCGAGCTGTTCCCGTCAATCCCTCCCTC CTTTACACAGGATGTCCATATTAGGACATCTGCGTCAGCAGGTTTCCACG GCCGGTCCCTGTTGTTCTGGGGGGGGGACCATCTCCGAAATCCTACACGC GGAAGGTCTAGGAGACCCCCTAAGATCCCAAATGTGAACACTCATAGGTG AAAGATGTATGCCAAGACGGGGGTTGAAAGCCTGGGGCGTAGAGTTGACG ACAGAGCGCCCGCAGAGGGCCTTGGGGCGCGCTTCCCCCCCCTTCCAGTT CCGCCCAGTGACGTAGGAAGTCCATCCATTCACAGCGCT

TABLE-US-00004 Nucleotide sequence of wild-type KCNA1 coding sequ ence, comprising an adenine at nucleotide position 1998(underlined) (SEQ ID NO: 4) ATGACGGTGATGTCTGGG GAGAACGTGGACGAGGCTTCGGCCGCCCCGGGCCACCCCCAGGATGGCAG CTACCCCCGGCAGGCCGACCACGACGACCACGAGTGCTGCGAGCGCGTGG TGATCAACATCTCCGGGCTGCGCTTCGAGACGCAGCTCAAGACCCTGGCG CAGTTCCCCAACACGCTGCTGGGCAACCCTAAGAAACGCATGCGCTACTT CGACCCCCTGAGGAACGAGTACTTCTTCGACCGCAACCGGCCCAGCTTCG ACGCCATCCTCTACTACTACCAGTCCGGCGGCCGCCTGCGGAGGCCGGTC AACGTGCCCCTGGACATGTTCTCCGAGGAGATCAAGTTTTACGAGTTGGG CGAGGAGGCCATGGAGAAGTTCCGGGAGGACGAGGGCTTCATCAAGGAGG AGGAGCGCCCTCTGCCCGAGAAGGAGTACCAGCGCCAGGTGTGGCTGCTC TTCGAGTACCCCGAGAGCTCGGGGCCCGCCAGGGTCATCGCCATCGTCTC CGTCATGGTCATCCTCATCTCCATCGTCATCTTTTGCCTGGAGACGCTCC CCGAGCTGAAGGATGACAAGGACTTCACGGGCACCGTCCACCGCATCGAC AACACCACGGTCATCTACAATTCCAACATCTTCACAGACCCCTTCTTCAT CGTGGAAACGCTGTGTATCATCTGGTTCTCCTTCGAGCTGGTGGTGCGCT TCTTCGCCTGCCCCAGCAAGACGGACTTCTTCAAAAACATCATGAACTTC ATAGACATTGTGGCCATCATTCCTTATTTCATCACGCTGGGCACCGAGAT AGCTGAGCAGGAAGGAAACCAGAAGGGCGAGCAGGCCACCTCCCTGGCCA TCCTCAGGGTCATCCGCTTGGTAAGGGTTTTTAGAATCTTCAAGCTCTCC CGCCACTCTAAGGGCCTCCAGATCCTGGGCCAGACCCTCAAAGCTAGTAT GAGAGAGCTAGGGCTGCTCATCTTTTTCCTCTTCATCGGGGTCATCCTGT TTTCTAGTGCAGTGTACTTTGCCGAGGCGGAAGAAGCTGAGTCGCACTTC TCCAGTATCCCCGATGCTTTCTGGTGGGCGGTGGTGTCCATGACCACTGT AGGATACGGTGACATGTACCCTGTGACAATTGGAGGCAAGATCGTGGGCT CCTTGTGTGCCATCGCTGGTGTGCTAACAATTGCCCTGCCCGTACCTGTC ATTGTGTCCAATTTCAACTATTTCTACCACCGAGAAACTGAGGGGGAAGA GCAGGCTCAGTTGCTCCACGTCAGTTCCCCTAACTTAGCCTCTGACAGTG ACCTCAGTCGCCGCAGTTCCTCTACTATGAGCAAGTCTGAGTACATGGAG ATCGAAGAGGATATGAATAATAGCATAGCCCATTATAGACAGGTCAATAT CAGAACTGCCAATTGCACCACTGCTAACCAAAACTGCGTTAATAAGAGCA AGCTACTGACCGATGTTTAA

TABLE-US-00005 Amino acid sequence of wild-type human Kv1.1, comp rising a isoleucine at position 400 (underlined) ( SEQ ID NO: 5) MTVMSGENVDEASAAPGHPQDGSYPRQADHDDHECC ERWINISGLRFETQLKTLAQFPNTLLGNPKKRMRYFDPLRNEYFFDRNRP SFDAILYYYQSGGRLRRPVNVPLDMFSEEIKFYELGEEAMEKFREDEGFI KEEERPLPEKEYQRQVWLLFEYPESSGPARVIAIVSVMVILISIVIFCLE TLPELKDDKDFTGTVHRIDNTTVIYNSNIFTDPFFIVETLCIIWFSFELW RFFACPSKTDFFKNIMNFIDIVAIIPYFITLGTEIAEQEGNQKGEQATSL AILRVIRLVRVFRIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGVI LFSSAVYFAEAEEAESHFSSIPDAFWWAWSMTTVGYGDMYPVTIGGKIVG SLCAIAGVLTIALPVPVIVSNFNYFYHRETEGEEQAQLLHVSSPNLASDS DLSRRSSSTMSKSEYMEIEEDMNNSIAHYRQVNIRTANCTTANQNCVNKS KLLTDV

TABLE-US-00006 Nucleotide sequence of cfos-GFP construct (SEQ ID  NO: 6) GCGGCCGCAGCTTTCCTTTAGGAACAGAGGCTTCGAGCCTTTA AGGCTGCGTACTTGCTTCTCCTAATACCAGAGACTCAAAAAAAAAAAAAA AGTTCCAGATTGCTGGACAATGACCCGGGTCTCATCCCTTGACCCTGGGA ACCGGGTCCACATTGAATCAGGTGCGAATGTTCGCTCGCCTTCTCTGCCT TTCCCGCCTCCCCTCCCCCGGCCGCGGCCCCGGTTCCCCCCCTGCGCTGC ACCCTCAGAGTTGGCTGCAGCCGGCGAGCTGTTCCCGTCAATCCCTCCCT CCTTTACACAGGATGTCCATATTAGGACATCTGCGTCAGCAGGTTTCCAC GGCCGGTCCCTGTTGTTCTGGGGGGGGGACCATCTCCGAAATCCTACACG CGGAAGGTCTAGGAGACCCCCTAAGATCCCAAATGTGAACACTCATAGGT GAAAGATGTATGCCAAGACGGGGGTTGAAAGCCTGGGGCGTAGAGTTGAC GACAGAGCGCCCGCAGAGGGCCTTGGGGCGCGCTTCCCCCCCCTTCCAGT TCCGCCCAGTGACGTAGGAAGTCCATCCATTCACAGCGCTTCTATAAAGG CGCCAGCTGAGGCGCCTACTACTCCAACCGCGACTGCAGCGAGCAACTGA GAAGACTGGATAGAGCCGGCGGTTCCGCGAACGAGCAGTGACCGCGCTCC CACCCAGCTCTGCTCTGCAGCTCCCACCAGTGTCTGGCCGCATCGATTCT AGAATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCA AAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGA GGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGT CCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGC AGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACATCCACTTTGCC TTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCGGAG GATCCGCCACCatgcccgccatgaagatcgagtgccgcatcaccggcacc ctgaacggcgtggagttcgagctggtgggcggcggagagggcacccccga GCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGGCGCCCTGACCT TCAGCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCTTCTACCACTTC GGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCACGCCATCAACAA CGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGACGGCGGCGTGC TGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCGTGATCGGCGAC TTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTGATCTTCACCGA CAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCACCCCATGGGCG ATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTGCGCGACGGC GGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTCAAGAGCGCCAT CCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGCCTTCCGCCGCG TGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGGAGTACCAGCAC GCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGATATCAGCCATGG CTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCTGCCCATGTCTT GTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCTGTGCTTCTGCT AGGATCAATGTGTGA

TABLE-US-00007 Nucleotide sequence of cfos-dsGFP-KCNA1 construct  (SEQ ID NO: 7) GCGGCCGCAGCTTTCCTTTAGGAACAGAGGCTTCG AGCCTTTAAGGCTGCGTACTTGCTTCTCCTAATACCAGAGACTCAAAAAA AAAAAAAAAGTTCCAGATTGCTGGACAATGACCCGGGTCTCATCCCTTGA CCCTGGGAACCGGGTCCACATTGAATCAGGTGCGAATGTTCGCTCGCCTT CTCTGCCTTTCCCGCCTCCCCTCCCCCGGCCGCGGCCCCGGTTCCCCCCC TGCGCTGCACCCTCAGAGTTGGCTGCAGCCGGCGAGCTGTTCCCGTCAAT CCCTCCCTCCTTTACACAGGATGTCCATATTAGGACATCTGCGTCAGCAG GTTTCCACGGCCGGTCCCTGTTGTTCTGGGGGGGGGACCATCTCCGAAAT CCTACACGCGGAAGGTCTAGGAGACCCCCTAAGATCCCAAATGTGAACAC TCATAGGTGAAAGATGTATGCCAAGACGGGGGTTGAAAGCCTGGGGCGTA GAGTTGACGACAGAGCGCCCGCAGAGGGCCTTGGGGCGCGCTTCCCCCCC CTTCCAGTTCCGCCCAGTGACGTAGGAAGTCCATCCATTCACAGCGCTTC TATAAAGGCGCCAGCTGAGGCGCCTACTACTCCAACCGCGACTGCAGCGA GCAACTGAGAAGACTGGATAGAGCCGGCGGTTCCGCGAACGAGCAGTGAC CGCGCTCCCACCCAGCTCTGCTCTGCAGCTCCCACCAGTGTCTGGCCGCA TCGATTCTAGAATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACT CCCTCTCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAA AACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGT GGCCGCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGA GGTGTGGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACATCC ACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCCC AAGCGGAGGATCCGCCACCatgcccgccatgaagatcgagtgccgcatca ccggcaccctgaacggcgtggagttcgagctggtgggcggcggagagggc acccccgaGCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGGCGC CCTGACCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCTTCT ACCACTTCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCACGCC ATCAACAACGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGACGG CGGCGTGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCGTGA TCGGCGACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTGATC TTCACCGACAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCACCC CATGGGCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTGC GCGACGGCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTCAAG AGCGCCATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGCCTT CCGCCGCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGGAGT ACCAGCACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGATATC AGCCATGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCTGCC CATGTCTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCTGTG CTTCTGCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTAACA TGCGGTGACGTGGAGGAGAATCCCGGCCCTATGACCGTGATGAGCGGCGA GAACGTGGACGAGGCCTCTGCCGCTCCTGGACACCCTCAGGATGGCAGCT ATCCCAGACAGGCCGACCACGACGATCACGAGTGCTGCGAGCGGGTCGTG ATCAACATCAGCGGCCTGAGATTCGAGACACAGCTGAAAACCCTGGCCCA GTTCCCCAACACCCTGCTGGGCAACCCCAAGAAACGGATGCGGTACTTCG ACCCCCTGCGGAACGAGTACTTCTTCGACCGGAACCGGCCCAGCTTCGAC GCCATCCTGTACTACTACCAGAGCGGCGGCAGACTGCGGAGGCCCGTGAA TGTGCCCCTGGACATGTTCAGCGAGGAAATCAAGTTCTACGAGCTGGGCG AGGAAGCCATGGAAAAGTTCAGAGAGGACGAGGGCTTCATCAAAGAGGAA GAGAGGCCCCTGCCCGAGAAAGAATACCAGAGACAAGTGTGGCTGCTGTT CGAGTACCCCGAGTCTAGCGGCCCTGCCAGAGTGATCGCCATCGTGTCCG TGATGGTCATCCTGATCTCTATCGTGATCTTCTGCCTGGAAACCCTGCCT GAGCTGAAGGACGACAAGGACTTCACCGGCACCGTGCACCGGATCGACAA CACCACCGTGATCTACAACAGCAATATCTTCACCGACCCATTCTTCATCG TGGAAACACTGTGCATCATCTGGTTCAGCTTCGAGCTGGTCGTGCGGTTC TTCGCCTGCCCCAGCAAGACCGACTTCTTCAAGAACATCATGAACTTCAT TGATATCGTGGCCATCATCCCCTACTTCATCACCCTGGGCACCGAGATCG CCGAGCAGGAAGGCAATCAGAAGGGCGAGCAGGCCACCAGCCTGGCCATT CTGAGAGTGATCAGACTCGTGCGGGTGTTCCGGATCTTCAAGCTGAGCCG GCACAGCAAGGGCCTGCAGATCCTGGGCCAGACACTGAAGGCCAGCATGA GAGAGCTGGGCCTGCTGATCTTCTTTCTGTTCATCGGCGTGATCCTGTTC AGCAGCGCCGTGTACTTCGCCGAGGCCGAAGAAGCCGAGAGCCACTTCAG CTCTATCCCCGACGCCTTTTGGTGGGCCGTGGTGTCCATGACCACAGTGG GCTACGGCGACATGGTGCCCGTGACAATCGGCGGCAAGATCGTGGGCAGC CTGTGTGCCATTGCCGGCGTGCTGACAGTCGCCCTGCCTGTGCCTGTGAT CGTGTCCAACTTCAACTACTTCTACCACCGGGAAACCGAGGGGGAGGAAC AGGCTCAGCTGCTGCACGTGTCCAGCCCCAATCTGGCCAGCGACAGCGAC CTGAGCAGACGGTCTAGCAGCACCATGAGCAAGAGCGAGTACATGGAAAT CGAAGAGGACATGAACAACTCTATCGCCCACTACCGCCAAGTGAACATCC GGACCGCCAACTGCACCACCGCCAACCAGAACTGCGTGAACAAGAGCAAG CTGCTGACCGATGTCTGA

TABLE-US-00008 Nucleotide sequence of optimised AAV-cfos-dsGFP-KC NA1 vector (SEQ ID NO: 8) cctgcaggcagctgcgcgctcgct cgctcactgaggccgcccgggcaaagcccgggcgtcgggcgacctttggt cgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaactc catcactaggggttcctgcggccgcacgcgtTTCGCTATTACGCCAGTTT TATTGCGGCCGCAGCTTTCCTTTAGGAACAGAGGCTTCGAGCCTTTAAGG CTGCGTACTTGCTTCTCCTAATACCAGAGACTCAAAAAAAAAAAAAAAGT TCCAGATTGCTGGACAATGACCCGGGTCTCATCCCTTGACCCTGGGAACC GGGTCCACATTGAATCAGGTGCGAATGTTCGCTCGCCTTCTCTGCCTTTC CCGCCTCCCCTCCCCCGGCCGCGGCCCCGGTTCCCCCCCTGCGCTGCACC CTCAGAGTTGGCTGCAGCCGGCGAGCTGTTCCCGTCAATCCCTCCCTCCT TTACACAGGATGTCCATATTAGGACATCTGCGTCAGCAGGTTTCCACGGC CGGTCCCTGTTGTTCTGGGGGGGGGACCATCTCCGAAATCCTACACGCGG AAGGTCTAGGAGACCCCCTAAGATCCCAAATGTGAACACTCATAGGTGAA AGATGTATGCCAAGACGGGGGTTGAAAGCCTGGGGCGTAGAGTTGACGAC AGAGCGCCCGCAGAGGGCCTTGGGGCGCGCTTCCCCCCCCTTCCAGTTCC GCCCAGTGACGTAGGAAGTCCATCCATTCACAGCGCTTCTATAAAGGCGC CAGCTGAGGCGCCTACTACTCCAACCGCGACTGCAGCGAGCAACTGAGAA GACTGGATAGAGCCGGCGGTTCCGCGAACGAGCAGTGACCGCGCTCCCAC CCAGCTCTGCTCTGCAGCTCCCACCAGTGTCTGGCCGCATCGATTCTAGA ATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAA GCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGA TTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCA TCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGG CTTGAGATCTGGCCATACACTTGAGTGACAATGACATCCACTTTGCCTTT CTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCGGAGGAT CCGCCACCatgcccgccatgaagatcgagtgccgcatcaccggcaccctg aacggcgtggagttcgagctggtgggcggcggagagggcacccccgaGCA GGGCCGCATGACCAACAAGATGAAGAGCACCAAAGGCGCCCTGACCTTCA GCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCTTCTACCACTTCGGC ACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCACGCCATCAACAACGG CGGCTACACCAACACCCGCATCGAGAAGTACGAGGACGGCGGCGTGCTGC ACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCGTGATCGGCGACTTC AAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTGATCTTCACCGACAA GATCATCCGCAGCAACGCCACCGTGGAGCACCTGCACCCCATGGGCGATA ACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTGCGCGACGGCGGC TACTACAGCTTCGTGGTGGACAGCCACATGCACTTCAAGAGCGCCATCCA CCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGCCTTCCGCCGCGTGG AGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGGAGTACCAGCACGCC TTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGATATCAGCCATGGCTT CCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCTGCCCATGTCTTGTG CCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCTGTGCTTCTGCTAGG ATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGT GGAGGAGAATCCCGGCCCTATGACCGTGATGAGCGGCGAGAACGTGGACG AGGCCTCTGCCGCTCCTGGACACCCTCAGGATGGCAGCTATCCCAGACAG GCCGACCACGACGATCACGAGTGCTGCGAGCGGGTCGTGATCAACATCAG CGGCCTGAGATTCGAGACACAGCTGAAAACCCTGGCCCAGTTCCCCAACA CCCTGCTGGGCAACCCCAAGAAACGGATGCGGTACTTCGACCCCCTGCGG AACGAGTACTTCTTCGACCGGAACCGGCCCAGCTTCGACGCCATCCTGTA CTACTACCAGAGCGGCGGCAGACTGCGGAGGCCCGTGAATGTGCCCCTGG ACATGTTCAGCGAGGAAATCAAGTTCTACGAGCTGGGCGAGGAAGCCATG GAAAAGTTCAGAGAGGACGAGGGCTTCATCAAAGAGGAAGAGAGGCCCCT GCCCGAGAAAGAATACCAGAGACAAGTGTGGCTGCTGTTCGAGTACCCCG AGTCTAGCGGCCCTGCCAGAGTGATCGCCATCGTGTCCGTGATGGTCATC CTGATCTCTATCGTGATCTTCTGCCTGGAAACCCTGCCTGAGCTGAAGGA CGACAAGGACTTCACCGGCACCGTGCACCGGATCGACAACACCACCGTGA TCTACAACAGCAATATCTTCACCGACCCATTCTTCATCGTGGAAACACTG TGCATCATCTGGTTCAGCTTCGAGCTGGTCGTGCGGTTCTTCGCCTGCCC CAGCAAGACCGACTTCTTCAAGAACATCATGAACTTCATTGATATCGTGG CCATCATCCCCTACTTCATCACCCTGGGCACCGAGATCGCCGAGCAGGAA GGCAATCAGAAGGGCGAGCAGGCCACCAGCCTGGCCATTCTGAGAGTGAT CAGACTCGTGCGGGTGTTCCGGATCTTCAAGCTGAGCCGGCACAGCAAGG GCCTGCAGATCCTGGGCCAGACACTGAAGGCCAGCATGAGAGAGCTGGGC CTGCTGATCTTCTTTCTGTTCATCGGCGTGATCCTGTTCAGCAGCGCCGT GTACTTCGCCGAGGCCGAAGAAGCCGAGAGCCACTTCAGCTCTATCCCCG ACGCCTTTTGGTGGGCCGTGGTGTCCATGACCACAGTGGGCTACGGCGAC ATGGTGCCCGTGACAATCGGCGGCAAGATCGTGGGCAGCCTGTGTGCCAT TGCCGGCGTGCTGACAGTCGCCCTGCCTGTGCCTGTGATCGTGTCCAACT TCAACTACTTCTACCACCGGGAAACCGAGGGGGAGGAACAGGCTCAGCTG CTGCACGTGTCCAGCCCCAATCTGGCCAGCGACAGCGACCTGAGCAGACG GTCTAGCAGCACCATGAGCAAGAGCGAGTACATGGAAATCGAAGAGGACA TGAACAACTCTATCGCCCACTACCGCCAAGTGAACATCCGGACCGCCAAC TGCACCACCGCCAACCAGAACTGCGTGAACAAGAGCAAGCTGCTGACCGA TGTCTGAgTCGACAATCAACCTCATcgataccgagcgctgctcgagagat ctacgggtggcatccctgtgacccctccccagtgcctctcctggccctgg aagttgccactccagtgcccaccagccttgtcctaataaaattaagttgc atcattttgtctgactaggtgtccttctataatattatggggtggagggg ggtggtatggagcaaggggcaagttgggaagacaacctgtagggcctgcg gggtctattgggaaccaagctggagtgcagtggcacaatcttggctcact gcaatctccgcctcctgggttcaagcgattctcctgcctcagcctcccga gttgttgggattccaggcatgcatgaccaggctcagctaatttttgtttt tttggtagagacggggtttcaccatattggccaggctggtctccaactcc taatctcaggtgatctacccaccttggcctcccaaattgctgggattaca ggcgtgaaccactgctcccttccctgtccttctgattttgtaggtaacca cgtgcggaccgagcggccgcaggaacccctagtgatggagttggccactc cctctctgcgcgctcgctcgctcactgaggccgggcgaccaaaggtcgcc cgacgcccgggctttgcccgggcggcctcagtgagcgagcgagcgcgcag ctgcctgcaggggcgcctgatgcggtattttctccttacgcatctgtgcg gtatttcacaccgcatacgtcaaagcaaccatagtacgcgccctgtagcg gcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccgctaca cttgccagcgccctagcgcccgctcctttcgctttcttcccttcctttct cgccacgttcgccggctttccccgtcaagctctaaatcgggggctccctt tagggttccgatttagtgctttacggcacctcgaccccaaaaaacttgat ttgggtgatggttcacgtagtgggccatcgccctgatagacggtttttcg ccctttgacgttggagtccacgttctttaatagtggactcttgttccaaa ctggaacaacactcaaccctatctcgggctattcttttgatttataaggg attttgccgatttcggcctattggttaaaaaatgagctgatttaacaaaa atttaacgcgaattttaacaaaatattaacgtttacaattttatggtgca ctctcagtacaatctgctctgatgccgcatagttaagccagccccgacac ccgccaacacccgctgacgcgccctgacgggcttgtctgctcccggcatc cgcttacagacaagctgtgaccgtctccgggagctgcatgtgtcagaggt tttcaccgtcatcaccgaaacgcgcgagacgaaagggcctcgtgatacgc ctatttttataggttaatgtcatgataataatggtttcttagacgtcagg tggcacttttcggggaaatgtgcgcggaacccctatttgtttatttttct aaatacattcaaatatgtatccgctcatgagacaataaccctgataaatg cttcaataatattgaaaaaggaagagtatgagtattcaacatttccgtgt cgcccttattcccttttttgcggcattttgccttcctgtttttgctcacc cagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcacga gtgggttacatcgaactggatctcaacagcggtaagatccttgagagttt tcgccccgaagaacgttttccaatgatgagcacttttaaagttctgctat gtggcgcggtattatcccgtattgacgccgggcaagagcaactcggtcgc cgcatacactattctcagaatgacttggttgagtactcaccagtcacaga aaagcatcttacggatggcatgacagtaagagaattatgcagtgctgcca taaccatgagtgataacactgcggccaacttacttctgacaacgatcgga ggaccgaaggagctaaccgcttttttgcacaacatgggggatcatgtaac tcgccttgatcgttgggaaccggagctgaatgaagccataccaaacgacg agcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgcaaacta ttaactggcgaactacttactctagcttcccggcaacaattaatagactg gatggaggcggataaagttgcaggaccacttctgcgctcggcccttccgg ctggctggtttattgctgataaatctggagccggtgagcgtgggtctcgc ggtatcattgcagcactggggccagatggtaagccctcccgtatcgtagt tatctacacgacggggagtcaggcaactatggatgaacgaaatagacaga tcgctgagataggtgcctcactgattaagcattggtaactgtcagaccaa gtttactcatatatactttagattgatttaaaacttcatttttaatttaa aaggatctaggtgaagatcctttttgataatctcatgaccaaaatccctt aacgtgagttttcgttccactgagcgtcagaccccgtagaaaagatcaaa ggatcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaac aaaaaaaccaccgctaccagcggtggtttgtttgccggatcaagagctac caactctttttccgaaggtaactggcttcagcagagcgcagataccaaat actgtccttctagtgtagccgtagttaggccaccacttcaagaactctgt agcaccgcctacatacctcgctctgctaatcctgttaccagtggctgctg ccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagtta ccggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagcc cagcttggagcgaacgacctacaccgaactgagatacctacagcgtgagc tatgagaaagcgccacgcttcccgaagggagaaaggcggacaggtatccg gtaagcggcagggtcggaacaggagagcgcacgagggagcttccaggggg aaacgcctggtatctttatagtcctgtcgggtttcgccacctctgacttg agcgtcgatttttgtgatgctcgtcaggggggcggagcctatggaaaaac gccagcaacgcggcctttttacggttcctggccttttgctggccttttgc tcacatgt

TABLE-US-00009 Nucleotide sequence of cfos-KCNA1 construct (SEQ I D NO: 9) GCGGCCGCAGCTTTCCTTTAGGAACAGAGGCTTCGAGCCTT TAAGGCTGCGTACTTGCTTCTCCTAATACCAGAGACTCAAAAAAAAAAAA AAAGTTCCAGATTGCTGGACAATGACCCGGGTCTCATCCCTTGACCCTGG GAACCGGGTCCACATTGAATCAGGTGCGAATGTTCGCTCGCCTTCTCTGC CTTTCCCGCCTCCCCTCCCCCGGCCGCGGCCCCGGTTCCCCCCCTGCGCT GCACCCTCAGAGTTGGCTGCAGCCGGCGAGCTGTTCCCGTCAATCCCTCC CTCCTTTACACAGGATGTCCATATTAGGACATCTGCGTCAGCAGGTTTCC ACGGCCGGTCCCTGTTGTTCTGGGGGGGGGACCATCTCCGAAATCCTACA CGCGGAAGGTCTAGGAGACCCCCTAAGATCCCAAATGTGAACACTCATAG GTGAAAGATGTATGCCAAGACGGGGGTTGAAAGCCTGGGGCGTAGAGTTG ACGACAGAGCGCCCGCAGAGGGCCTTGGGGCGCGCTTCCCCCCCCTTCCA GTTCCGCCCAGTGACGTAGGAAGTCCATCCATTCACAGCGCTTCTATAAA GGCGCCAGCTGAGGCGCCTACTACTCCAACCGCGACTGCAGCGAGCAACT GAGAAGACTGGATAGAGCCGGCGGTTCCGCGAACGAGCAGTGACCGCGCT CCCACCCAGCTCTGCTCTGCAGCTCCCACCAGTGTCTGGCCGCATCGATT CTAGAATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCT CAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAG GAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGC GTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGTG GCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACATCCACTTTG AGGATCCGCCACCATGACCGTGATGAGCGGCGAGAACGTGGACGAGGCCT CTGCCGCTCCTGGACACCCTCAGGATGGCAGCTATCCCAGACAGGCCGAC CACGACGATCACGAGTGCTGCGAGCGGGTCGTGATCAACATCAGCGGCCT GAGATTCGAGACACAGCTGAAAACCCTGGCCCAGTTCCCCAACACCCTGC TGGGCAACCCCAAGAAACGGATGCGGTACTTCGACCCCCTGCGGAACGAG TACTTCTTCGACCGGAACCGGCCCAGCTTCGACGCCATCCTGTACTACTA CCAGAGCGGCGGCAGACTGCGGAGGCCCGTGAATGTGCCCCTGGACATGT TCAGCGAGGAAATCAAGTTCTACGAGCTGGGCGAGGAAGCCATGGAAAAG TTCAGAGAGGACGAGGGCTTCATCAAAGAGGAAGAGAGGCCCCTGCCCGA GAAAGAATACCAGAGACAAGTGTGGCTGCTGTTCGAGTACCCCGAGTCTA GCGGCCCTGCCAGAGTGATCGCCATCGTGTCCGTGATGGTCATCCTGATC TCTATCGTGATCTTCTGCCTGGAAACCCTGCCTGAGCTGAAGGACGACAA GGACTTCACCGGCACCGTGCACCGGATCGACAACACCACCGTGATCTACA ACAGCAATATCTTCACCGACCCATTCTTCATCGTGGAAACACTGTGCATC ATCTGGTTCAGCTTCGAGCTGGTCGTGCGGTTCTTCGCCTGCCCCAGCAA GACCGACTTCTTCAAGAACATCATGAACTTCATTGATATCGTGGCCATCA TCCCCTACTTCATCACCCTGGGCACCGAGATCGCCGAGCAGGAAGGCAAT CAGAAGGGCGAGCAGGCCACCAGCCTGGCCATTCTGAGAGTGATCAGACT CGTGCGGGTGTTCCGGATCTTCAAGCTGAGCCGGCACAGCAAGGGCCTGC AGATCCTGGGCCAGACACTGAAGGCCAGCATGAGAGAGCTGGGCCTGCTG ATCTTCTTTCTGTTCATCGGCGTGATCCTGTTCAGCAGCGCCGTGTACTT CGCCGAGGCCGAAGAAGCCGAGAGCCACTTCAGCTCTATCCCCGACGCCT TTTGGTGGGCCGTGGTGTCCATGACCACAGTGGGCTACGGCGACATGGTG CCCGTGACAATCGGCGGCAAGATCGTGGGCAGCCTGTGTGCCATTGCCGG CGTGCTGACAGTCGCCCTGCCTGTGCCTGTGATCGTGTCCAACTTCAACT ACTTCTACCACCGGGAAACCGAGGGGGAGGAACAGGCTCAGCTGCTGCAC GTGTCCAGCCCCAATCTGGCCAGCGACAGCGACCTGAGCAGACGGTCTAG CAGCACCATGAGCAAGAGCGAGTACATGGAAATCGAAGAGGACATGAACA ACTCTATCGCCCACTACCGCCAAGTGAACATCCGGACCGCCAACTGCACC ACCGCCAACCAGAACTGCGTGAACAAGAGCAAGCTGCTGACCGATGTCTG A

TABLE-US-00010 Nucleotide sequence of optimised AAV-cfos-KCNA1 ve ctor (SEQ ID NO: 10) cctgcaggcagctgcgcgctcgctcgctc actgaggccgcccgggcaaagcccgggcgtcgggcgacctttggtcgccc ggcctcagtgagcgagcgagcgcgcagagagggagtggccaactccatca ctaggggttcctgcggccgcacgcgtTTCGCTATTACGCCAGTTTTATTG CGGCCGCAGCTTTCCTTTAGGAACAGAGGCTTCGAGCCTTTAAGGCTGCG TACTTGCTTCTCCTAATACCAGAGACTCAAAAAAAAAAAAAAAGTTCCAG ATTGCTGGACAATGACCCGGGTCTCATCCCTTGACCCTGGGAACCGGGTC CACATTGAATCAGGTGCGAATGTTCGCTCGCCTTCTCTGCCTTTCCCGCC TCCCCTCCCCCGGCCGCGGCCCCGGTTCCCCCCCTGCGCTGCACCCTCAG AGTTGGCTGCAGCCGGCGAGCTGTTCCCGTCAATCCCTCCCTCCTTTACA CAGGATGTCCATATTAGGACATCTGCGTCAGCAGGTTTCCACGGCCGGTC CCTGTTGTTCTGGGGGGGGGACCATCTCCGAAATCCTACACGCGGAAGGT CTAGGAGACCCCCTAAGATCCCAAATGTGAACACTCATAGGTGAAAGATG TATGCCAAGACGGGGGTTGAAAGCCTGGGGCGTAGAGTTGACGACAGAGC GCCCGCAGAGGGCCTTGGGGCGCGCTTCCCCCCCCTTCCAGTTCCGCCCA GTGACGTAGGAAGTCCATCCATTCACAGCGCTTCTATAAAGGCGCCAGCT GAGGCGCCTACTACTCCAACCGCGACTGCAGCGAGCAACTGAGAAGACTG GATAGAGCCGGCGGTTCCGCGAACGAGCAGTGACCGCGCTCCCACCCAGC TCTGCTCTGCAGCTCCCACCAGTGTCTGGCCGCATCGATTCTAGAATTCG CTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGG CATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGA TATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCATCTGG TCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGA CACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCGGAGGATCCGCC ACCACCGGTATGACCGTGATGAGCGGCGAGAACGTGGACGAGGCCTCTGC CGCTCCTGGACACCCTCAGGATGGCAGCTATCCCAGACAGGCCGACCACG ACGATCACGAGTGCTGCGAGCGGGTCGTGATCAACATCAGCGGCCTGAGA TTCGAGACACAGCTGAAAACCCTGGCCCAGTTCCCCAACACCCTGCTGGG CAACCCCAAGAAACGGATGCGGTACTTCGACCCCCTGCGGAACGAGTACT TCTTCGACCGGAACCGGCCCAGCTTCGACGCCATCCTGTACTACTACCAG AGCGGCGGCAGACTGCGGAGGCCCGTGAATGTGCCCCTGGACATGTTCAG CGAGGAAATCAAGTTCTACGAGCTGGGCGAGGAAGCCATGGAAAAGTTCA GAGAGGACGAGGGCTTCATCAAAGAGGAAGAGAGGCCCCTGCCCGAGAAA GAATACCAGAGACAAGTGTGGCTGCTGTTCGAGTACCCCGAGTCTAGCGG CCCTGCCAGAGTGATCGCCATCGTGTCCGTGATGGTCATCCTGATCTCTA TCGTGATCTTCTGCCTGGAAACCCTGCCTGAGCTGAAGGACGACAAGGAC TTCACCGGCACCGTGCACCGGATCGACAACACCACCGTGATCTACAACAG CAATATCTTCACCGACCCATTCTTCATCGTGGAAACACTGTGCATCATCT GGTTCAGCTTCGAGCTGGTCGTGCGGTTCTTCGCCTGCCCCAGCAAGACC GACTTCTTCAAGAACATCATGAACTTCATTGATATCGTGGCCATCATCCC CTACTTCATCACCCTGGGCACCGAGATCGCCGAGCAGGAAGGCAATCAGA AGGGCGAGCAGGCCACCAGCCTGGCCATTCTGAGAGTGATCAGACTCGTG CGGGTGTTCCGGATCTTCAAGCTGAGCCGGCACAGCAAGGGCCTGCAGAT CCTGGGCCAGACACTGAAGGCCAGCATGAGAGAGCTGGGCCTGCTGATCT TCTTTCTGTTCATCGGCGTGATCCTGTTCAGCAGCGCCGTGTACTTCGCC GAGGCCGAAGAAGCCGAGAGCCACTTCAGCTCTATCCCCGACGCCTTTTG GTGGGCCGTGGTGTCCATGACCACAGTGGGCTACGGCGACATGGTGCCCG TGACAATCGGCGGCAAGATCGTGGGCAGCCTGTGTGCCATTGCCGGCGTG CTGACAGTCGCCCTGCCTGTGCCTGTGATCGTGTCCAACTTCAACTACTT CTACCACCGGGAAACCGAGGGGGAGGAACAGGCTCAGCTGCTGCACGTGT CCAGCCCCAATCTGGCCAGCGACAGCGACCTGAGCAGACGGTCTAGCAGC ACCATGAGCAAGAGCGAGTACATGGAAATCGAAGAGGACATGAACAACTC TATCGCCCACTACCGCCAAGTGAACATCCGGACCGCCAACTGCACCACCG CCAACCAGAACTGCGTGAACAAGAGCAAGCTGCTGACCGATGTCTGAgTC GACAATCAACCTCATcgataccgagcgctgctcgagagatctacgggtgg catccctgtgacccctccccagtgcctctcctggccctggaagttgccac tccagtgcccaccagccttgtcctaataaaattaagttgcatcattttgt ctgactaggtgtccttctataatattatggggtggaggggggtggtatgg agcaaggggcaagttgggaagacaacctgtagggcctgcggggtctattg ggaaccaagctggagtgcagtggcacaatcttggctcactgcaatctccg cctcctgggttcaagcgattctcctgcctcagcctcccgagttgttggga ttccaggcatgcatgaccaggctcagctaatttttgtttttttggtagag acggggtttcaccatattggccaggctggtctccaactcctaatctcagg tgatctacccaccttggcctcccaaattgctgggattacaggcgtgaacc actgctcccttccctgtccttctgattttgtaggtaaccacgtgcggacc gagcggccgcaggaacccctagtgatggagttggccactccctctctgcg cgctcgctcgctcactgaggccgggcgaccaaaggtcgcccgacgcccgg gctttgcccgggcggcctcagtgagcgagcgagcgcgcagctgcctgcag gggcgcctgatgcggtattttctccttacgcatctgtgcggtatttcaca ccgcatacgtcaaagcaaccatagtacgcgccctgtagcggcgcattaag cgcggcgggtgtggtggttacgcgcagcgtgaccgctacacttgccagcg ccctagcgcccgctcctttcgctttcttcccttcctttctcgccacgttc gccggctttccccgtcaagctctaaatcgggggctccctttagggttccg atttagtgctttacggcacctcgaccccaaaaaacttgatttgggtgatg gttcacgtagtgggccatcgccctgatagacggtttttcgccctttgacg ttggagtccacgttctttaatagtggactcttgttccaaactggaacaac actcaaccctatctcgggctattcttttgatttataagggattttgccga tttcggcctattggttaaaaaatgagctgatttaacaaaaatttaacgcg aattttaacaaaatattaacgtttacaattttatggtgcactctcagtac aatctgctctgatgccgcatagttaagccagccccgacacccgccaacac ccgctgacgcgccctgacgggcttgtctgctcccggcatccgcttacaga caagctgtgaccgtctccgggagctgcatgtgtcagaggttttcaccgtc atcaccgaaacgcgcgagacgaaagggcctcgtgatacgcctatttttat aggttaatgtcatgataataatggtttcttagacgtcaggtggcactttt cggggaaatgtgcgcggaacccctatttgtttatttttctaaatacattc aaatatgtatccgctcatgagacaataaccctgataaatgcttcaataat attgaaaaaggaagagtatgagtattcaacatttccgtgtcgcccttatt cccttttttgcggcattttgccttcctgtttttgctcacccagaaacgct ggtgaaagtaaaagatgctgaagatcagttgggtgcacgagtgggttaca tcgaactggatctcaacagcggtaagatccttgagagttttcgccccgaa gaacgttttccaatgatgagcacttttaaagttctgctatgtggcgcggt attatcccgtattgacgccgggcaagagcaactcggtcgccgcatacact attctcagaatgacttggttgagtactcaccagtcacagaaaagcatctt acggatggcatgacagtaagagaattatgcagtgctgccataaccatgag tgataacactgcggccaacttacttctgacaacgatcggaggaccgaagg agctaaccgcttttttgcacaacatgggggatcatgtaactcgccttgat cgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacac cacgatgcctgtagcaatggcaacaacgttgcgcaaactattaactggcg aactacttactctagcttcccggcaacaattaatagactggatggaggcg gataaagttgcaggaccacttctgcgctcggcccttccggctggctggtt tattgctgataaatctggagccggtgagcgtgggtctcgcggtatcattg cagcactggggccagatggtaagccctcccgtatcgtagttatctacacg acggggagtcaggcaactatggatgaacgaaatagacagatcgctgagat aggtgcctcactgattaagcattggtaactgtcagaccaagtttactcat atatactttagattgatttaaaacttcatttttaatttaaaaggatctag gtgaagatcctttttgataatctcatgaccaaaatcccttaacgtgagtt ttcgttccactgagcgtcagaccccgtagaaaagatcaaaggatcttctt gagatcctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaacca ccgctaccagcggtggtttgtttgccggatcaagagctaccaactctttt tccgaaggtaactggcttcagcagagcgcagataccaaatactgtccttc tagtgtagccgtagttaggccaccacttcaagaactctgtagcaccgcct acatacctcgctctgctaatcctgttaccagtggctgctgccagtggcga taagtcgtgtcttaccgggttggactcaagacgatagttaccggataagg cgcagcggtcgggctgaacggggggttcgtgcacacagcccagcttggag cgaacgacctacaccgaactgagatacctacagcgtgagctatgagaaag cgccacgcttcccgaagggagaaaggcggacaggtatccggtaagcggca gggtcggaacaggagagcgcacgagggagcttccagggggaaacgcctgg tatctttatagtcctgtcgggtttcgccacctctgacttgagcgtcgatt tttgtgatgctcgtcaggggggcggagcctatggaaaaacgccagcaacg cggcctttttacggttcctggccttttgctggccttttgctcacatgt

TABLE-US-00011 Engineered human KCNA1 gene encoding an edited Kv1 .1 with a Y379V substitution (SEQ ID NO: 11) atgac cgtgatgagcggcgagaacgtggacgaggcctctgccgctcctggacacc ctcaggatggcagctatcccagacaggccgaccacgacgatcacgagtgc tgcgagcgggtcgtgatcaacatcagcggcctgagattcgagacacagct gaaaaccctggcccagttccccaacaccctgctgggcaaccccaagaaac ggatgcggtacttcgaccccctgcggaacgagtacttcttcgaccggaac cggcccagcttcgacgccatcctgtactactaccagagcggcggcagact gcggaggcccgtgaatgtgcccctggacatgttcagcgaggaaatcaagt tctacgagctgggcgaggaagccatggaaaagttcagagaggacgagggc ttcatcaaagaggaagagaggcccctgcccgagaaagaataccagagaca agtgtggctgctgttcgagtaccccgagtctagcggccctgccagagtga tcgccatcgtgtccgtgatggtcatcctgatctctatcgtgatcttctgc ctggaaaccctgcctgagctgaaggacgacaaggacttcaccggcaccgt gcaccggatcgacaacaccaccgtgatctacaacagcaatatcttcaccg acccattcttcatcgtggaaacactgtgcatcatctggttcagcttcgag ctggtcgtgcggttcttcgcctgccccagcaagaccgacttcttcaagaa catcatgaacttcattgatatcgtggccatcatcccctacttcatcaccc tgggcaccgagatcgccgagcaggaaggcaatcagaagggcgagcaggcc accagcctggccattctgagagtgatcagactcgtgcgggtgttccggat cttcaagctgagccggcacagcaagggcctgcagatcctgggccagacac tgaaggccagcatgagagagctgggcctgctgatcttctttctgttcatc ggcgtgatcctgttcagcagcgccgtgtacttcgccgaggccgaagaagc cgagagccacttcagctctatccccgacgccttttggtgggccgtggtgt ccatgaccacagtgggctacggcgacatggtgcccgtgacaatcggcggc aagatcgtgggcagcctgtgtgccattgccggcgtgctgacagtcgccct gcctgtgcctgtgatcgtgtccaacttcaactacttctaccaccgggaaa ccgagggggaggaacaggctcagctgctgcacgtgtccagccccaatctg gccagcgacagcgacctgagcagacggtctagcagcaccatgagcaagag cgagtacatggaaatcgaagaggacatgaacaactctatcgcccactacc gccaagtgaacatccggaccgccaactgcaccaccgccaaccagaactgc gtgaacaagagcaagctgctgaccgatgtctga

TABLE-US-00012 Amino acid sequence of an edited human Kv1.1 compr ising a valine at position 400 (underlined) and a  valine at position 379 substitution (bolded) (SEQ  ID NO: 12)MTVMSGENVDEASAAPGHPQDGSYPRQADHDDHECCERWI NISGLRFETQLKTLAQFPNTLLGNPKKRMRYFDPLRNEYFFDRNRPSFDA ILYYYQSGGRLRRPVNVPLDMFSEEIKFYELGEEAMEKFREDEGFIKEEE RPLPEKEYQRQVWLLFEYPESSGPARVIAIVSVMVILISIVIFCLETLPE LKDDKDFTGTVHRIDNTTVIYNSNIFTDPFFIVETLCIIWFSFELWRFFA CPSKTDFFKNIMNFIDIVAIIPYFITLGTEIAEQEGNQKGEQATSLAILR VIRLVRVFRIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGVILFSS AVYFAEAEEAESHFSSIPDAFWWAWSMTTVGYGDMVPVTIGGKIVGSLCA IAGVLTVALPVPVIVSNFNYFYHRETEGEEQAQLLHVSSPNLASDSDLSR RSSSTMSKSEYMEIEEDMNNSIAHYRQVNIRTANCTTANQNCVNKSKLLT DV

TABLE-US-00013 Nucleotide sequence of an exemplary KCNJ2 gene (SE Q ID NO: 13) ATGGGCAGTGTGAGAACCAACCGCTACAGCATCGTCT CTTCAGAAGAAGACGGTATGAAGTTGGCCACCATGGCAGTTGCAAATGGC TTTGGGAACGGGAAGAGTAAAGTCCACACCCGACAACAGTGCAGGAGCCG CTTTGTGAAGAAAGATGGCCACTGTAATGTTCACCACGTGTGTGGACATT CGCTGGCGGTGGATGCTGGTTATCTTCTGCCTGGCTTTCGTCCTGTCATG GCTGTTTTTTGGCTGTGTGTTTTGGTTGATAGCTCTGCTCCATGGGGACC TGGATGCATCCAAAGAGGGCAAAGCTTGTGTGTCCGAGGTCAACAGCTTC ACGGCTGCCTTCCTCTTCTCCATTGAGACCCAGACAACCATAGGCTATGG TTTCAGATGTGTCACGGATGAATGCCCAATTGCTGTTTTCATGGTGGTGT TCCAGTCAATCGTGGGCTGCATCATCGATGCTTTCATCATTGGCGCAGTC ATGGCCAAGATGGCAAAGCCAAAGAAGAGAAACGAGACTCTTGTCTTCAG TCACAATGCCGTGATTGCCATGAGAGACGGCAAGCTGTGTTTGATGTGGC GAGTGGGCAATCTTCGGAAAAGCCACTTGGTGGAAGCTCATGTTCGAGCA CAGCTCCTCAAATCCAGAATTACTTCTGAAGGGGAGTATATCCCTCTGGA TCAAATAGACATCAATGTTGGGTTTGACAGTGGAATCGATCGTATATTTC TGGTGTCCCCAATCACTATAGTCCATGAAATAGATGAAGACAGTCCTTTA TATGATTTGAGTAAACAGGACATTGACAACGCAGACTTTGAAATCGTGGT CATACTGGAAGGCATGGTGGAAGCCACTGCCATGACGACACAGTGCCGTA GCTCTTATCTAGCAAATGAAATCCTGTGGGGCCACCGCTATGAGCCTGTG CTCTTTGAAGAGAAGCACTACTACAAAGTGGACTACTCCAGGTTCCACAA AACTTACGAAGTCCCCAACACTCCCCTTTGTAGTGCCAGAGACTTAGCAG AAAAGAAATATATCCTCTCAAATGCAAATTCATTTTGCTATGAAAATGAA GTTGCCCTCACAAGCAAAGAGGAAGACGACAGTGAAAATGGAGTTCCAGA AAGCACTAGTACGGACACGCCCCCTGACATAGACCTTCACAACCAGGCAA GTGTACCTCTAGAGCCCAGGCCCTTACGGCGAGAGTCGGAGATATGA

TABLE-US-00014 Amino acid sequence of Kir2.1 (SEQ ID NO: 14) MGSV RTNRYSIVSSEEDGMKLATMAVANGFGNGKSKVHTRQQCRSRFVKKDGHC NVQFINVGEKGQRYLADIFTTCVDIRWRWMLVIFCLAFVLSWLFFGCVFW LIALLHGDLDASKEGKACVSEVNSFTAAFLFSIETQTTIGYGFRCVTDEC PIAVFMVVFQSIVGCIIDAFIIGAVMAKMAKPKKRNETLVFSHNAVIAMR DGKLCLMWRVGNLRKSHLVEAHVRAQLLKSRITSEGEYIPLDQIDINVGF DSGIDRIFLVSPITIVHEIDEDSPLYDLSKQDIDNADFEIWILEGMVEAT AMTTQCRSSYLANEILWGHRYEPVLFEEKHYYKVDYSRFHKTYEVPNTPL CSARDLAEKKYILSNANSFCYENEVALTSKEEDDSENGVPESTSTDTPPD IDLHNQASVPLEPRPLRRESEI

TABLE-US-00015 Nucleotide sequence of the mArc promoter (SEQ ID NO : 15) CGCGCAGCAGAGCACATTAGTCACTCGGGGCTGTGAAGGGGCGGG TCCTTGAGGGCACCCACGGGAGGGGAGCGAGTAGGCGCGGAAGGCGGGGCC TGCGGCAGGAGAGGGCGCGGGCGGGCTCTGGCGCGGAGCCTGGGCGCCGCC AATGGGAGCCAGGGCTCCACGAGCTGCCGCCCACGGGCCCCGCGCAGCATA AATAGCCGCTGGTGGCGGTTTCGGTGCAGAGCTCAAGCGAGTTCTCCCGCA GCCGCAGTCTCTGGGCCTCTCTAGCTTCAGCGGCGACGAGCCTGCCACACT CGCTAAGCTCCTCCGGCACCGCACACCTGCCACTGCCGCTGCAGCCGCCGG CTCTGCTCCCTTCCGGCTTCTGCCTCAGAGGAGTTCTTAGCCTGTTCGGAG CCGCAGCACCGACGACCAG

TABLE-US-00016 Nucleotide sequence of the ESARE promoter (SEQ ID  NO: 16) AGCGCACAGAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGT CATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGG CAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCTGCGTGGGGAAGCTC CTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGC CGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCTGCGT GGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCT TTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGC CTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAG CCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTAGATCCAG CGCACAGAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAG CTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTG CTCGCGCAGCAGAGCACATTAGTCACTCGGGGCTGTGAAGGGGCGGGTCC TTGAGGGCACCCACGGGAGGGGAGCGAGTAGGCGCGGAAGGCGGGGCCTG CGGCAGGAGAGGGCGCGGGCGGGCTCTGGCGCGGAGCCTGGGCGCCGCCA ATGGGAGCCAGGGCTCCACGAGCTGCCGCCCACGGGCCCCGCGCAGCATA AATAGCCGCTGGTGGCGGTTTCGGTGCAGAGCTCAAGCGAGTTCTCCCGC AGCCGCAGTCTCTGGGCCTCTCTAGCTTCAGCGGCGACGAGCCTGCCACA CTCGCTAAGCTCCTCCGGCACCGCACACCTGCCACTGCCGCTGCAGCCGC CGGCTCTGCTCCCTTCCGGCTTCTGCCTCAGAGGAGTTCTTAGCCTGTTC GGAGCCGCAGCACCGACGACCAG

TABLE-US-00017 Nucleotide sequence of the NRAM-human cFos promote r (SEQ ID NO: 17) CTAGAAGTTTGTTCGTGACTGTGACTAGAAGT TTGTTCGTGACTGTGACTAGAAGTTTGTTCGTGACTGTGACTAGAAGTTT GTTCGTGACTGTGAACTCATTCATAAAACGCTTGTTATAAAAGCAGTGGC TGCGGCGCCTCGTACTCCAACCGCATCTGCAGCGAGCAACTGAGAAGCCA AGACTGAGCCGGCGGCC

TABLE-US-00018 Nucleotide sequence of the Eqr1 promoter (SEQ ID N O: 18) GCTGGCCCTCCCCACGCGGGCGTCCCCGACTCCCGCGCGCGCT CAGGCTCCCAGTTGGGAACCAAGGAGGGGGAGGATGGGGGGGGGGGTGTG CGCCGACCCGGAAACGCCATATAAGGAGCAGGAAGGATCCCCCGCCGGAA CAGACCTTATTTGGGCAGCGCCTTATATGGAGTGGCCCAATATGGCCCTG CCGCTTCCGGCTCTGGGAGGAGGGGCGAGCGGGGGTTGGGGCGGGGGCAA GCTGGGAACTCCAGGCGCCTGGCCCGGGAGGCCACTGCTGCTGTTCCAAT ACTAGGCTTTCCAGGAGCCTGAGCGCTCGCGATGCCGGAGCGGGTCGCAG GGTGGAGGTGCCCACCACTCTTGGATGGGAGGGCTTCACGTCACTCCGGG TCCTCCCGGCCGGTCCTTCCATATTAGGGCTTCCTGCTTCCCATATATGG CCATGTACGTCACGGCGGAGGCGGGCCCGTGCTGTTCCAGACCCTTGAAA TAGAGGCCGATTCGGGGAGTCGC

TABLE-US-00019 Nucleotide sequence of mArc-dsGFP-KCNA1 construct  (SEQ ID NO: 19) CAGAGCACATTAGTCACTCGGGGCTGTGAAGGGG CGGGTCCTTGAGGGCACCCACGGGAGGGGAGCGAGTAGGCGCGGAAGGCG GGGCCTGCGGCAGGAGAGGGCGCGGGCGGGCTCTGGCGCGGAGCCTGGGC GCCGCCAATGGGAGCCAGGGCTCCACGAGCTGCCGCCCACGGGCCCCGCG CAGCATAAATAGCCGCTGGTGGCGGTTTCGGTGCAGAGCTCAAGCGAGTT CTCCCGCAGCCGCAGTCTCTGGGCCTCTCTAGCTTCAGCGGCGACGAGCC TGCCACACTCGCTAAGCTCCTCCGGCACCGCACACCTGCCACTGCCGCTG CAGCCGCCGGCTCTGCTCCCTTCCGGCTTCTGCCTCAGAGGAGTTCTTAG CCTGTTCGGAGCCGCAGCACCGACGACCAGGCTAGCAGagaattcGCTGT CTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGGCATG ACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGATATT CACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCATCTGGTCAG AAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGAGATC TGGCCATACACTTGAGTGACAATGACATCCACTTTGCCTTTCTCTCCACA GGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCGGAGGATCCGCCACCa tgcccgccatgaagatcgagtgccgcatcaccggcaccctgaacggcgtg gagttcgagctggtgggcggcggagagggcacccccgaGCAGGGCCGCAT GACCAACAAGATGAAGAGCACCAAAGGCGCCCTGACCTTCAGCCCCTACC TGCTGAGCCACGTGATGGGCTACGGCTTCTACCACTTCGGCACCTACCCC AGCGGCTACGAGAACCCCTTCCTGCACGCCATCAACAACGGCGGCTACAC CAACACCCGCATCGAGAAGTACGAGGACGGCGGCGTGCTGCACGTGAGCT TCAGCTACCGCTACGAGGCCGGCCGCGTGATCGGCGACTTCAAGGTGGTG GGCACCGGCTTCCCCGAGGACAGCGTGATCTTCACCGACAAGATCATCCG CAGCAACGCCACCGTGGAGCACCTGCACCCCATGGGCGATAACGTGCTGG TGGGCAGCTTCGCCCGCACCTTCAGCCTGCGCGACGGCGGCTACTACAGC TTCGTGGTGGACAGCCACATGCACTTCAAGAGCGCCATCCACCCCAGCAT CCTGCAGAACGGGGGCCCCATGTTCGCCTTCCGCCGCGTGGAGGAGCTGC ACAGCAACACCGAGCTGGGCATCGTGGAGTACCAGCACGCCTTCAAGACC CCCATCGCCTTCGCCAGATCTCGAGATATCAGCCATGGCTTCCCGCCGGC GGTGGCGGCGCAGGATGATGGCACGCTGCCCATGTCTTGTGCCCAGGAGA GCGGGATGGACCGTCACCCTGCAGCCTGTGCTTCTGCTAGGATCAATGTG ACCGGTGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAA TCCCGGCCCTATGACCGTGATGAGCGGCGAGAACGTGGACGAGGCCTCTG CCGCTCCTGGACACCCTCAGGATGGCAGCTATCCCAGACAGGCCGACCAC GACGATCACGAGTGCTGCGAGCGGGTCGTGATCAACATCAGCGGCCTGAG ATTCGAGACACAGCTGAAAACCCTGGCCCAGTTCCCCAACACCCTGCTGG GCAACCCCAAGAAACGGATGCGGTACTTCGACCCCCTGCGGAACGAGTAC TTCTTCGACCGGAACCGGCCCAGCTTCGACGCCATCCTGTACTACTACCA GAGCGGCGGCAGACTGCGGAGGCCCGTGAATGTGCCCCTGGACATGTTCA GCGAGGAAATCAAGTTCTACGAGCTGGGCGAGGAAGCCATGGAAAAGTTC AGAGAGGACGAGGGCTTCATCAAAGAGGAAGAGAGGCCCCTGCCCGAGAA AGAATACCAGAGACAAGTGTGGCTGCTGTTCGAGTACCCCGAGTCTAGCG GCCCTGCCAGAGTGATCGCCATCGTGTCCGTGATGGTCATCCTGATCTCT ATCGTGATCTTCTGCCTGGAAACCCTGCCTGAGCTGAAGGACGACAAGGA CTTCACCGGCACCGTGCACCGGATCGACAACACCACCGTGATCTACAACA GCAATATCTTCACCGACCCATTCTTCATCGTGGAAACACTGTGCATCATC TGGTTCAGCTTCGAGCTGGTCGTGCGGTTCTTCGCCTGCCCCAGCAAGAC CGACTTCTTCAAGAACATCATGAACTTCATTGATATCGTGGCCATCATCC CCTACTTCATCACCCTGGGCACCGAGATCGCCGAGCAGGAAGGCAATCAG AAGGGCGAGCAGGCCACCAGCCTGGCCATTCTGAGAGTGATCAGACTCGT GCGGGTGTTCCGGATCTTCAAGCTGAGCCGGCACAGCAAGGGCCTGCAGA TCCTGGGCCAGACACTGAAGGCCAGCATGAGAGAGCTGGGCCTGCTGATC TTCTTTCTGTTCATCGGCGTGATCCTGTTCAGCAGCGCCGTGTACTTCGC CGAGGCCGAAGAAGCCGAGAGCCACTTCAGCTCTATCCCCGACGCCTTTT GGTGGGCCGTGGTGTCCATGACCACAGTGGGCTACGGCGACATGGTGCCC GTGACAATCGGCGGCAAGATCGTGGGCAGCCTGTGTGCCATTGCCGGCGT GCTGACAGTCGCCCTGCCTGTGCCTGTGATCGTGTCCAACTTCAACTACT TCTACCACCGGGAAACCGAGGGGGAGGAACAGGCTCAGCTGCTGCACGTG TCCAGCCCCAATCTGGCCAGCGACAGCGACCTGAGCAGACGGTCTAGCAG CACCATGAGCAAGAGCGAGTACATGGAAATCGAAGAGGACATGAACAACT CTATCGCCCACTACCGCCAAGTGAACATCCGGACCGCCAACTGCACCACC GCCAACCAGAACTGCGTGAACAAGAGCAAGCTGCTGACCGATGTC

TABLE-US-00020 Nucleotide sequence of optimised AAV- mArc-dsGFP-K CNA1 vector (SEQ ID NO: 20) gcaggcagctgcgcgctcgctc gctcactgaggccgcccgggcaaagcccgggcgtcgggcgacctttggtc gcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaactcc atcactaggggttcctgcggccgcacgcgtCGCGCAGCAGAGCACATTAG TCACTCGGGGCTGTGAAGGGGCGGGTCCTTGAGGGCACCCACGGGAGGGG AGCGAGTAGGCGCGGAAGGCGGGGCCTGCGGCAGGAGAGGGCGCGGGCGG GCTCTGGCGCGGAGCCTGGGCGCCGCCAATGGGAGCCAGGGCTCCACGAG CTGCCGCCCACGGGCCCCGCGCAGCATAAATAGCCGCTGGTGGCGGTTTC GGTGCAGAGCTCAAGCGAGTTCTCCCGCAGCCGCAGTCTCTGGGCCTCTC TAGCTTCAGCGGCGACGAGCCTGCCACACTCGCTAAGCTCCTCCGGCACC GCACACCTGCCACTGCCGCTGCAGCCGCCGGCTCTGCTCCCTTCCGGCTT CTGCCTCAGAGGAGTTCTTAGCCTGTTCGGAGCCGCAGCACCGACGACCA GGCTAGCAGagaattcGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTAC TCCCTCTCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAA AAACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGG TGGCCGCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTG AGGTGTGGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACATC CACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCC CAAGCGGAGGATCCGCCACCatgcccgccatgaagatcgagtgccgcatc accggcaccctgaacggcgtggagttcgagctggtgggcggcggagaggg cacccccgaGCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGGCG CCCTGACCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCTTC TACCACTTCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCACGC CATCAACAACGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGACG GCGGCGTGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCGTG ATCGGCGACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTGAT CTTCACCGACAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCACC CCATGGGCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTG CGCGACGGCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTCAA GAGCGCCATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGCCT TCCGCCGCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGGAG TACCAGCACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGATAT CAGCCATGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCTGC CCATGTCTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCTGT GCTTCTGCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTAAC ATGCGGTGACGTGGAGGAGAATCCCGGCCCTATGACCGTGATGAGCGGCG AGAACGTGGACGAGGCCTCTGCCGCTCCTGGACACCCTCAGGATGGCAGC TATCCCAGACAGGCCGACCACGACGATCACGAGTGCTGCGAGCGGGTCGT GATCAACATCAGCGGCCTGAGATTCGAGACACAGCTGAAAACCCTGGCCC AGTTCCCCAACACCCTGCTGGGCAACCCCAAGAAACGGATGCGGTACTTC GACCCCCTGCGGAACGAGTACTTCTTCGACCGGAACCGGCCCAGCTTCGA CGCCATCCTGTACTACTACCAGAGCGGCGGCAGACTGCGGAGGCCCGTGA ATGTGCCCCTGGACATGTTCAGCGAGGAAATCAAGTTCTACGAGCTGGGC GAGGAAGCCATGGAAAAGTTCAGAGAGGACGAGGGCTTCATCAAAGAGGA AGAGAGGCCCCTGCCCGAGAAAGAATACCAGAGACAAGTGTGGCTGCTGT TCGAGTACCCCGAGTCTAGCGGCCCTGCCAGAGTGATCGCCATCGTGTCC GTGATGGTCATCCTGATCTCTATCGTGATCTTCTGCCTGGAAACCCTGCC TGAGCTGAAGGACGACAAGGACTTCACCGGCACCGTGCACCGGATCGACA ACACCACCGTGATCTACAACAGCAATATCTTCACCGACCCATTCTTCATC GTGGAAACACTGTGCATCATCTGGTTCAGCTTCGAGCTGGTCGTGCGGTT CTTCGCCTGCCCCAGCAAGACCGACTTCTTCAAGAACATCATGAACTTCA TTGATATCGTGGCCATCATCCCCTACTTCATCACCCTGGGCACCGAGATC GCCGAGCAGGAAGGCAATCAGAAGGGCGAGCAGGCCACCAGCCTGGCCAT TCTGAGAGTGATCAGACTCGTGCGGGTGTTCCGGATCTTCAAGCTGAGCC GGCACAGCAAGGGCCTGCAGATCCTGGGCCAGACACTGAAGGCCAGCATG AGAGAGCTGGGCCTGCTGATCTTCTTTCTGTTCATCGGCGTGATCCTGTT CAGCAGCGCCGTGTACTTCGCCGAGGCCGAAGAAGCCGAGAGCCACTTCA GCTCTATCCCCGACGCCTTTTGGTGGGCCGTGGTGTCCATGACCACAGTG GGCTACGGCGACATGGTGCCCGTGACAATCGGCGGCAAGATCGTGGGCAG CCTGTGTGCCATTGCCGGCGTGCTGACAGTCGCCCTGCCTGTGCCTGTGA TCGTGTCCAACTTCAACTACTTCTACCACCGGGAAACCGAGGGGGAGGAA CAGGCTCAGCTGCTGCACGTGTCCAGCCCCAATCTGGCCAGCGACAGCGA CCTGAGCAGACGGTCTAGCAGCACCATGAGCAAGAGCGAGTACATGGAAA TCGAAGAGGACATGAACAACTCTATCGCCCACTACCGCCAAGTGAACATC CGGACCGCCAACTGCACCACCGCCAACCAGAACTGCGTGAACAAGAGCAA GCTGCTGACCGATGTCTGAgTCGACAATCAACCTCATcgataccgagcgc tgctcgagagatctacgggtggcatccctgtgacccctccccagtgcctc tcctggccctggaagttgccactccagtgcccaccagccttgtcctaata aaattaagttgcatcattttgtctgactaggtgtccttctataatattat ggggtggaggggggtggtatggagcaaggggcaagttgggaagacaacct gtagggcctgcggggtctattgggaaccaagctggagtgcagtggcacaa tcttggctcactgcaatctccgcctcctgggttcaagcgattctcctgcc tcagcctcccgagttgttgggattccaggcatgcatgaccaggctcagct aatttttgtttttttggtagagacggggtttcaccatattggccaggctg gtctccaactcctaatctcaggtgatctacccaccttggcctcccaaatt gctgggattacaggcgtgaaccactgctcccttccctgtccttctgattt tgtaggtaaccacgtgcggaccgagcggccgcaggaacccctagtgatgg agttggccactccctctctgcgcgctcgctcgctcactgaggccgggcga ccaaaggtcgcccgacgcccgggctttgcccgggcggcctcagtgagcga gcgagcgcgcagctgcctgcaggggcgcctgatgcggtattttctcctta cgcatctgtgcggtatttcacaccgcatacgtcaaagcaaccatagtacg cgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgcagc gtgaccgctacacttgccagcgccctagcgcccgctcctttcgctttctt cccttcctttctcgccacgttcgccggctttccccgtcaagctctaaatc gggggctccctttagggttccgatttagtgctttacggcacctcgacccc aaaaaacttgatttgggtgatggttcacgtagtgggccatcgccctgata gacggtttttcgccctttgacgttggagtccacgttctttaatagtggac tcttgttccaaactggaacaacactcaaccctatctcgggctattctttt gatttataagggattttgccgatttcggcctattggttaaaaaatgagct gatttaacaaaaatttaacgcgaattttaacaaaatattaacgtttacaa ttttatggtgcactctcagtacaatctgctctgatgccgcatagttaagc cagccccgacacccgccaacacccgctgacgcgccctgacgggcttgtct gctcccggcatccgcttacagacaagctgtgaccgtctccgggagctgca tgtgtcagaggttttcaccgtcatcaccgaaacgcgcgagacgaaagggc ctcgtgatacgcctatttttataggttaatgtcatgataataatggtttc ttagacgtcaggtggcacttttcggggaaatgtgcgcggaacccctattt gtttatttttctaaatacattcaaatatgtatccgctcatgagacaataa ccctgataaatgcttcaataatattgaaaaaggaagagtatgagtattca acatttccgtgtcgcccttattcccttttttgcggcattttgccttcctg tttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcag ttgggtgcacgagtgggttacatcgaactggatctcaacagcggtaagat ccttgagagttttcgccccgaagaacgttttccaatgatgagcactttta aagttctgctatgtggcgcggtattatcccgtattgacgccgggcaagag caactcggtcgccgcatacactattctcagaatgacttggttgagtactc accagtcacagaaaagcatcttacggatggcatgacagtaagagaattat gcagtgctgccataaccatgagtgataacactgcggccaacttacttctg acaacgatcggaggaccgaaggagctaaccgcttttttgcacaacatggg ggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaagcca taccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaacg ttgcgcaaactattaactggcgaactacttactctagcttcccggcaaca attaatagactggatggaggcggataaagttgcaggaccacttctgcgct cggcccttccggctggctggtttattgctgataaatctggagccggtgag cgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctc ccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaac gaaatagacagatcgctgagataggtgcctcactgattaagcattggtaa ctgtcagaccaagtttactcatatatactttagattgatttaaaacttca tttttaatttaaaaggatctaggtgaagatcctttttgataatctcatga ccaaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgta gaaaagatcaaaggatcttcttgagatcctttttttctgcgcgtaatctg ctgcttgcaaacaaaaaaaccaccgctaccagcggtggtttgtttgccgg atcaagagctaccaactctttttccgaaggtaactggcttcagcagagcg cagataccaaatactgtccttctagtgtagccgtagttaggccaccactt caagaactctgtagcaccgcctacatacctcgctctgctaatcctgttac cagtggctgctgccagtggcgataagtcgtgtcttaccgggttggactca agacgatagttaccggataaggcgcagcggtcgggctgaacggggggttc gtgcacacagcccagcttggagcgaacgacctacaccgaactgagatacc tacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaaggcg gacaggtatccggtaagcggcagggtcggaacaggagagcgcacgaggga gcttccagggggaaacgcctggtatctttatagtcctgtcgggtttcgcc acctctgacttgagcgtcgatttttgtgatgctcgtcaggggggcggagc ctatggaaaaacgccagcaacgcggcctttttacggttcctggccttttg ctggccttttgctcac

TABLE-US-00021 Nucleotide sequence of mArc-dsGFP-KCNJ2 construct  (SEQ ID NO: 21) GCAGCAGAGCACATTAGTCACTCGGGGCTGTGAA GGGGCGGGTCCTTGAGGGCACCCACGGGAGGGGAGCGAGTAGGCGCGGAA GGCGGGGCCTGCGGCAGGAGAGGGCGCGGGCGGGCTCTGGCGCGGAGCCT GGGCGCCGCCAATGGGAGCCAGGGCTCCACGAGCTGCCGCCCACGGGCCC CGCGCAGCATAAATAGCCGCTGGTGGCGGTTTCGGTGCAGAGCTCAAGCG AGTTCTCCCGCAGCCGCAGTCTCTGGGCCTCTCTAGCTTCAGCGGCGACG AGCCTGCCACACTCGCTAAGCTCCTCCGGCACCGCACACCTGCCACTGCC GCTGCAGCCGCCGGCTCTGCTCCCTTCCGGCTTCTGCCTCAGAGGAGTTC TTAGCCTGTTCGGAGCCGCAGCACCGACGACCAGGCTAGCAGagaattcG CTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGG CATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGA TATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCATCTGG TCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGA GATCTGGCCATACACTTGAGTGACAATGACATCCACTTTGCCTTTCTCTC CACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCGGAGGATCCGCC ACCatgcccgccatgaagatcgagtgccgcatcaccggcaccctgaacgg cgtggagttcgagctggtgggcggcggagagggcacccccgaGCAGGGCC GCATGACCAACAAGATGAAGAGCACCAAAGGCGCCCTGACCTTCAGCCCC TACCTGCTGAGCCACGTGATGGGCTACGGCTTCTACCACTTCGGCACCTA CCCCAGCGGCTACGAGAACCCCTTCCTGCACGCCATCAACAACGGCGGCT ACACCAACACCCGCATCGAGAAGTACGAGGACGGCGGCGTGCTGCACGTG AGCTTCAGCTACCGCTACGAGGCCGGCCGCGTGATCGGCGACTTCAAGGT GGTGGGCACCGGCTTCCCCGAGGACAGCGTGATCTTCACCGACAAGATCA TCCGCAGCAACGCCACCGTGGAGCACCTGCACCCCATGGGCGATAACGTG CTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTGCGCGACGGCGGCTACTA CAGCTTCGTGGTGGACAGCCACATGCACTTCAAGAGCGCCATCCACCCCA GCATCCTGCAGAACGGGGGCCCCATGTTCGCCTTCCGCCGCGTGGAGGAG CTGCACAGCAACACCGAGCTGGGCATCGTGGAGTACCAGCACGCCTTCAA GACCCCCATCGCCTTCGCCAGATCTCGAGATATCAGCCATGGCTTCCCGC CGGCGGTGGCGGCGCAGGATGATGGCACGCTGCCCATGTCTTGTGCCCAG GAGAGCGGGATGGACCGTCACCCTGCAGCCTGTGCTTCTGCTAGGATCAA TGTGACCGGTGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGG AGAATCCCGGCCCTatgggcagtgtgagaaccaaccgctacagcatcgtc tcttcagaagaagacggtatgaagttggccaccatggcagttgcaaatgg ctttgggaacgggaagagtaaagtccacacccgacaacagtgcaggagcc gctttgtgaagaaagatggccactgtaatgttcagttcatcaatgtgggt gagaaggggcaacggtacctcgcagacatcttcaccacgtgtgtggacat tcgctggcggtggatgctggttatcttctgcctggctttcgtcctgtcat ggctgttttttggctgtgtgttttggttgatagctctgctccatggggac ctggatgcatccaaagagggcaaagcttgtgtgtccgaggtcaacagctt cacggctgccttcctcttctccattgagacccagacaaccataggctatg gtttcagatgtgtcacggatgaatgcccaattgctgttttcatggtggtg ttccagtcaatcgtgggctgcatcatcgatgctttcatcattggcgcagt catggccaagatggcaaagccaaagaagagaaacgagactcttgtcttca gtcacaatgccgtgattgccatgagagacggcaagctgtgtttgatgtgg cgagtgggcaatcttcggaaaagccacttggtggaagctcatgttcgagc acagctcctcaaatccagaattacttctgaaggggagtatatccctctgg atcaaatagacatcaatgttgggtttgacagtggaatcgatcgtatattt ctggtgtccccaatcactatagtccatgaaatagatgaagacagtccttt atatgatttgagtaaacaggacattgacaacgcagactttgaaatcgtgg tcatactggaaggcatggtggaagccactgccatgacgacacagtgccgt agctcttatctagcaaatgaaatcctgtggggccaccgctatgagcctgt gctctttgaagagaagcactactacaaagtggactactccaggttccaca aaacttacgaagtccccaacactcccctttgtagtgccagagacttagca gaaaagaaatatatcctctcaaatgcaaattcattttgctatgaaaatga agttgccctcacaagcaaagaggaagacgacagtgaaaatggagttccag aaagcactagtacggacacgccccctgacatagaccttcacaaccaggca agtgtacctctagagcccaggcccttacggcgagagtcggaga

TABLE-US-00022 Nucleotide sequence of optimised AAV- mArc-dsGFP-K CNJ2 vector (SEQ ID NO: 22) ggcagctgcgcgctcgctcgct cactgaggccgcccgggcaaagcccgggcgtcgggcgacctttggtcgcc cggcctcagtgagcgagcgagcgcgcagagagggagtggccaactccatc actaggggttcctgcggccgcacgcgtCGCGCAGCAGAGCACATTAGTCA CTCGGGGCTGTGAAGGGGCGGGTCCTTGAGGGCACCCACGGGAGGGGAGC GAGTAGGCGCGGAAGGCGGGGCCTGCGGCAGGAGAGGGCGCGGGCGGGCT CTGGCGCGGAGCCTGGGCGCCGCCAATGGGAGCCAGGGCTCCACGAGCTG CCGCCCACGGGCCCCGCGCAGCATAAATAGCCGCTGGTGGCGGTTTCGGT GCAGAGCTCAAGCGAGTTCTCCCGCAGCCGCAGTCTCTGGGCCTCTCTAG CTTCAGCGGCGACGAGCCTGCCACACTCGCTAAGCTCCTCCGGCACCGCA CACCTGCCACTGCCGCTGCAGCCGCCGGCTCTGCTCCCTTCCGGCTTCTG CCTCAGAGGAGTTCTTAGCCTGTTCGGAGCCGCAGCACCGACGACCAGGC TAGCAGagaattcGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCC CTCTCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAA CGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGG CCGCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGG TGTGGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACATCCAC TTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCAA GCGGAGGATCCGCCACCatgcccgccatgaagatcgagtgccgcatcacc ggcaccctgaacggcgtggagttcgagctggtgggcggcggagagggcac ccccgaGCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGGCGCCC TGACCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCTTCTAC CACTTCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCACGCCAT CAACAACGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGACGGCG GCGTGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCGTGATC GGCGACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTGATCTT CACCGACAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCACCCCA TGGGCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTGCGC GACGGCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTCAAGAG CGCCATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGCCTTCC GCCGCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGGAGTAC CAGCACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGATATCAG CCATGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCTGCCCA TGTCTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCTGTGCT TCTGCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTAACATG CGGTGACGTGGAGGAGAATCCCGGCCCTatgggcagtgtgagaaccaacc gctacagcatcgtctcttcagaagaagacggtatgaagttggccaccatg gcagttgcaaatggctttgggaacgggaagagtaaagtccacacccgaca acagtgcaggagccgctttgtgaagaaagatggccactgtaatgttcagt tcatcaatgtgggtgagaaggggcaacggtacctcgcagacatcttcacc acgtgtgtggacattcgctggcggtggatgctggttatcttctgcctggc tttcgtcctgtcatggctgttttttggctgtgtgttttggttgatagctc tgctccatggggacctggatgcatccaaagagggcaaagcttgtgtgtcc gaggtcaacagcttcacggctgccttcctcttctccattgagacccagac aaccataggctatggtttcagatgtgtcacggatgaatgcccaattgctg ttttcatggtggtgttccagtcaatcgtgggctgcatcatcgatgctttc atcattggcgcagtcatggccaagatggcaaagccaaagaagagaaacga gactcttgtcttcagtcacaatgccgtgattgccatgagagacggcaagc tgtgtttgatgtggcgagtgggcaatcttcggaaaagccacttggtggaa gctcatgttcgagcacagctcctcaaatccagaattacttctgaagggga gtatatccctctggatcaaatagacatcaatgttgggtttgacagtggaa tcgatcgtatatttctggtgtccccaatcactatagtccatgaaatagat gaagacagtcctttatatgatttgagtaaacaggacattgacaacgcaga ctttgaaatcgtggtcatactggaaggcatggtggaagccactgccatga cgacacagtgccgtagctcttatctagcaaatgaaatcctgtggggccac cgctatgagcctgtgctctttgaagagaagcactactacaaagtggacta ctccaggttccacaaaacttacgaagtccccaacactcccctttgtagtg ccagagacttagcagaaaagaaatatatcctctcaaatgcaaattcattt tgctatgaaaatgaagttgccctcacaagcaaagaggaagacgacagtga aaatggagttccagaaagcactagtacggacacgccccctgacatagacc ttcacaaccaggcaagtgtacctctagagcccaggcccttacggcgagag tcggagatatgagTCGACAATCAACCTCATcgataccgagcgctgctcga gagatctacgggtggcatccctgtgacccctccccagtgcctctcctggc cctggaagttgccactccagtgcccaccagccttgtcctaataaaattaa gttgcatcattttgtctgactaggtgtccttctataatattatggggtgg aggggggtggtatggagcaaggggcaagttgggaagacaacctgtagggc ctgcggggtctattgggaaccaagctggagtgcagtggcacaatcttggc tcactgcaatctccgcctcctgggttcaagcgattctcctgcctcagcct cccgagttgttgggattccaggcatgcatgaccaggctcagctaattttt gtttttttggtagagacggggtttcaccatattggccaggctggtctcca actcctaatctcaggtgatctacccaccttggcctcccaaattgctggga ttacaggcgtgaaccactgctcccttccctgtccttctgattttgtaggt aaccacgtgcggaccgagcggccgcaggaacccctagtgatggagttggc cactccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaagg tcgcccgacgcccgggctttgcccgggcggcctcagtgagcgagcgagcg cgcagctgcctgcaggggcgcctgatgcggtattttctccttacgcatct gtgcggtatttcacaccgcatacgtcaaagcaaccatagtacgcgccctg tagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccg ctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttcc tttctcgccacgttcgccggctttccccgtcaagctctaaatcgggggct ccctttagggttccgatttagtgctttacggcacctcgaccccaaaaaac ttgatttgggtgatggttcacgtagtgggccatcgccctgatagacggtt tttcgccctttgacgttggagtccacgttctttaatagtggactcttgtt ccaaactggaacaacactcaaccctatctcgggctattcttttgatttat aagggattttgccgatttcggcctattggttaaaaaatgagctgatttaa caaaaatttaacgcgaattttaacaaaatattaacgtttacaattttatg gtgcactctcagtacaatctgctctgatgccgcatagttaagccagcccc gacacccgccaacacccgctgacgcgccctgacgggcttgtctgctcccg gcatccgcttacagacaagctgtgaccgtctccgggagctgcatgtgtca gaggttttcaccgtcatcaccgaaacgcgcgagacgaaagggcctcgtga tacgcctatttttataggttaatgtcatgataataatggtttcttagacg tcaggtggcacttttcggggaaatgtgcgcggaacccctatttgtttatt tttctaaatacattcaaatatgtatccgctcatgagacaataaccctgat aaatgcttcaataatattgaaaaaggaagagtatgagtattcaacatttc cgtgtcgcccttattcccttttttgcggcattttgccttcctgtttttgc tcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtg cacgagtgggttacatcgaactggatctcaacagcggtaagatccttgag agttttcgccccgaagaacgttttccaatgatgagcacttttaaagttct gctatgtggcgcggtattatcccgtattgacgccgggcaagagcaactcg gtcgccgcatacactattctcagaatgacttggttgagtactcaccagtc acagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgc tgccataaccatgagtgataacactgcggccaacttacttctgacaacga tcggaggaccgaaggagctaaccgcttttttgcacaacatgggggatcat gtaactcgccttgatcgttgggaaccggagctgaatgaagccataccaaa cgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgca aactattaactggcgaactacttactctagcttcccggcaacaattaata gactggatggaggcggataaagttgcaggaccacttctgcgctcggccct tccggctggctggtttattgctgataaatctggagccggtgagcgtgggt ctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatc gtagttatctacacgacggggagtcaggcaactatggatgaacgaaatag acagatcgctgagataggtgcctcactgattaagcattggtaactgtcag accaagtttactcatatatactttagattgatttaaaacttcatttttaa tttaaaaggatctaggtgaagatcctttttgataatctcatgaccaaaat cccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaaga tcaaaggatcttcttgagatcctttttttctgcgcgtaatctgctgcttg caaacaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaaga gctaccaactctttttccgaaggtaactggcttcagcagagcgcagatac caaatactgtccttctagtgtagccgtagttaggccaccacttcaagaac tctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtggc tgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgat agttaccggataaggcgcagcggtcgggctgaacggggggttcgtgcaca cagcccagcttggagcgaacgacctacaccgaactgagatacctacagcg tgagctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggt atccggtaagcggcagggtcggaacaggagagcgcacgagggagcttcca gggggaaacgcctggtatctttatagtcctgtcgggtttcgccacctctg acttgagcgtcgatttttgtgatgctcgtcaggggggcggagcctatgga aaaacgccagcaacgcggcctttttacggttcctggccttttgctggcct tttgctcaca

TABLE-US-00023 Nucleotide sequence of ESARE-dsGFP-KCNA1 construct  (SEQ ID NO: 23) TTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATG GCTCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGG CTGCTGCTAGATCCAGCGCACAGAGCCTTCCTGCGTGGGGAAGCTCCTTG CTGCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGA AGCAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCTGCGTGGGG AAGCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTA TGGTGCCGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTC CTGCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTC TCTCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCA CAGAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTAT TCTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTCG CGCAGCAGAGCACATTAGTCACTCGGGGCTGTGAAGGGGCGGGTCCTTGA AGGAGAGGGCGCGGGCGGGCTCTGGCGCGGAGCCTGGGCGCCGCCAATGG GAGCCAGGGCTCCACGAGCTGCCGCCCACGGGCCCCGCGCAGCATAAATA GCCGCTGGTGGCGGTTTCGGTGCAGAGCTCAAGCGAGTTCTCCCGCAGCC GCAGTCTCTGGGCCTCTCTAGCTTCAGCGGCGACGAGCCTGCCACACTCG CTAAGCTCCTCCGGCACCGCACACCTGCCACTGCCGCTGCAGCCGCCGGC TCTGCTCCCTTCCGGCTTCTGCCTCAGAGGAGTTCTTAGCCTGTTCGGAG CCGCAGCACCGACGACCAGGCTAGCAGagaattcGCTGTCTGCGAGGGCC AGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGGCATGACTTCTGCGCT AAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGATATTCACCTGGCCCG CGGTGATGCCTTTGAGGGTGGCCGCGTCCATCTGGTCAGAAAAGACAATC TTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGAGATCTGGCCATACAC TTGAGTGACAATGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTC CCAGGTCCAACTGCAGCCCAAGCGGAGGATCCGCCACCatgcccgccatg aagatcgagtgccgcatcaccggcaccctgaacggcgtggagttcgagct ggtgggcggcggagagggcacccccgaGCAGGGCCGCATGACCAACAAGA TGAAGAGCACCAAAGGCGCCCTGACCTTCAGCCCCTACCTGCTGAGCCAC GTGATGGGCTACGGCTTCTACCACTTCGGCACCTACCCCAGCGGCTACGA GAACCCCTTCCTGCACGCCATCAACAACGGCGGCTACACCAACACCCGCA TCGAGAAGTACGAGGACGGCGGCGTGCTGCACGTGAGCTTCAGCTACCGC TACGAGGCCGGCCGCGTGATCGGCGACTTCAAGGTGGTGGGCACCGGCTT CCCCGAGGACAGCGTGATCTTCACCGACAAGATCATCCGCAGCAACGCCA CCGTGGAGCACCTGCACCCCATGGGCGATAACGTGCTGGTGGGCAGCTTC GCCCGCACCTTCAGCCTGCGCGACGGCGGCTACTACAGCTTCGTGGTGGA CAGCCACATGCACTTCAAGAGCGCCATCCACCCCAGCATCCTGCAGAACG GGGGCCCCATGTTCGCCTTCCGCCGCGTGGAGGAGCTGCACAGCAACACC GAGCTGGGCATCGTGGAGTACCAGCACGCCTTCAAGACCCCCATCGCCTT AGGATGATGGCACGCTGCCCATGTCTTGTGCCCAGGAGAGCGGGATGGAC CGTCACCCTGCAGCCTGTGCTTCTGCTAGGATCAATGTGACCGGTGAGGG CAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCTA TGACCGTGATGAGCGGCGAGAACGTGGACGAGGCCTCTGCCGCTCCTGGA CACCCTCAGGATGGCAGCTATCCCAGACAGGCCGACCACGACGATCACGA GTGCTGCGAGCGGGTCGTGATCAACATCAGCGGCCTGAGATTCGAGACAC AGCTGAAAACCCTGGCCCAGTTCCCCAACACCCTGCTGGGCAACCCCAAG AAACGGATGCGGTACTTCGACCCCCTGCGGAACGAGTACTTCTTCGACCG GAACCGGCCCAGCTTCGACGCCATCCTGTACTACTACCAGAGCGGCGGCA GACTGCGGAGGCCCGTGAATGTGCCCCTGGACATGTTCAGCGAGGAAATC AAGTTCTACGAGCTGGGCGAGGAAGCCATGGAAAAGTTCAGAGAGGACGA GGGCTTCATCAAAGAGGAAGAGAGGCCCCTGCCCGAGAAAGAATACCAGA GACAAGTGTGGCTGCTGTTCGAGTACCCCGAGTCTAGCGGCCCTGCCAGA GTGATCGCCATCGTGTCCGTGATGGTCATCCTGATCTCTATCGTGATCTT CTGCCTGGAAACCCTGCCTGAGCTGAAGGACGACAAGGACTTCACCGGCA CCGTGCACCGGATCGACAACACCACCGTGATCTACAACAGCAATATCTTC ACCGACCCATTCTTCATCGTGGAAACACTGTGCATCATCTGGTTCAGCTT CGAGCTGGTCGTGCGGTTCTTCGCCTGCCCCAGCAAGACCGACTTCTTCA AGAACATCATGAACTTCATTGATATCGTGGCCATCATCCCCTACTTCATC ACCCTGGGCACCGAGATCGCCGAGCAGGAAGGCAATCAGAAGGGCGAGCA GGCCACCAGCCTGGCCATTCTGAGAGTGATCAGACTCGTGCGGGTGTTCC GGATCTTCAAGCTGAGCCGGCACAGCAAGGGCCTGCAGATCCTGGGCCAG ACACTGAAGGCCAGCATGAGAGAGCTGGGCCTGCTGATCTTCTTTCTGTT CATCGGCGTGATCCTGTTCAGCAGCGCCGTGTACTTCGCCGAGGCCGAAG AAGCCGAGAGCCACTTCAGCTCTATCCCCGACGCCTTTTGGTGGGCCGTG GTGTCCATGACCACAGTGGGCTACGGCGACATGGTGCCCGTGACAATCGG CGGCAAGATCGTGGGCAGCCTGTGTGCCATTGCCGGCGTGCTGACAGTCG CCCTGCCTGTGCCTGTGATCGTGTCCAACTTCAACTACTTCTACCACCGG GAAACCGAGGGGGAGGAACAGGCTCAGCTGCTGCACGTGTCCAGCCCCAA TCTGGCCAGCGACAGCGACCTGAGCAGACGGTCTAGCAGCACCATGAGCA AGAGCGAGTACATGGAAATCGAAGAGGACATGAACAACTCTATCGCCCAC TACCGCCAAGTGAACATCCGGACCGCCAACTGCACCACCGCCAACCAGAA CTGCGTGAACAAGAGCAAGCTGCTGACCGATGTCTGA

TABLE-US-00024 Nucleotide sequence of optimised AAV- ESARE-dsGFP- KCNA1 vector (SEQ ID No: 24) gcgctcgctcactgaggccgc ccgggcaaagcccgggcgtcgggcgacctttggtcgcccggcctcagtga gcgagcgagcgcgcagagagggagtggccaactccatcactaggggttcc tgcggccgcACGCGTGTGTCTAGACTGCAGACCATGGGGATCCAGCGCAC AGAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATT CTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTAGA TCCAGCGCACAGAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGG CTCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGC GCTGCTAGATCCAGCGCACAGAGCCTTCCTGCGTGGGGAAGCTCCTTGCT GCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAG CAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCTGCGTGGGGAA GCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATG GTGCCGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCT GCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTC TCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTCGCGCAGCAGAGCA CATTAGTCACTCGGGGCTGTGAAGGGGCGGGTCCTTGAGGGCACCCACGG GAGGGGAGCGAGTAGGCGCGGAAGGCGGGGCCTGCGGCAGGAGAGGGCGC GGGCGGGCTCTGGCGCGGAGCCTGGGCGCCGCCAATGGGAGCCAGGGCTC CACGAGCTGCCGCCCACGGGCCCCGCGCAGCATAAATAGCCGCTGGTGGC GGTTTCGGTGCAGAGCTCAAGCGAGTTCTCCCGCAGCCGCAGTCTCTGGG CCTCTCTAGCTTCAGCGGCGACGAGCCTGCCACACTCGCTAAGCTCCTCC GGCACCGCACACCTGCCACTGCCGCTGCAGCCGCCGGCTCTGCTCCCTTC CGGCTTCTGCCTCAGAGGAGTTCTTAGCCTGTTCGGAGCCGCAGCACCGA CGACCAGGCTAGCAGagaattcGCTGTCTGCGAGGGCCAGCTGTTGGGGT GAGTACTCCCTCTCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGT TTCCAAAAACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTT TGAGGGTGGCCGCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCA AGCTTGAGGTGTGGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAAT GACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACT GCAGCCCAAGCGGAGGATCCGCCACCatgcccgccatgaagatcgagtgc cgcatcaccggcaccctgaacggcgtggagttcgagctggtgggcggcgg agagggcacccccgaGCAGGGCCGCATGACCAACAAGATGAAGAGCACCA AAGGCGCCCTGACCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGCTAC GGCTTCTACCACTTCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCT GCACGCCATCAACAACGGCGGCTACACCAACACCCGCATCGAGAAGTACG AGGACGGCGGCGTGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGC CGCGTGATCGGCGACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAG CGTGATCTTCACCGACAAGATCATCCGCAGCAACGCCACCGTGGAGCACC TGCACCCCATGGGCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTC AGCCTGCGCGACGGCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCA CTTCAAGAGCGCCATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGT TCGCCTTCCGCCGCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATC GTGGAGTACCAGCACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCG AGATATCAGCCATGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCA CGCTGCCCATGTCTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCA GCCTGTGCTTCTGCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCT TCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCTATGACCGTGATGA GCGGCGAGAACGTGGACGAGGCCTCTGCCGCTCCTGGACACCCTCAGGAT GGCAGCTATCCCAGACAGGCCGACCACGACGATCACGAGTGCTGCGAGCG GGTCGTGATCAACATCAGCGGCCTGAGATTCGAGACACAGCTGAAAACCC TGGCCCAGTTCCCCAACACCCTGCTGGGCAACCCCAAGAAACGGATGCGG TACTTCGACCCCCTGCGGAACGAGTACTTCTTCGACCGGAACCGGCCCAG CTTCGACGCCATCCTGTACTACTACCAGAGCGGCGGCAGACTGCGGAGGC CCGTGAATGTGCCCCTGGACATGTTCAGCGAGGAAATCAAGTTCTACGAG CTGGGCGAGGAAGCCATGGAAAAGTTCAGAGAGGACGAGGGCTTCATCAA AGAGGAAGAGAGGCCCCTGCCCGAGAAAGAATACCAGAGACAAGTGTGGC TGCTGTTCGAGTACCCCGAGTCTAGCGGCCCTGCCAGAGTGATCGCCATC GTGTCCGTGATGGTCATCCTGATCTCTATCGTGATCTTCTGCCTGGAAAC CCTGCCTGAGCTGAAGGACGACAAGGACTTCACCGGCACCGTGCACCGGA TCGACAACACCACCGTGATCTACAACAGCAATATCTTCACCGACCCATTC TTCATCGTGGAAACACTGTGCATCATCTGGTTCAGCTTCGAGCTGGTCGT GCGGTTCTTCGCCTGCCCCAGCAAGACCGACTTCTTCAAGAACATCATGA ACTTCATTGATATCGTGGCCATCATCCCCTACTTCATCACCCTGGGCACC GAGATCGCCGAGCAGGAAGGCAATCAGAAGGGCGAGCAGGCCACCAGCCT GGCCATTCTGAGAGTGATCAGACTCGTGCGGGTGTTCCGGATCTTCAAGC TGAGCCGGCACAGCAAGGGCCTGCAGATCCTGGGCCAGACACTGAAGGCC AGCATGAGAGAGCTGGGCCTGCTGATCTTCTTTCTGTTCATCGGCGTGAT CCTGTTCAGCAGCGCCGTGTACTTCGCCGAGGCCGAAGAAGCCGAGAGCC ACTTCAGCTCTATCCCCGACGCCTTTTGGTGGGCCGTGGTGTCCATGACC ACAGTGGGCTACGGCGACATGGTGCCCGTGACAATCGGCGGCAAGATCGT GGGCAGCCTGTGTGCCATTGCCGGCGTGCTGACAGTCGCCCTGCCTGTGC CTGTGATCGTGTCCAACTTCAACTACTTCTACCACCGGGAAACCGAGGGG GAGGAACAGGCTCAGCTGCTGCACGTGTCCAGCCCCAATCTGGCCAGCGA CAGCGACCTGAGCAGACGGTCTAGCAGCACCATGAGCAAGAGCGAGTACA TGGAAATCGAAGAGGACATGAACAACTCTATCGCCCACTACCGCCAAGTG AACATCCGGACCGCCAACTGCACCACCGCCAACCAGAACTGCGTGAACAA GAGCAAGCTGCTGACCGATGTCTGAgTCGACAATCAACCTCATcgatacc gagcgctgctcgagagatctacgggtggcatccctgtgacccctccccag tgcctctcctggccctggaagttgccactccagtgcccaccagccttgtc ctaataaaattaagttgcatcattttgtctgactaggtgtccttctataa tattatggggtggaggggggtggtatggagcaaggggcaagttgggaaga caacctgtagggcctgcggggtctattgggaaccaagctggagtgcagtg gcacaatcttggctcactgcaatctccgcctcctgggttcaagcgattct cctgcctcagcctcccgagttgttgggattccaggcatgcatgaccaggc tcagctaatttttgtttttttggtagagacggggtttcaccatattggcc aggctggtctccaactcctaatctcaggtgatctacccaccttggcctcc caaattgctgggattacaggcgtgaaccactgctcccttccctgtccttc tgattttgtaggtaaccacgtgcggaccgagcggccgcaggaacccctag tgatggagttggccactccctctctgcgcgctcgctcgctcactgaggcc gggcgaccaaaggtcgcccgacgcccgggctttgcccgggcggcctcagt gagcgagcgagcgcgcagctgcctgcaggggcgcctgatgcggtattttc tccttacgcatctgtgcggtatttcacaccgcatacgtcaaagcaaccat agtacgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacg cgcagcgtgaccgctacacttgccagcgccctagcgcccgctcctttcgc tttcttcccttcctttctcgccacgttcgccggctttccccgtcaagctc taaatcgggggctccctttagggttccgatttagtgctttacggcacctc gaccccaaaaaacttgatttgggtgatggttcacgtagtgggccatcgcc ctgatagacggtttttcgccctttgacgttggagtccacgttctttaata gtggactcttgttccaaactggaacaacactcaaccctatctcgggctat tcttttgatttataagggattttgccgatttcggcctattggttaaaaaa tgagctgatttaacaaaaatttaacgcgaattttaacaaaatattaacgt ttacaattttatggtgcactctcagtacaatctgctctgatgccgcatag ttaagccagccccgacacccgccaacacccgctgacgcgccctgacgggc ttgtctgctcccggcatccgcttacagacaagctgtgaccgtctccggga gctgcatgtgtcagaggttttcaccgtcatcaccgaaacgcgcagacgaa agggcctcgtgatacgcctatttttataggttaatgtcatgataataatg gtttcttagacgtcaggtggcacttttcggggaaatgtgcgcggaacccc tatttgtttatttttctaaatacattcaaatatgtatccgctcatgagac aataaccctgataaatgcttcaataatattgaaaaaggaagagtatgagt attcaacatttccgtgtcgcccttattcccttttttgcggcattttgcct tcctgtttttgctcacccagaaacgctggtgaaagtaaaagatgctgaag atcagttgggtgcacgagtgggttacatcgaactggatctcaacagcggt aagatccttgagagttttcgccccgaagaacgttttccaatgatgagcac ttttaaagttctgctatgtggcgcggtattatcccgtattgacgccgggc aagagcaactcggtcgccgcatacactattctcagaatgacttggttgag tactcaccagtcacagaaaagcatcttacggatggcatgacagtaagaga attatgcagtgctgccataaccatgagtgataacactgcggccaacttac ttctgacaacgatcggaggaccgaaggagctaaccgcttttttgcacaac atgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatga agccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaa caacgttgcgcaaactattaactggcgaactacttactctagcttcccgg caacaattaatagactggatggaggcggataaagttgcaggaccacttct gcgctcggcccttccggctggctggtttattgctgataaatctggagccg gtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaag ccctcccgtatcgtagttatctacacgacggggagtcaggcaactatgga tgaacgaaatagacagatcgctgagataggtgcctcactgattaagcatt ggtaactgtcagaccaagtttactcatatatactttagattgatttaaaa cttcatttttaatttaaaaggatctaggtgaagatcctttttgataatct catgaccaaaatcccttaacgtgagttttcgttccactgagcgtcagacc ccgtagaaaagatcaaaggatcttcttgagatcctttttttctgcgcgta atctgctgcttgcaaacaaaaaaaccaccgctaccagcggtggtttgttt gccggatcaagagctaccaactctttttccgaaggtaactggcttcagca gagcgcagataccaaatactgtccttctagtgtagccgtagttaggccac cacttcaagaactctgtagcaccgcctacatacctcgctctgctaatcct gttaccagtggctgctgccagtggcgataagtcgtgtcttaccgggttgg actcaagacgatagttaccggataaggcgcagcggtcgggctgaacgggg ggttcgtgcacacagcccagcttggagcgaacgacctacaccgaactgag atacctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaa aggcggacaggtatccggtaagcggcagggtcggaacaggagagcgcacg agggagcttccagggggaaacgcctggtatctttatagtcctgtcgggtt tcgccacctctgacttgagcgtcgatttttgtgatgctcgtcaggggggc ggagcctatggaaaaacgccagcaacgcggcctttttacggttcctggcc ttttgctggccttttgctcacatgtcctgcag

TABLE-US-00025 Nucleotide sequence of ESARE-dsGFP-KCNJ2 construct  (SEQ ID NO: 25) AGAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGC GTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCA GGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCTGCGTGGGGAAGC TCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATGGT GCCGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCTGC GTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTCTC CTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCACAGA GCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATTCTC AGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTAGATCC AGCGCACAGAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGGCTC AGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGCTGC TGCTCGCGCAGCAGAGCACATTAGTCACTCGGGGCTGTGAAGGGGCGGGT CCTTGAGGGCACCCACGGGAGGGGAGCGAGTAGGCGCGGAAGGCGGGGCC TGCGGCAGGAGAGGGCGCGGGCGGGCTCTGGCGCGGAGCCTGGGCGCCGC CAATGGGAGCCAGGGCTCCACGAGCTGCCGCCCACGGGCCCCGCGCAGCA TAAATAGCCGCTGGTGGCGGTTTCGGTGCAGAGCTCAAGCGAGTTCTCCC GCAGCCGCAGTCTCTGGGCCTCTCTAGCTTCAGCGGCGACGAGCCTGCCA CACTCGCTAAGCTCCTCCGGCACCGCACACCTGCCACTGCCGCTGCAGCC GCCGGCTCTGCTCCCTTCCGGCTTCTGCCTCAGAGGAGTTCTTAGCCTGT TCGGAGCCGCAGCACCGACGACCAGGCTAGCAGagaattcGCTGTCTGCG AGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGGCATGACTTC TGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGATATTCACCT GGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCATCTGGTCAGAAAAG ACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGAGATCTGGCC ATACACTTGAGTGACAATGACATCCACTTTGCCTTTCTCTCCACAGGTGT CCACTCCCAGGTCCAACTGCAGCCCAAGCGGAGGATCCGCCACCatgccc gccatgaagatcgagtgccgcatcaccggcaccctgaacggcgtggagtt cgagctggtgggcggcggagagggcacccccgaGCAGGGCCGCATGACCA ACAAGATGAAGAGCACCAAAGGCGCCCTGACCTTCAGCCCCTACCTGCTG AGCCACGTGATGGGCTACGGCTTCTACCACTTCGGCACCTACCCCAGCGG CTACGAGAACCCCTTCCTGCACGCCATCAACAACGGCGGCTACACCAACA CCCGCATCGAGAAGTACGAGGACGGCGGCGTGCTGCACGTGAGCTTCAGC TACCGCTACGAGGCCGGCCGCGTGATCGGCGACTTCAAGGTGGTGGGCAC CGGCTTCCCCGAGGACAGCGTGATCTTCACCGACAAGATCATCCGCAGCA ACGCCACCGTGGAGCACCTGCACCCCATGGGCGATAACGTGCTGGTGGGC AGCTTCGCCCGCACCTTCAGCCTGCGCGACGGCGGCTACTACAGCTTCGT GGTGGACAGCCACATGCACTTCAAGAGCGCCATCCACCCCAGCATCCTGC AGAACGGGGGCCCCATGTTCGCCTTCCGCCGCGTGGAGGAGCTGCACAGC AACACCGAGCTGGGCATCGTGGAGTACCAGCACGCCTTCAAGACCCCCAT CGCCTTCGCCAGATCTCGAGATATCAGCCATGGCTTCCCGCCGGCGGTGG CGGCGCAGGATGATGGCACGCTGCCCATGTCTTGTGCCCAGGAGAGCGGG ATGGACCGTCACCCTGCAGCCTGTGCTTCTGCTAGGATCAATGTGACCGG TGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCG GCCCTatgggcagtgtgagaaccaaccgctacagcatcgtctcttcagaa gaagacggtatgaagttggccaccatggcagttgcaaatggctttgggaa cgggaagagtaaagtccacacccgacaacagtgcaggagccgctttgtga agaaagatggccactgtaatgttcagttcatcaatgtgggtgagaagggg caacggtacctcgcagacatcttcaccacgtgtgtggacattcgctggcg gtggatgctggttatcttctgcctggctttcgtcctgtcatggctgtttt ttggctgtgtgttttggttgatagctctgctccatggggacctggatgca tccaaagagggcaaagcttgtgtgtccgaggtcaacagcttcacggctgc cttcctcttctccattgagacccagacaaccataggctatggtttcagat gtgtcacggatgaatgcccaattgctgttttcatggtggtgttccagtca atcgtgggctgcatcatcgatgctttcatcattggcgcagtcatggccaa gatggcaaagccaaagaagagaaacgagactcttgtcttcagtcacaatg ccgtgattgccatgagagacggcaagctgtgtttgatgtggcgagtgggc aatcttcggaaaagccacttggtggaagctcatgttcgagcacagctcct caaatccagaattacttctgaaggggagtatatccctctggatcaaatag acatcaatgttgggtttgacagtggaatcgatcgtatatttctggtgtcc ccaatcactatagtccatgaaatagatgaagacagtcctttatatgattt gagtaaacaggacattgacaacgcagactttgaaatcgtggtcatactgg aaggcatggtggaagccactgccatgacgacacagtgccgtagctcttat ctagcaaatgaaatcctgtggggccaccgctatgagcctgtgctctttga agagaagcactactacaaagtggactactccaggttccacaaaacttacg aagtccccaacactcccctttgtagtgccagagacttagcagaaaagaaa tatatcctctcaaatgcaaattcattttgctatgaaaatgaagttgccct cacaagcaaagaggaagacgacagtgaaaatggagttccagaaagcacta gtacggacacgccccctgacatagaccttcacaaccaggcaagtgtacct ctagagcccaggcccttacggcgagagtcggagatatga

TABLE-US-00026 Nucleotide sequence of optimised AAV- ESARE-dsGFP- KCNJ2 vector (SEQ ID NO: 26) cctgcaggcagctgcgcgctc gctcgctcactgaggccgcccgggcaaagcccgggcgtcgggcgaccttt ggtcgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaa ctccatcactaggggttcctgcggccgcACGCGTGTGTCTAGACTGCAGA CCATGGGGATCCAGCGCACAGAGCCTTCCTGCGTGGGGAAGCTCCTTGCT GCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAG CAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCTGCGTGGGGAA GCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTCTCCTTTTATG GTGCCGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCACAGAGCCTTCCT GCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATTCTCAGCCTCTC TCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTAGATCCAGCGCACA GAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGGCTCAGCTATTC TCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGCTGCTGCTAGAT CCAGCGCACAGAGCCTTCCTGCGTGGGGAAGCTCCTTGCTGCGTCATGGC TCAGCTATTCTCAGCCTCTCTCCTTTTATGGTGCCGGAAGCAGGCAGGCT GCTGCTCGCGCAGCAGAGCACATTAGTCACTCGGGGCTGTGAAGGGGCGG GTCCTTGAGGGCACCCACGGGAGGGGAGCGAGTAGGCGCGGAAGGCGGGG CCTGCGGCAGGAGAGGGCGCGGGCGGGCTCTGGCGCGGAGCCTGGGCGCC GCCAATGGGAGCCAGGGCTCCACGAGCTGCCGCCCACGGGCCCCGCGCAG CATAAATAGCCGCTGGTGGCGGTTTCGGTGCAGAGCTCAAGCGAGTTCTC CCGCAGCCGCAGTCTCTGGGCCTCTCTAGCTTCAGCGGCGACGAGCCTGC CACACTCGCTAAGCTCCTCCGGCACCGCACACCTGCCACTGCCGCTGCAG CCGCCGGCTCTGCTCCCTTCCGGCTTCTGCCTCAGAGGAGTTCTTAGCCT GTTCGGAGCCGCAGCACCGACGACCAGGCTAGCAGagaattcGCTGTCTG CGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGGCATGACT TCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGATATTCAC CTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCATCTGGTCAGAAA AGACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGAGATCTGG CCATACACTTGAGTGACAATGACATCCACTTTGCCTTTCTCTCCACAGGT GTCCACTCCCAGGTCCAACTGCAGCCCAAGCGGAGGATCCGCCACCatgc ccgccatgaagatcgagtgccgcatcaccggcaccctgaacggcgtggag ttcgagctggtgggcggcggagagggcacccccgaGCAGGGCCGCATGAC CAACAAGATGAAGAGCACCAAAGGCGCCCTGACCTTCAGCCCCTACCTGC TGAGCCACGTGATGGGCTACGGCTTCTACCACTTCGGCACCTACCCCAGC GGCTACGAGAACCCCTTCCTGCACGCCATCAACAACGGCGGCTACACCAA CACCCGCATCGAGAAGTACGAGGACGGCGGCGTGCTGCACGTGAGCTTCA GCTACCGCTACGAGGCCGGCCGCGTGATCGGCGACTTCAAGGTGGTGGGC ACCGGCTTCCCCGAGGACAGCGTGATCTTCACCGACAAGATCATCCGCAG CAACGCCACCGTGGAGCACCTGCACCCCATGGGCGATAACGTGCTGGTGG GCAGCTTCGCCCGCACCTTCAGCCTGCGCGACGGCGGCTACTACAGCTTC GTGGTGGACAGCCACATGCACTTCAAGAGCGCCATCCACCCCAGCATCCT GCAGAACGGGGGCCCCATGTTCGCCTTCCGCCGCGTGGAGGAGCTGCACA GCAACACCGAGCTGGGCATCGTGGAGTACCAGCACGCCTTCAAGACCCCC ATCGCCTTCGCCAGATCTCGAGATATCAGCCATGGCTTCCCGCCGGCGGT GGCGGCGCAGGATGATGGCACGCTGCCCATGTCTTGTGCCCAGGAGAGCG GGATGGACCGTCACCCTGCAGCCTGTGCTTCTGCTAGGATCAATGTGACC GGTGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCC CGGCCCTatgggcagtgtgagaaccaaccgctacagcatcgtctcttcag aagaagacggtatgaagttggccaccatggcagttgcaaatggctttggg aacgggaagagtaaagtccacacccgacaacagtgcaggagccgctttgt gaagaaagatggccactgtaatgttcagttcatcaatgtgggtgagaagg ggcaacggtacctcgcagacatcttcaccacgtgtgtggacattcgctgg cggtggatgctggttatcttctgcctggctttcgtcctgtcatggctgtt ttttggctgtgtgttttggttgatagctctgctccatggggacctggatg catccaaagagggcaaagcttgtgtgtccgaggtcaacagcttcacggct gccttcctcttctccattgagacccagacaaccataggctatggtttcag atgtgtcacggatgaatgcccaattgctgttttcatggtggtgttccagt caatcgtgggctgcatcatcgatgctttcatcattggcgcagtcatggcc aagatggcaaagccaaagaagagaaacgagactcttgtcttcagtcacaa tgccgtgattgccatgagagacggcaagctgtgtttgatgtggcgagtgg gcaatcttcggaaaagccacttggtggaagctcatgttcgagcacagctc ctcaaatccagaattacttctgaaggggagtatatccctctggatcaaat agacatcaatgttgggtttgacagtggaatcgatcgtatatttctggtgt ccccaatcactatagtccatgaaatagatgaagacagtcctttatatgat ttgagtaaacaggacattgacaacgcagactttgaaatcgtggtcatact ggaaggcatggtggaagccactgccatgacgacacagtgccgtagctctt atctagcaaatgaaatcctgtggggccaccgctatgagcctgtgctcttt gaagagaagcactactacaaagtggactactccaggttccacaaaactta cgaagtccccaacactcccctttgtagtgccagagacttagcagaaaaga aatatatcctctcaaatgcaaattcattttgctatgaaaatgaagttgcc ctcacaagcaaagaggaagacgacagtgaaaatggagttccagaaagcac tagtacggacacgccccctgacatagaccttcacaaccaggcaagtgtac ctctagagcccaggcccttacggcgagagtcggagatatgagTCGACAAT CAACCTCATcgataccgagcgctgctcgagagatctacgggtggcatccc tgtgacccctccccagtgcctctcctggccctggaagttgccactccagt gcccaccagccttgtcctaataaaattaagttgcatcattttgtctgact aggtgtccttctataatattatggggtggaggggggtggtatggagcaag gggcaagttgggaagacaacctgtagggcctgcggggtctattgggaacc aagctggagtgcagtggcacaatcttggctcactgcaatctccgcctcct gggttcaagcgattctcctgcctcagcctcccgagttgttgggattccag gcatgcatgaccaggctcagctaatttttgtttttttggtagagacgggg tttcaccatattggccaggctggtctccaactcctaatctcaggtgatct acccaccttggcctcccaaattgctgggattacaggcgtgaaccactgct cccttccctgtccttctgattttgtaggtaaccacgtgcggaccgagcgg ccgcaggaacccctagtgatggagttggccactccctctctgcgcgctcg ctcgctcactgaggccgggcgaccaaaggtcgcccgacgcccgggctttg cccgggcggcctcagtgagcgagcgagcgcgcagctgcctgcaggggcgc ctgatgcggtattttctccttacgcatctgtgcggtatttcacaccgcat acgtcaaagcaaccatagtacgcgccctgtagcggcgcattaagcgcggc gggtgtggtggttacgcgcagcgtgaccgctacacttgccagcgccctag cgcccgctcctttcgctttcttcccttcctttctcgccacgttcgccggc tttccccgtcaagctctaaatcgggggctccctttagggttccgatttag tgctttacggcacctcgaccccaaaaaacttgatttgggtgatggttcac gtagtgggccatcgccctgatagacggtttttcgccctttgacgttggag tccacgttctttaatagtggactcttgttccaaactggaacaacactcaa ccctatctcgggctattcttttgatttataagggattttgccgatttcgg cctattggttaaaaaatgagctgatttaacaaaaatttaacgcgaatttt aacaaaatattaacgtttacaattttatggtgcactctcagtacaatctg ctctgatgccgcatagttaagccagccccgacacccgccaacacccgctg acgcgccctgacgggcttgtctgctcccggcatccgcttacagacaagct gtgaccgtctccgggagctgcatgtgtcagaggttttcaccgtcatcacc gaaacgcgcgagacgaaagggcctcgtgatacgcctatttttataggtta atgtcatgataataatggtttcttagacgtcaggtggcacttttcgggga aatgtgcgcggaacccctatttgtttatttttctaaatacattcaaatat gtatccgctcatgagacaataaccctgataaatgcttcaataatattgaa aaaggaagagtatgagtattcaacatttccgtgtcgcccttattcccttt tttgcggcattttgccttcctgtttttgctcacccagaaacgctggtgaa agtaaaagatgctgaagatcagttgggtgcacgagtgggttacatcgaac tggatctcaacagcggtaagatccttgagagttttcgccccgaagaacgt tttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatc ccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctc agaatgacttggttgagtactcaccagtcacagaaaagcatcttacggat ggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataa cactgcggccaacttacttctgacaacgatcggaggaccgaaggagctaa ccgcttttttgcacaacatgggggatcatgtaactcgccttgatcgttgg gaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgat gcctgtagcaatggcaacaacgttgcgcaaactattaactggcgaactac ttactctagcttcccggcaacaattaatagactggatggaggcggataaa gttgcaggaccacttctgcgctcggcccttccggctggctggtttattgc tgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcac tggggccagatggtaagccctcccgtatcgtagttatctacacgacgggg agtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgc ctcactgattaagcattggtaactgtcagaccaagtttactcatatatac tttagattgatttaaaacttcatttttaatttaaaaggatctaggtgaag atcctttttgataatctcatgaccaaaatcccttaacgtgagttttcgtt ccactgagcgtcagaccccgtagaaaagatcaaaggatcttcttgagatc ctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaaccaccgcta ccagcggtggtttgtttgccggatcaagagctaccaactctttttccgaa ggtaactggcttcagcagagcgcagataccaaatactgtccttctagtgt agccgtagttaggccaccacttcaagaactctgtagcaccgcctacatac ctcgctctgctaatcctgttaccagtggctgctgccagtggcgataagtc gtgtcttaccgggttggactcaagacgatagttaccggataaggcgcagc ggtcgggctgaacggggggttcgtgcacacagcccagcttggagcgaacg acctacaccgaactgagatacctacagcgtgagctatgagaaagcgccac gcttcccgaagggagaaaggcggacaggtatccggtaagcggcagggtcg gaacaggagagcgcacgagggagcttccagggggaaacgcctggtatctt tatagtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgtg atgctcgtcaggggggcggagcctatggaaaaacgccagcaacgcggcct ttttacggttcctggccttttgctggccttttgctcacatgt

TABLE-US-00027 Nucleotide sequence of NRAM-hCfos-dsGFP-KCNA1 cons truct (SEQ ID NO: 27) TGTTCGTGACTGTGACTAGAAGTTTGTT CGTGACTGTGACTAGAAGTTTGTTCGTGACTGTGACTAGAAGTTTGTTCG TGACTGTGAactcattcataaaacgcttgttataaaagcagtggctgcgg cgcctcgtactccaaccgcatctgcagcgagcaactgagaagccaagact gagccggcggccGAATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGT ACTCCCTCTCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCC AAAAACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAG GGTGGCCGCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCT TGAGGTGTGGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACA TCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAG CCCAAGCGGAGGATCCGCCACCatgcccgccatgaagatcgagtgccgca tcaccggcaccctgaacggcgtggagttcgagctggtgggcggcggagag ggcacccccgaGCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGG CGCCCTGACCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCT TCTACCACTTCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCAC GCCATCAACAACGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGA CGGCGGCGTGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCG TGATCGGCGACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTG ATCTTCACCGACAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCA CCCCATGGGCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCC TGCGCGACGGCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTC AAGAGCGCCATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGC CTTCCGCCGCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGG AGTACCAGCACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGAT ATCAGCCATGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCT GCCCATGTCTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCT GTGCTTCTGCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTA ACATGCGGTGACGTGGAGGAGAATCCCGGCCCTATGACCGTGATGAGCGG CGAGAACGTGGACGAGGCCTCTGCCGCTCCTGGACACCCTCAGGATGGCA GCTATCCCAGACAGGCCGACCACGACGATCACGAGTGCTGCGAGCGGGTC GTGATCAACATCAGCGGCCTGAGATTCGAGACACAGCTGAAAACCCTGGC CCAGTTCCCCAACACCCTGCTGGGCAACCCCAAGAAACGGATGCGGTACT TCGACCCCCTGCGGAACGAGTACTTCTTCGACCGGAACCGGCCCAGCTTC GACGCCATCCTGTACTACTACCAGAGCGGCGGCAGACTGCGGAGGCCCGT GAATGTGCCCCTGGACATGTTCAGCGAGGAAATCAAGTTCTACGAGCTGG GCGAGGAAGCCATGGAAAAGTTCAGAGAGGACGAGGGCTTCATCAAAGAG GAAGAGAGGCCCCTGCCCGAGAAAGAATACCAGAGACAAGTGTGGCTGCT GTTCGAGTACCCCGAGTCTAGCGGCCCTGCCAGAGTGATCGCCATCGTGT CCGTGATGGTCATCCTGATCTCTATCGTGATCTTCTGCCTGGAAACCCTG CCTGAGCTGAAGGACGACAAGGACTTCACCGGCACCGTGCACCGGATCGA CAACACCACCGTGATCTACAACAGCAATATCTTCACCGACCCATTCTTCA TCGTGGAAACACTGTGCATCATCTGGTTCAGCTTCGAGCTGGTCGTGCGG TTCTTCGCCTGCCCCAGCAAGACCGACTTCTTCAAGAACATCATGAACTT CATTGATATCGTGGCCATCATCCCCTACTTCATCACCCTGGGCACCGAGA TCGCCGAGCAGGAAGGCAATCAGAAGGGCGAGCAGGCCACCAGCCTGGCC ATTCTGAGAGTGATCAGACTCGTGCGGGTGTTCCGGATCTTCAAGCTGAG CCGGCACAGCAAGGGCCTGCAGATCCTGGGCCAGACACTGAAGGCCAGCA TGAGAGAGCTGGGCCTGCTGATCTTCTTTCTGTTCATCGGCGTGATCCTG TTCAGCAGCGCCGTGTACTTCGCCGAGGCCGAAGAAGCCGAGAGCCACTT CAGCTCTATCCCCGACGCCTTTTGGTGGGCCGTGGTGTCCATGACCACAG TGGGCTACGGCGACATGGTGCCCGTGACAATCGGCGGCAAGATCGTGGGC AGCCTGTGTGCCATTGCCGGCGTGCTGACAGTCGCCCTGCCTGTGCCTGT GATCGTGTCCAACTTCAACTACTTCTACCACCGGGAAACCGAGGGGGAGG AACAGGCTCAGCTGCTGCACGTGTCCAGCCCCAATCTGGCCAGCGACAGC GACCTGAGCAGACGGTCTAGCAGCACCATGAGCAAGAGCGAGTACATGGA AATCGAAGAGGACATGAACAACTCTATCGCCCACTACCGCCAAGTGAACA TCCGGACCGCCAACTGCACCACCGCCAACCAGAACTGCGTGAACAAGAGC AAGCTGCTGACCGATGTCTGAgTCGACAATCAACCTCA

TABLE-US-00028 Nucleotide sequence of optimised AAV- NRAM-hCfos - dsGFP-KCNA1 vector (SEQ ID NO: 28) cctgcaggcagctgc gcgctcgctcgctcactgaggccgcccgggcaaagcccgggcgtcgggcg acctttggtcgcccggcctcagtgagcgagcgagcgcgcagagagggagt ggccaactccatcactaggggttcctgcggccgcacgcgtTTCGCTATTA CGCCAGTTTTATTCTAGAAGTTTGTTCGTGACTGTGACTAGAAGTTTGTT CGTGACTGTGACTAGAAGTTTGTTCGTGACTGTGACTAGAAGTTTGTTCG TGACTGTGAactcattcataaaacgcttgttataaaagcagtggctgcgg cgcctcgtactccaaccgcatctgcagcgagcaactgagaagccaagact gagccggcggccGAATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGT ACTCCCTCTCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCC AAAAACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAG GGTGGCCGCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCT TGAGGTGTGGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACA TCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAG CCCAAGCGGAGGATCCGCCACCatgcccgccatgaagatcgagtgccgca tcaccggcaccctgaacggcgtggagttcgagctggtgggcggcggagag ggcacccccgaGCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGG CGCCCTGACCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCT TCTACCACTTCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCAC GCCATCAACAACGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGA CGGCGGCGTGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCG TGATCGGCGACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTG ATCTTCACCGACAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCA CCCCATGGGCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCC TGCGCGACGGCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTC AAGAGCGCCATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGC CTTCCGCCGCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGG AGTACCAGCACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGAT ATCAGCCATGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCT GCCCATGTCTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCT GTGCTTCTGCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTA ACATGCGGTGACGTGGAGGAGAATCCCGGCCCTATGACCGTGATGAGCGG CGAGAACGTGGACGAGGCCTCTGCCGCTCCTGGACACCCTCAGGATGGCA GCTATCCCAGACAGGCCGACCACGACGATCACGAGTGCTGCGAGCGGGTC GTGATCAACATCAGCGGCCTGAGATTCGAGACACAGCTGAAAACCCTGGC CCAGTTCCCCAACACCCTGCTGGGCAACCCCAAGAAACGGATGCGGTACT TCGACCCCCTGCGGAACGAGTACTTCTTCGACCGGAACCGGCCCAGCTTC GACGCCATCCTGTACTACTACCAGAGCGGCGGCAGACTGCGGAGGCCCGT GAATGTGCCCCTGGACATGTTCAGCGAGGAAATCAAGTTCTACGAGCTGG GCGAGGAAGCCATGGAAAAGTTCAGAGAGGACGAGGGCTTCATCAAAGAG GAAGAGAGGCCCCTGCCCGAGAAAGAATACCAGAGACAAGTGTGGCTGCT GTTCGAGTACCCCGAGTCTAGCGGCCCTGCCAGAGTGATCGCCATCGTGT CCGTGATGGTCATCCTGATCTCTATCGTGATCTTCTGCCTGGAAACCCTG CCTGAGCTGAAGGACGACAAGGACTTCACCGGCACCGTGCACCGGATCGA CAACACCACCGTGATCTACAACAGCAATATCTTCACCGACCCATTCTTCA TCGTGGAAACACTGTGCATCATCTGGTTCAGCTTCGAGCTGGTCGTGCGG TTCTTCGCCTGCCCCAGCAAGACCGACTTCTTCAAGAACATCATGAACTT CATTGATATCGTGGCCATCATCCCCTACTTCATCACCCTGGGCACCGAGA TCGCCGAGCAGGAAGGCAATCAGAAGGGCGAGCAGGCCACCAGCCTGGCC ATTCTGAGAGTGATCAGACTCGTGCGGGTGTTCCGGATCTTCAAGCTGAG CCGGCACAGCAAGGGCCTGCAGATCCTGGGCCAGACACTGAAGGCCAGCA TGAGAGAGCTGGGCCTGCTGATCTTCTTTCTGTTCATCGGCGTGATCCTG TTCAGCAGCGCCGTGTACTTCGCCGAGGCCGAAGAAGCCGAGAGCCACTT CAGCTCTATCCCCGACGCCTTTTGGTGGGCCGTGGTGTCCATGACCACAG TGGGCTACGGCGACATGGTGCCCGTGACAATCGGCGGCAAGATCGTGGGC AGCCTGTGTGCCATTGCCGGCGTGCTGACAGTCGCCCTGCCTGTGCCTGT GATCGTGTCCAACTTCAACTACTTCTACCACCGGGAAACCGAGGGGGAGG AACAGGCTCAGCTGCTGCACGTGTCCAGCCCCAATCTGGCCAGCGACAGC GACCTGAGCAGACGGTCTAGCAGCACCATGAGCAAGAGCGAGTACATGGA AATCGAAGAGGACATGAACAACTCTATCGCCCACTACCGCCAAGTGAACA TCCGGACCGCCAACTGCACCACCGCCAACCAGAACTGCGTGAACAAGAGC AAGCTGCTGACCGATGTCTGAgTCGACAATCAACCTCATcgataccgagc gctgctcgagagatctacgggtggcatccctgtgacccctccccagtgcc tctcctggccctggaagttgccactccagtgcccaccagccttgtcctaa taaaattaagttgcatcattttgtctgactaggtgtccttctataatatt atggggtggaggggggtggtatggagcaaggggcaagttgggaagacaac ctgtagggcctgcggggtctattgggaaccaagctggagtgcagtggcac aatcttggctcactgcaatctccgcctcctgggttcaagcgattctcctg cctcagcctcccgagttgttgggattccaggcatgcatgaccaggctcag ctaatttttgtttttttggtagagacggggtttcaccatattggccaggc tggtctccaactcctaatctcaggtgatctacccaccttggcctcccaaa ttgctgggattacaggcgtgaaccactgctcccttccctgtccttctgat tttgtaggtaaccacgtgcggaccgagcggccgcaggaacccctagtgat ggagttggccactccctctctgcgcgctcgctcgctcactgaggccgggc gaccaaaggtcgcccgacgcccgggctttgcccgggcggcctcagtgagc gagcgagcgcgcagctgcctgcaggggcgcctgatgcggtattttctcct tacgcatctgtgcggtatttcacaccgcatacgtcaaagcaaccatagta cgcgccctgtagcggcgcattaagcgcggcgggtgtggtggttacgcgca gcgtgaccgctacacttgccagcgccctagcgcccgctcctttcgctttc ttcccttcctttctcgccacgttcgccggctttccccgtcaagctctaaa tcgggggctccctttagggttccgatttagtgctttacggcacctcgacc ccaaaaaacttgatttgggtgatggttcacgtagtgggccatcgccctga tagacggtttttcgccctttgacgttggagtccacgttctttaatagtgg actcttgttccaaactggaacaacactcaaccctatctcgggctattctt ttgatttataagggattttgccgatttcggcctattggttaaaaaatgag ctgatttaacaaaaatttaacgcgaattttaacaaaatattaacgtttac aattttatggtgcactctcagtacaatctgctctgatgccgcatagttaa gccagccccgacacccgccaacacccgctgacgcgccctgacgggcttgt ctgctcccggcatccgcttacagacaagctgtgaccgtctccgggagctg catgtgtcagaggttttcaccgtcatcaccgaaacgcgcgagacgaaagg gcctcgtgatacgcctatttttataggttaatgtcatgataataatggtt tcttagacgtcaggtggcacttttcggggaaatgtgcgcggaacccctat ttgtttatttttctaaatacattcaaatatgtatccgctcatgagacaat aaccctgataaatgcttcaataatattgaaaaaggaagagtatgagtatt caacatttccgtgtcgcccttattcccttttttgcggcattttgccttcc tgtttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatc agttgggtgcacgagtgggttacatcgaactggatctcaacagcggtaag atccttgagagttttcgccccgaagaacgttttccaatgatgagcacttt taaagttctgctatgtggcgcggtattatcccgtattgacgccgggcaag agcaactcggtcgccgcatacactattctcagaatgacttggttgagtac tcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaatt atgcagtgctgccataaccatgagtgataacactgcggccaacttacttc tgacaacgatcggaggaccgaaggagctaaccgcttttttgcacaacatg ggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaagc cataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaa cgttgcgcaaactattaactggcgaactacttactctagcttcccggcaa caattaatagactggatggaggcggataaagttgcaggaccacttctgcg ctcggcccttccggctggctggtttattgctgataaatctggagccggtg agcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccc tcccgtatcgtagttatctacacgacggggagtcaggcaactatggatga acgaaatagacagatcgctgagataggtgcctcactgattaagcattggt aactgtcagaccaagtttactcatatatactttagattgatttaaaactt catttttaatttaaaaggatctaggtgaagatcctttttgataatctcat gaccaaaatcccttaacgtgagttttcgttccactgagcgtcagaccccg tagaaaagatcaaaggatcttcttgagatcctttttttctgcgcgtaatc tgctgcttgcaaacaaaaaaaccaccgctaccagcggtggtttgtttgcc ggatcaagagctaccaactctttttccgaaggtaactggcttcagcagag cgcagataccaaatactgtccttctagtgtagccgtagttaggccaccac ttcaagaactctgtagcaccgcctacatacctcgctctgctaatcctgtt accagtggctgctgccagtggcgataagtcgtgtcttaccgggttggact caagacgatagttaccggataaggcgcagcggtcgggctgaacggggggt tcgtgcacacagcccagcttggagcgaacgacctacaccgaactgagata cctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaagg cggacaggtatccggtaagcggcagggtcggaacaggagagcgcacgagg gagcttccagggggaaacgcctggtatctttatagtcctgtcgggtttcg ccacctctgacttgagcgtcgatttttgtgatgctcgtcaggggggcgga gcctatggaaaaacgccagcaacgcggcctttttacggttcctggccttt tgctggccttttgctcacatgt

TABLE-US-00029 Nucleotide sequence of NRAM-hCfos -dsGFP-KCNJ2 con struct (SEQ ID NO: 29) GAAGTTTGTTCGTGACTGTGACTAGAA GTTTGTTCGTGACTGTGACTAGAAGTTTGTTCGTGACTGTGACTAGAAGT TTGTTCGTGACTGTGAACTCATTCATAAAACGCTTGTTATAAAAGCAGTG GCTGCGGCGCCTCGTACTCCAACCGCATCTGCAGCGAGCAACTGAGAAGC CAAGACTGAGCCGGCGGCCGAATTCGCTGTCTGCGAGGGCCAGCTGTTGG GGTGAGTACTCCCTCTCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTC AGTTTCCAAAAACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGC CTTTGAGGGTGGCCGCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTG TCAAGCTTGAGGTGTGGCAGGCTTGAGATCTGGCCATACACTTGAGTGAC AATGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCA ACTGCAGCCCAAGCGGAGGATCCGCCACCATGCCCGCCATGAAGATCGAG TGCCGCATCACCGGCACCCTGAACGGCGTGGAGTTCGAGCTGGTGGGCGG CGGAGAGGGCACCCCCGAGCAGGGCCGCATGACCAACAAGATGAAGAGCA CCAAAGGCGCCCTGACCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGC TACGGCTTCTACCACTTCGGCACCTACCCCAGCGGCTACGAGAACCCCTT CCTGCACGCCATCAACAACGGCGGCTACACCAACACCCGCATCGAGAAGT ACGAGGACGGCGGCGTGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCC GGCCGCGTGATCGGCGACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGA CAGCGTGATCTTCACCGACAAGATCATCCGCAGCAACGCCACCGTGGAGC ACCTGCACCCCATGGGCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACC TTCAGCCTGCGCGACGGCGGCTACTACAGCTTCGTGGTGGACAGCCACAT GCACTTCAAGAGCGCCATCCACCCCAGCATCCTGCAGAACGGGGGCCCCA TGTTCGCCTTCCGCCGCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGC ATCGTGGAGTACCAGCACGCCTTCAAGACCCCCATCGCCTTCGCCAGATC TCGAGATATCAGCCATGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATG GCACGCTGCCCATGTCTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCT GCAGCCTGTGCTTCTGCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAG TCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCTATGGGCAGTG TGAGAACCAACCGCTACAGCATCGTCTCTTCAGAAGAAGACGGTATGAAG TTGGCCACCATGGCAGTTGCAAATGGCTTTGGGAACGGGAAGAGTAAAGT CCACACCCGACAACAGTGCAGGAGCCGCTTTGTGAAGAAAGATGGCCACT GTAATGTTCAGTTCATCAATGTGGGTGAGAAGGGGCAACGGTACCTCGCA GACATCTTCACCACGTGTGTGGACATTCGCTGGCGGTGGATGCTGGTTAT CTTCTGCCTGGCTTTCGTCCTGTCATGGCTGTTTTTTGGCTGTGTGTTTT GGTTGATAGCTCTGCTCCATGGGGACCTGGATGCATCCAAAGAGGGCAAA GCTTGTGTGTCCGAGGTCAACAGCTTCACGGCTGCCTTCCTCTTCTCCAT TGAGACCCAGACAACCATAGGCTATGGTTTCAGATGTGTCACGGATGAAT GCCCAATTGCTGTTTTCATGGTGGTGTTCCAGTCAATCGTGGGCTGCATC ATCGATGCTTTCATCATTGGCGCAGTCATGGCCAAGATGGCAAAGCCAAA GAAGAGAAACGAGACTCTTGTCTTCAGTCACAATGCCGTGATTGCCATGA GAGACGGCAAGCTGTGTTTGATGTGGCGAGTGGGCAATCTTCGGAAAAGC CACTTGGTGGAAGCTCATGTTCGAGCACAGCTCCTCAAATCCAGAATTAC TTCTGAAGGGGAGTATATCCCTCTGGATCAAATAGACATCAATGTTGGGT TTGACAGTGGAATCGATCGTATATTTCTGGTGTCCCCAATCACTATAGTC CATGAAATAGATGAAGACAGTCCTTTATATGATTTGAGTAAACAGGACAT TGACAACGCAGACTTTGAAATCGTGGTCATACTGGAAGGCATGGTGGAAG CCACTGCCATGACGACACAGTGCCGTAGCTCTTATCTAGCAAATGAAATC CTGTGGGGCCACCGCTATGAGCCTGTGCTCTTTGAAGAGAAGCACTACTA CAAAGTGGACTACTCCAGGTTCCACAAAACTTACGAAGTCCCCAACACTC CCCTTTGTAGTGCCAGAGACTTAGCAGAAAAGAAATATATCCTCTCAAAT GCAAATTCATTTTGCTATGAAAATGAAGTTGCCCTCACAAGCAAAGAGGA AGACGACAGTGAAAATGGAGTTCCAGAAAGCACTAGTACGGACACGCCCC CTGACATAGACCTTCACAACCAGGCAAGTGTACCTCTAGAGCCCAGGCCC TTACGGCGAGAGTCGGAGATATGA

TABLE-US-00030 Nucleotide sequence of optimised AAV- NRAM-hCfos - dsGFP-KCNJ2 vector (SEQ ID NO: 30) CAGGCAGCTGCGCGC TCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCT TTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTTTCGCTATTACGCC AGTTTTATTCTAGAAGTTTGTTCGTGACTGTGACTAGAAGTTTGTTCGTG ACTGTGACTAGAAGTTTGTTCGTGACTGTGACTAGAAGTTTGTTCGTGAC TGTGAACTCATTCATAAAACGCTTGTTATAAAAGCAGTGGCTGCGGCGCC TCGTACTCCAACCGCATCTGCAGCGAGCAACTGAGAAGCCAAGACTGAGC CGGCGGCCGAATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTC CCTCTCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAA ACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTG GCCGCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAG GTGTGGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACATCCA CTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCA AGCGGAGGATCCGCCACCATGCCCGCCATGAAGATCGAGTGCCGCATCAC CGGCACCCTGAACGGCGTGGAGTTCGAGCTGGTGGGCGGCGGAGAGGGCA CCCCCGAGCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGGCGCC CTGACCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCTTCTA CCACTTCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCACGCCA TCAACAACGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGACGGC GGCGTGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCGTGAT CGGCGACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTGATCT TCACCGACAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCACCCC ATGGGCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTGCG CGACGGCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTCAAGA GCGCCATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGCCTTC CGCCGCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGGAGTA CCAGCACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGATATCA GCCATGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCTGCCC ATGTCTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCTGTGC TTCTGCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTAACAT GCGGTGACGTGGAGGAGAATCCCGGCCCTATGGGCAGTGTGAGAACCAAC CGCTACAGCATCGTCTCTTCAGAAGAAGACGGTATGAAGTTGGCCACCAT GGCAGTTCAAATGGCTTTGGGAACGGGAAGAGTAAAGTCCACACCCGACA ACAGTGCAGGAGCCGCTTTGTGAAGAAAGATGGCCACTGTAATGTTCAGT TCATCAATGTGGGTGAGAAGGGGCAACGGTACCTCGCAGACATCTTCACC ACGTGTGTGGACATTCGCTGGCGGTGGATGCTGGTTATCTTCTGCCTGGC TTTCGTCCTGTCATGGCTGTTTTTTGGCTGTGTGTTTTGGTTGATAGCTC TGCTCCATGGGGACCTGGATGCATCCAAAGAGGGCAAAGCTTGTGTGTCC GAGGTCAACAGCTTCACGGCTGCCTTCCTCTTCTCCATTGAGACCCAGAC AACCATAGGCTATGGTTTCAGATGTGTCACGGATGAATGCCCAATTGCTG TTTTCATGGTGGTGTTCCAGTCAATCGTGGGCTGCATCATCGATGCTTTC ATCATTGGCGCAGTCATGGCCAAGATGGCAAAGCCAAAGAAGAGAAACGA GACTCTTGTCTTCAGTCACAATGCCGTGATTGCCATGAGAGACGGCAAGC TGTGTTTGATGTGGCGAGTGGGCAATCTTCGGAAAAGCCACTTGGTGGAA GCTCATGTTCGAGCACAGCTCCTCAAATCCAGAATTACTTCTGAAGGGGA GTATATCCCTCTGGATCAAATAGACATCAATGTTGGGTTTGACAGTGGAA TCGATCGTATATTTCTGGTGTCCCCAATCACTATAGTCCATGAAATAGAT GAAGACAGTCCTTTATATGATTTGAGTAAACAGGACATTGACAACGCAGA CTTTGAAATCGTGGTCATACTGGAAGGCATGGTGGAAGCCACTGCCATGA CGACACAGTGCCGTAGCTCTTATCTAGCAAATGAAATCCTGTGGGGCCAC CGCTATGAGCCTGTGCTCTTTGAAGAGAAGCACTACTACAAAGTGGACTA CTCCAGGTTCCACAAAACTTACGAAGTCCCCAACACTCCCCTTTGTAGTG CCAGAGACTTAGCAGAAAAGAAATATATCCTCTCAAATGCAAATTCATTT TGCTATGAAAATGAAGTTGCCCTCACAAGCAAAGAGGAAGACGACAGTGA AAATGGAGTTCCAGAAAGCACTAGTACGGACACGCCCCCTGACATAGACC TTCACAACCAGGCAAGTGTACCTCTAGAGCCCAGGCCCTTACGGCGAGAG TCGGAGATATGAGTCGACAATCAACCTCATCGATACCGAGCGCTGCTCGA GAGATCTACGGGTGGCATCCCTGTGACCCCTCCCCAGTGCCTCTCCTGGC CCTGGAAGTTGCCACTCCAGTGCCCACCAGCCTTGTCCTAATAAAATTAA GTTGCATCATTTTGTCTGACTAGGTGTCCTTCTATAATATTATGGGGTGG AGGGGGGTGGTATGGAGCAAGGGGCAAGTTGGGAAGACAACCTGTAGGGC CTGCGGGGTCTATTGGGAACCAAGCTGGAGTGCAGTGGCACAATCTTGGC TCACTGCAATCTCCGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCT CCCGAGTTGTTGGGATTCCAGGCATGCATGACCAGGCTCAGCTAATTTTT GTTTTTTTGGTAGAGACGGGGTTTCACCATATTGGCCAGGCTGGTCTCCA ACTCCTAATCTCAGGTGATCTACCCACCTTGGCCTCCCAAATTGCTGGGA TTACAGGCGTGAACCACTGCTCCCTTCCCTGTCCTTCTGATTTTGTAGGT AACCACGTGCGGACCGAGCGGCCGCAGGAACCCCTAGTGATGGAGTTGGC CACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGG TCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCG CGCAGCTGCCTGCAGGGGCGCCTGATGCGGTATTTTCTCCTTACGCATCT GTGCGGTATTTCACACCGCATACGTCAAAGCAACCATAGTACGCGCCCTG TAGCGGCGCATTAAGCGCGGCGGGTGTGGTGGTTACGCGCAGCGTGACCG CTACACTTGCCAGCGCCCTAGCGCCCGCTCCTTTCGCTTTCTTCCCTTCC TTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTCTAAATCGGGGGCT CCCTTTAGGGTTCCGATTTAGTGCTTTACGGCACCTCGACCCCAAAAAAC TTGATTTGGGTGATGGTTCACGTAGTGGGCCATCGCCCTGATAGACGGTT TTTCGCCCTTTGACGTTGGAGTCCACGTTCTTTAATAGTGGACTCTTGTT CCAAACTGGAACAACACTCAACCCTATCTCGGGCTATTCTTTTGATTTAT AAGGGATTTTGCCGATTTCGGCCTATTGGTTAAAAAATGAGCTGATTTAA CAAAAATTTAACGCGAATTTTAACAAAATATTAACGTTTACAATTTTATG GTGCACTCTCAGTACAATCTGCTCTGATGCCGCATAGTTAAGCCAGCCCC GACACCCGCCAACACCCGCTGACGCGCCCTGACGGGCTTGTCTGCTCCCG GCATCCGCTTACAGACAAGCTGTGACCGTCTCCGGGAGCTGCATGTGTCA GAGGTTTTCACCGTCATCACCGAAACGCGCGAGACGAAAGGGCCTCGTGA TACGCCTATTTTTATAGGTTAATGTCATGATAATAATGGTTTCTTAGACG TCAGGTGGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATTTGTTTATT TTTCTAAATACATTCAAATATGTATCCGCTCATGAGACAATAACCCTGAT AAATGCTTCAATAATATTGAAAAAGGAAGAGTATGAGTATTCAACATTTC CGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGC TCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTG CACGAGTGGGTTACATCGAACTGGATCTCAACAGCGGTAAGATCCTTGAG AGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCACTTTTAAAGTTCT GCTATGTGGCGCGGTATTATCCCGTATTGACGCCGGGCAAGAGCAACTCG GTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTACTCACCAGTC ACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCAGTGC TGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAACGA TCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCAT GTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAA CGACGAGCGTGACACCACGATGCCTGTAGCAATGGCAACAACGTTGCGCA AACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAATA GACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCT TCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGT CTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATC GTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAG ACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAG ACCAAGTTTACTCATATATACTTTAGATTGATTTAAAACTTCATTTTTAA TTTAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAAT CCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGA TCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTG CAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGA GCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATAC CAAATACTGTCCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAAC TCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGC TGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGAT AGTTACCGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACA CAGCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCG TGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGT ATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCA GGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTG ACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGA AAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCT TTTGCTCACATGT

TABLE-US-00031 Nucleotide sequence of Eqr1-dsGFP-KCNA1 construct  (SEQ ID NO: 31) cgtctcgagctggccctccccacgcgggcgtccc cgactcccgcgcgcgctcaggctcccagttgggaaccaaggagggggagg atgggggggggggtgtgcgccgacccggaaacgccatataaggagcagga aggatcccccgccggaacagaccttatttgggcagcgccttatatggagt ggcccaatatggccctgccgcttccggctctgggaggaggggcgagcggg ggttggggcgggggcaagctgggaactccaggcgcctggcccgggaggcc actgctgctgttccaatactaggctttccaggagcctgagcgctcgcgat gccggagcgggtcgcagggtggaggtgcccaccactcttggatgggaggg cttcacgtcactccgggtcctcccggccggtccttccatattagggcttc ctgcttcccatatatggccatgtacgtcacggcggaggcgggcccgtgct gttccagacccttgaaatagaggccgattcggggagtcgcGAATTCGCTG TCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGGCAT GACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGATAT TCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCATCTGGTCA GAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGAGAT CTGGCCATACACTTGAGTGACAATGACATCCACTTTGCCTTTCTCTCCAC AGGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCGGAGGATCCGCCACC atgcccgccatgaagatcgagtgccgcatcaccggcaccctgaacggcgt ggagttcgagctggtgggcggcggagagggcacccccgaGCAGGGCCGCA TGACCAACAAGATGAAGAGCACCAAAGGCGCCCTGACCTTCAGCCCCTAC CTGCTGAGCCACGTGATGGGCTACGGCTTCTACCACTTCGGCACCTACCC CAGCGGCTACGAGAACCCCTTCCTGCACGCCATCAACAACGGCGGCTACA CCAACACCCGCATCGAGAAGTACGAGGACGGCGGCGTGCTGCACGTGAGC TTCAGCTACCGCTACGAGGCCGGCCGCGTGATCGGCGACTTCAAGGTGGT GGGCACCGGCTTCCCCGAGGACAGCGTGATCTTCACCGACAAGATCATCC GCAGCAACGCCACCGTGGAGCACCTGCACCCCATGGGCGATAACGTGCTG GTGGGCAGCTTCGCCCGCACCTTCAGCCTGCGCGACGGCGGCTACTACAG CTTCGTGGTGGACAGCCACATGCACTTCAAGAGCGCCATCCACCCCAGCA TCCTGCAGAACGGGGGCCCCATGTTCGCCTTCCGCCGCGTGGAGGAGCTG CACAGCAACACCGAGCTGGGCATCGTGGAGTACCAGCACGCCTTCAAGAC CCCCATCGCCTTCGCCAGATCTCGAGATATCAGCCATGGCTTCCCGCCGG CGGTGGCGGCGCAGGATGATGGCACGCTGCCCATGTCTTGTGCCCAGGAG AGCGGGATGGACCGTCACCCTGCAGCCTGTGCTTCTGCTAGGATCAATGT GACCGGTGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGA ATCCCGGCCCTATGACCGTGATGAGCGGCGAGAACGTGGACGAGGCCTCT GCCGCTCCTGGACACCCTCAGGATGGCAGCTATCCCAGACAGGCCGACCA CGACGATCACGAGTGCTGCGAGCGGGTCGTGATCAACATCAGCGGCCTGA GATTCGAGACACAGCTGAAAACCCTGGCCCAGTTCCCCAACACCCTGCTG GGCAACCCCAAGAAACGGATGCGGTACTTCGACCCCCTGCGGAACGAGTA CTTCTTCGACCGGAACCGGCCCAGCTTCGACGCCATCCTGTACTACTACC AGAGCGGCGGCAGACTGCGGAGGCCCGTGAATGTGCCCCTGGACATGTTC AGCGAGGAAATCAAGTTCTACGAGCTGGGCGAGGAAGCCATGGAAAAGTT CAGAGAGGACGAGGGCTTCATCAAAGAGGAAGAGAGGCCCCTGCCCGAGA AAGAATACCAGAGACAAGTGTGGCTGCTGTTCGAGTACCCCGAGTCTAGC GGCCCTGCCAGAGTGATCGCCATCGTGTCCGTGATGGTCATCCTGATCTC TATCGTGATCTTCTGCCTGGAAACCCTGCCTGAGCTGAAGGACGACAAGG ACTTCACCGGCACCGTGCACCGGATCGACAACACCACCGTGATCTACAAC AGCAATATCTTCACCGACCCATTCTTCATCGTGGAAACACTGTGCATCAT CTGGTTCAGCTTCGAGCTGGTCGTGCGGTTCTTCGCCTGCCCCAGCAAGA CCGACTTCTTCAAGAACATCATGAACTTCATTGATATCGTGGCCATCATC CCCTACTTCATCACCCTGGGCACCGAGATCGCCGAGCAGGAAGGCAATCA GAAGGGCGAGCAGGCCACCAGCCTGGCCATTCTGAGAGTGATCAGACTCG TGCGGGTGTTCCGGATCTTCAAGCTGAGCCGGCACAGCAAGGGCCTGCAG ATCCTGGGCCAGACACTGAAGGCCAGCATGAGAGAGCTGGGCCTGCTGAT CTTCTTTCTGTTCATCGGCGTGATCCTGTTCAGCAGCGCCGTGTACTTCG CCGAGGCCGAAGAAGCCGAGAGCCACTTCAGCTCTATCCCCGACGCCTTT TGGTGGGCCGTGGTGTCCATGACCACAGTGGGCTACGGCGACATGGTGCC CGTGACAATCGGCGGCAAGATCGTGGGCAGCCTGTGTGCCATTGCCGGCG TGCTGACAGTCGCCCTGCCTGTGCCTGTGATCGTGTCCAACTTCAACTAC TTCTACCACCGGGAAACCGAGGGGGAGGAACAGGCTCAGCTGCTGCACGT GTCCAGCCCCAATCTGGCCAGCGACAGCGACCTGAGCAGACGGTCTAGCA GCACCATGAGCAAGAGCGAGTACATGGAAATCGAAGAGGACATGAACAAC TCTATCGCCCACTACCGCCAAGTGAACATCCGGACCGCCAACTGCACCAC CGCCAACCAGAACTGCGTGAACAAGAGCAAGCTGCTGACCGATGTCTGAg TC

TABLE-US-00032 Nucleotide sequence of optimised AAV- Eqr1-dsGFP-K CNA1 vector (SEQ ID NO: 32) cctgcaggcagctgcgcgctcg ctcgctcactgaggccgcccgggcaaagcccgggcgtcgggcgacctttg gtcgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaac tccatcactaggggttcctgcggccgcacgcgtctcgagctggccctccc cacgcgggcgtccccgactcccgcgcgcgctcaggctcccagttgggaac caaggagggggaggatgggggggggggtgtgcgccgacccggaaacgcca tataaggagcaggaaggatcccccgccggaacagaccttatttgggcagc gccttatatggagtggcccaatatggccctgccgcttccggctctgggag gaggggcgagcgggggttggggcgggggcaagctgggaactccaggcgcc tggcccgggaggccactgctgctgttccaatactaggctttccaggagcc tgagcgctcgcgatgccggagcgggtcgcagggtggaggtgcccaccact cttggatgggagggcttcacgtcactccgggtcctcccggccggtccttc catattagggcttcctgcttcccatatatggccatgtacgtcacggcgga ggcgggcccgtgctgttccagacccttgaaatagaggccgattcggggag tcgcGAATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTC TCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGA GGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCG CGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGT GGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACATCCACTTT GCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCG GAGGATCCGCCACCatgcccgccatgaagatcgagtgccgcatcaccggc accctgaacggcgtggagttcgagctggtgggcggcggagagggcacccc cgaGCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGGCGCCCTGA CCTTCAGCCCCTACCTGCTGAGCCACGTGATGGGCTACGGCTTCTACCAC TTCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCACGCCATCAA CAACGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGACGGCGGCG TGCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCGTGATCGGC GACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTGATCTTCAC CGACAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCACCCCATGG GCGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTGCGCGAC GGCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTCAAGAGCGC CATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGCCTTCCGCC GCGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGGAGTACCAG CACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGATATCAGCCA TGGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCTGCCCATGT CTTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCTGTGCTTCT GCTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTAACATGCGG TGACGTGGAGGAGAATCCCGGCCCTATGACCGTGATGAGCGGCGAGAACG TGGACGAGGCCTCTGCCGCTCCTGGACACCCTCAGGATGGCAGCTATCCC AGACAGGCCGACCACGACGATCACGAGTGCTGCGAGCGGGTCGTGATCAA CATCAGCGGCCTGAGATTCGAGACACAGCTGAAAACCCTGGCCCAGTTCC CCAACACCCTGCTGGGCAACCCCAAGAAACGGATGCGGTACTTCGACCCC CTGCGGAACGAGTACTTCTTCGACCGGAACCGGCCCAGCTTCGACGCCAT CCTGTACTACTACCAGAGCGGCGGCAGACTGCGGAGGCCCGTGAATGTGC CCCTGGACATGTTCAGCGAGGAAATCAAGTTCTACGAGCTGGGCGAGGAA GCCATGGAAAAGTTCAGAGAGGACGAGGGCTTCATCAAAGAGGAAGAGAG GCCCCTGCCCGAGAAAGAATACCAGAGACAAGTGTGGCTGCTGTTCGAGT ACCCCGAGTCTAGCGGCCCTGCCAGAGTGATCGCCATCGTGTCCGTGATG GTCATCCTGATCTCTATCGTGATCTTCTGCCTGGAAACCCTGCCTGAGCT GAAGGACGACAAGGACTTCACCGGCACCGTGCACCGGATCGACAACACCA CCGTGATCTACAACAGCAATATCTTCACCGACCCATTCTTCATCGTGGAA ACACTGTGCATCATCTGGTTCAGCTTCGAGCTGGTCGTGCGGTTCTTCGC CTGCCCCAGCAAGACCGACTTCTTCAAGAACATCATGAACTTCATTGATA TCGTGGCCATCATCCCCTACTTCATCACCCTGGGACCGAGATCGCCGAGC AGGAAGGCAATCAGAAGGGCGAGCAGGCCACCAGCCTGGCCATTCTGAGA GTGATCAGACTCGTGCGGGTGTTCCGGATCTTCAAGCTGAGCCGGCACAG CAAGGGCCTGCAGATCCTGGGCCAGACACTGAAGGCCAGCATGAGAGAGC TGGGCCTGCTGATCTTCTTTCTGTTCATCGGCGTGATCCTGTTCAGCAGC GCCGTGTACTTCGCCGAGGCCGAAGAAGCCGAGAGCCACTTCAGCTCTAT CCCCGACGCCTTTTGGTGGGCCGTGGTGTCCATGACCACAGTGGGCTACG GCGACATGGTGCCCGTGACAATCGGCGGCAAGATCGTGGGCAGCCTGTGT GCCATTGCCGGCGTGCTGACAGTCGCCCTGCCTGTGCCTGTGATCGTGTC CAACTTCAACTACTTCTACCACCGGGAAACCGAGGGGGAGGAACAGGCTC AGCTGCTGCACGTGTCCAGCCCCAATCTGGCCAGCGACAGCGACCTGAGC AGACGGTCTAGCAGCACCATGAGCAAGAGCGAGTACATGGAAATCGAAGA GGACATGAACAACTCTATCGCCCACTACCGCCAAGTGAACATCCGGACCG CCAACTGCACCACCGCCAACCAGAACTGCGTGAACAAGAGCAAGCTGCTG ACCGATGTCTGAgTCGACAATCAACCTCATcgataccgagcgctgctcga gagatctacgggtggcatccctgtgacccctccccagtgcctctcctggc cctggaagttgccactccagtgcccaccagccttgtcctaataaaattaa gttgcatcattttgtctgactaggtgtccttctataatattatggggtgg aggggggtggtatggagcaaggggcaagttgggaagacaacctgtagggc ctgcggggtctattgggaaccaagctggagtgcagtggcacaatcttggc tcactgcaatctccgcctcctgggttcaagcgattctcctgcctcagcct cccgagttgttgggattccaggcatgcatgaccaggctcagctaattttt gtttttttggtagagacggggtttcaccatattggccaggctggtctcca actcctaatctcaggtgatctacccaccttggcctcccaaattgctggga ttacaggcgtgaaccactgctcccttccctgtccttctgattttgtaggt aaccacgtgcggaccgagcggccgcaggaacccctagtgatggagttggc cactccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaagg tcgcccgacgcccgggctttgcccgggcggcctcagtgagcgagcgagcg cgcagctgcctgcaggggcgcctgatgcggtattttctccttacgcatct gtgcggtatttcacaccgcatacgtcaaagcaaccatagtacgcgccctg tagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccg ctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttcc tttctcgccacgttcgccggctttccccgtcaagctctaaatcgggggct ccctttagggttccgatttagtgctttacggcacctcgaccccaaaaaac ttgatttgggtgatggttcacgtagtgggccatcgccctgatagacggtt tttcgccctttgacgttggagtccacgttctttaatagtggactcttgtt ccaaactggaacaacactcaaccctatctcgggctattcttttgatttat aagggattttgccgatttcggcctattggttaaaaaatgagctgatttaa caaaaatttaacgcgaattttaacaaaatattaacgtttacaattttatg gtgcactctcagtacaatctgctctgatgccgcatagttaagccagcccc gacacccgccaacacccgctgacgcgccctgacgggcttgtctgctcccg gcatccgcttacagacaagctgtgaccgtctccgggagctgcatgtgtca gaggttttcaccgtcatcaccgaaacgcgcgagacgaaagggcctcgtga tacgcctatttttataggttaatgtcatgataataatggtttcttagacg tcaggtggcacttttcggggaaatgtgcgcggaacccctatttgtttatt tttctaaatacattcaaatatgtatccgctcatgagacaataaccctgat aaatgcttcaataatattgaaaaaggaagagtatgagtattcaacatttc cgtgtcgcccttattcccttttttgcggcattttgccttcctgtttttgc tcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtg cacgagtgggttacatcgaactggatctcaacagcggtaagatccttgag agttttcgccccgaagaacgttttccaatgatgagcacttttaaagttct gctatgtggcgcggtattatcccgtattgacgccgggcaagagcaactcg gtcgccgcatacactattctcagaatgacttggttgagtactcaccagtc acagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgc tgccataaccatgagtgataacactgcggccaacttacttctgacaacga tcggaggaccgaaggagctaaccgcttttttgcacaacatgggggatcat gtaactcgccttgatcgttgggaaccggagctgaatgaagccataccaaa cgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgca aactattaactggcgaactacttactctagcttcccggcaacaattaata gactggatggaggcggataaagttgcaggaccacttctgcgctcggccct tccggctggctggtttattgctgataaatctggagccggtgagcgtgggt ctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatc gtagttatctacacgacggggagtcaggcaactatggatgaacgaaatag acagatcgctgagataggtgcctcactgattaagcattggtaactgtcag accaagtttactcatatatactttagattgatttaaaacttcatttttaa tttaaaaggatctaggtgaagatcctttttgataatctcatgaccaaaat cccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaaga tcaaaggatcttcttgagatcctttttttctgcgcgtaatctgctgcttg caaacaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaaga gctaccaactctttttccgaaggtaactggcttcagcagagcgcagatac caaatactgtccttctagtgtagccgtagttaggccaccacttcaagaac tctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtggc tgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgat agttaccggataaggcgcagcggtcgggctgaacggggggttcgtgcaca cagcccagcttggagcgaacgacctacaccgaactgagatacctacagcg tgagctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggt atccggtaagcggcagggtcggaacaggagagcgcacgagggagcttcca gggggaaacgcctggtatctttatagtcctgtcgggtttcgccacctctg acttgagcgtcgatttttgtgatgctcgtcaggggggcggagcctatgga aaaacgccagcaacgcggcctttttacggttcctggccttttgctggcct tttgctcacatgt

TABLE-US-00033 Nucleotide sequence of Egr1-dsGFP-KCNJ2 construct  (SEQ ID NO: 33) ctggccctccccacgcgggcgtccccgactcccg cgcgcgctcaggctcccagttgggaaccaaggagggggaggatggggggg ggggtgtgcgccgacccggaaacgccatataaggagcaggaaggatcccc cgccggaacagaccttatttgggcagcgccttatatggagtggcccaata tggccctgccgcttccggctctgggaggaggggcgagcgggggttggggc gggggcaagctgggaactccaggcgcctggcccgggaggccactgctgct gttccaatactaggctttccaggagcctgagcgctcgcgatgccggagcg ggtcgcagggtggaggtgcccaccactcttggatgggagggcttcacgtc actccgggtcctcccggccggtccttccatattagggcttcctgcttccc atatatggccatgtacgtcacggcggaggcgggcccgtgctgttccagac ccttgaaatagaggccgattcggggagtcgcGAATTCGCTGTCTGCGAGG GCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGGCATGACTTCTGC GCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGATATTCACCTGGC CCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCATCTGGTCAGAAAAGACA ATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGAGATCTGGCCATA CACTTGAGTGACAATGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCA CTCCCAGGTCCAACTGCAGCCCAAGCGGAGGATCCGCCACCatgcccgcc atgaagatcgagtgccgcatcaccggcaccctgaacggcgtggagttcga gctggtgggcggcggagagggcacccccgaGCAGGGCCGCATGACCAACA AGATGAAGAGCACCAAAGGCGCCCTGACCTTCAGCCCCTACCTGCTGAGC CACGTGATGGGCTACGGCTTCTACCACTTCGGCACCTACCCCAGCGGCTA CGAGAACCCCTTCCTGCACGCCATCAACAACGGCGGCTACACCAACACCC GCATCGAGAAGTACGAGGACGGCGGCGTGCTGCACGTGAGCTTCAGCTAC CGCTACGAGGCCGGCCGCGTGATCGGCGACTTCAAGGTGGTGGGCACCGG CTTCCCCGAGGACAGCGTGATCTTCACCGACAAGATCATCCGCAGCAACG CCACCGTGGAGCACCTGCACCCCATGGGCGATAACGTGCTGGTGGGCAGC TTCGCCCGCACCTTCAGCCTGCGCGACGGCGGCTACTACAGCTTCGTGGT GGACAGCCACATGCACTTCAAGAGCGCCATCCACCCCAGCATCCTGCAGA ACGGGGGCCCCATGTTCGCCTTCCGCCGCGTGGAGGAGCTGCACAGCAAC ACCGAGCTGGGCATCGTGGAGTACCAGCACGCCTTCAAGACCCCCATCGC CTTCGCCAGATCTCGAGATATCAGCCATGGCTTCCCGCCGGCGGTGGCGG CGCAGGATGATGGCACGCTGCCCATGTCTTGTGCCCAGGAGAGCGGGATG GACCGTCACCCTGCAGCCTGTGCTTCTGCTAGGATCAATGTGACCGGTGA GGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCC CTatgggcagtgtgagaaccaaccgctacagcatcgtctcttcagaagaa gacggtatgaagttggccaccatggcagttgcaaatggctttgggaacgg gaagagtaaagtccacacccgacaacagtgcaggagccgctttgtgaaga aagatggccactgtaatgttcagttcatcaatgtgggtgagaaggggcaa cggtacctcgcagacatcttcaccacgtgtgtggacattcgctggcggtg gatgctggttatcttctgcctggctttcgtcctgtcatggctgttttttg gctgtgtgttttggttgatagctctgctccatggggacctggatgcatcc aaagagggcaaagcttgtgtgtccgaggtcaacagcttcacggctgcctt cctcttctccattgagacccagacaaccataggctatggtttcagatgtg tcacggatgaatgcccaattgctgttttcatggtggtgttccagtcaatc gtgggctgcatcatcgatgctttcatcattggcgcagtcatggccaagat ggcaaagccaaagaagagaaacgagactcttgtcttcagtcacaatgccg tgattgccatgagagacggcaagctgtgtttgatgtggcgagtgggcaat cttcggaaaagccacttggtggaagctcatgttcgagcacagctcctcaa atccagaattacttctgaaggggagtatatccctctggatcaaatagaca tcaatgttgggtttgacagtggaatcgatcgtatatttctggtgtcccca atcactatagtccatgaaatagatgaagacagtcctttatatgatttgag taaacaggacattgacaacgcagactttgaaatcgtggtcatactggaag gcatggtggaagccactgccatgacgacacagtgccgtagctcttatcta gcaaatgaaatcctgtggggccaccgctatgagcctgtgctctttgaaga gaagcactactacaaagtggactactccaggttccacaaaacttacgaag tccccaacactcccctttgtagtgccagagacttagcagaaaagaaatat atcctctcaaatgcaaattcattttgctatgaaaatgaagttgccctcac aagcaaagaggaagacgacagtgaaaatggagttccagaaagcactagta cggacacgccccctgacatagaccttcacaaccaggcaagtgtacctcta gagcccaggcccttacggcgagagtcggagatatgagTCGACAATC

TABLE-US-00034 Nucleotide sequence of optimised AAV- Egr1-dsGFP-K CNJ2 vector (SEQ ID NO: 34) cctgcaggcagctgcgcgctcg ctcgctcactgaggccgcccgggcaaagcccgggcgtcgggcgacctttg gtcgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaac tccatcactaggggttcctgcggccgcacgcgtctcgagctggccctccc cacgcgggcgtccccgactcccgcgcgcgctcaggctcccagttgggaac caaggagggggaggatgggggggggggtgtgcgccgacccggaaacgcca tataaggagcaggaaggatcccccgccggaacagaccttatttgggcagc gccttatatggagtggcccaatatggccctgccgcttccggctctgggag gaggggcgagcgggggttggggcgggggcaagctgggaactccaggcgcc tggcccgggaggccactgctgctgttccaatactaggctttccaggagcc tgagcgctcgcgatgccggagcgggtcgcagggtggaggtgcccaccact cttggatgggagggcttcacgtcactccgggtcctcccggccggtccttc catattagggcttcctgcttcccatatatggccatgtacgtcacggcgga ggcgggcccgtgctgttccagacccttgaaatagaggccgattcggggag tcgcGAATTCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTC TCAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGA GGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCG CGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGT GGCAGGCTTGAGATCTGGCCATACACTTGAGTGACAATGACATCCACTTT GCCTTTCTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCG GAGGATCCGCCACCatgcccgccatgaagatcgagtgccgcatcaccggc accctgaacggcgtggagttcgagctggtgggcggcggagagggcacccc cgaGCAGGGCCGCATGACCAACAAGATGAAGAGCACCAAAGGCGCCCTGA CCTTCAGCCCCTACCTGCTGAGCCACGTGAGGGCTACGGCTTCTACCACT TCGGCACCTACCCCAGCGGCTACGAGAACCCCTTCCTGCACGCCATCAAC AACGGCGGCTACACCAACACCCGCATCGAGAAGTACGAGGACGGCGGCGT GCTGCACGTGAGCTTCAGCTACCGCTACGAGGCCGGCCGCGTGATCGGCG ACTTCAAGGTGGTGGGCACCGGCTTCCCCGAGGACAGCGTGATCTTCACC GACAAGATCATCCGCAGCAACGCCACCGTGGAGCACCTGCACCCCATGGG CGATAACGTGCTGGTGGGCAGCTTCGCCCGCACCTTCAGCCTGCGCGACG GCGGCTACTACAGCTTCGTGGTGGACAGCCACATGCACTTCAAGAGCGCC ATCCACCCCAGCATCCTGCAGAACGGGGGCCCCATGTTCGCCTTCCGCCG CGTGGAGGAGCTGCACAGCAACACCGAGCTGGGCATCGTGGAGTACCAGC ACGCCTTCAAGACCCCCATCGCCTTCGCCAGATCTCGAGATATCAGCCAT GGCTTCCCGCCGGCGGTGGCGGCGCAGGATGATGGCACGCTGCCCATGTC TTGTGCCCAGGAGAGCGGGATGGACCGTCACCCTGCAGCCTGTGCTTCTG CTAGGATCAATGTGACCGGTGAGGGCAGAGGAAGTCTTCTAACATGCGGT GACGTGGAGGAGAATCCCGGCCCTatgggcagtgtgagaaccaaccgcta cagcatcgtctcttcagaagaagacggtatgaagttggccaccatggcag ttgcaaatggctttgggaacgggaagagtaaagtccacacccgacaacag tgcaggagccgctttgtgaagaaagatggccactgtaatgttcagttcat caatgtgggtgagaaggggcaacggtacctcgcagacatcttcaccacgt gtgtggacattcgctggcggtggatgctggttatcttctgcctggctttc gtcctgtcatggctgttttttggctgtgtgttttggttgatagctctgct ccatggggacctggatgcatccaaagagggcaaagcttgtgtgtccgagg tcaacagcttcacggctgccttcctcttctccattgagacccagacaacc ataggctatggtttcagatgtgtcacggatgaatgcccaattgctgtttt catggtggtgttccagtcaatcgtgggctgcatcatcgatgctttcatca ttggcgcagtcatggccaagatggcaaagccaaagaagagaaacgagact cttgtcttcagtcacaatgccgtgattgccatgagagacggcaagctgtg tttgatgtggcgagtgggcaatcttcggaaaagccacttggtggaagctc atgttcgagcacagctcctcaaatccagaattacttctgaaggggagtat atccctctggatcaaatagacatcaatgttgggtttgacagtggaatcga tcgtatatttctggtgtccccaatcactatagtccatgaaatagatgaag acagtcctttatatgatttgagtaaacaggacattgacaacgcagacttt gaaatcgtggtcatactggaaggcatggtggaagccactgccatgacgac acagtgccgtagctcttatctagcaaatgaaatcctgtggggccaccgct atgagcctgtgctctttgaagagaagcactactacaaagtggactactcc aggttccacaaaacttacgaagtccccaacactcccctttgtagtgccag agacttagcagaaaagaaatatatcctctcaaatgcaaattcattttgct atgaaaatgaagttgccctcacaagcaaagaggaagacgacagtgaaaat ggagttccagaaagcactagtacggacacgccccctgacatagaccttca caaccaggcaagtgtacctctagagcccaggcccttacggcgagagtcgg agatatgagTCGACAATCAACCTCATcgataccgagcgctgctcgagaga tctacgggtggcatccctgtgacccctccccagtgcctctcctggccctg gaagttgccactccagtgcccaccagccttgtcctaataaaattaagttg catcattttgtctgactaggtgtccttctataatattatggggtggaggg gggtggtatggagcaaggggcaagttgggaagacaacctgtagggcctgc ggggtctattgggaaccaagctggagtgcagtggcacaatcttggctcac tgcaatctccgcctcctgggttcaagcgattctcctgcctcagcctcccg agttgttgggattccaggcatgcatgaccaggctcagctaatttttgttt ttttggtagagacggggtttcaccatattggccaggctggtctccaactc ctaatctcaggtgatctacccaccttggcctcccaaattgctgggattac aggcgtgaaccactgctcccttccctgtccttctgattttgtaggtaacc acgtgcggaccgagcggccgcaggaacccctagtgatggagttggccact ccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaaggtcgc ccgacgcccgggctttgcccgggcggcctcagtgagcgagcgagcgcgca gctgcctgcaggggcgcctgatgcggtattttctccttacgcatctgtgc ggtatttcacaccgcatacgtcaaagcaaccatagtacgcgccctgtagc ggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgaccgctac acttgccagcgccctagcgcccgctcctttcgctttcttcccttcctttc tcgccacgttcgccggctttccccgtcaagctctaaatcgggggctccct ttagggttccgatttagtgctttacggcacctcgaccccaaaaaacttga tttgggtgatggttcacgtagtgggccatcgccctgatagacggtttttc gccctttgacgttggagtccacgttctttaatagtggactcttgttccaa actggaacaacactcaaccctatctcgggctattcttttgatttataagg gattttgccgatttcggcctattggttaaaaaatgagctgatttaacaaa aatttaacgcgaattttaacaaaatattaacgtttacaattttatggtgc actctcagtacaatctgctctgatgccgcatagttaagccagccccgaca cccgccaacacccgctgacgcgccctgacgggcttgtctgctcccggcat ccgcttacagacaagctgtgaccgtctccgggagctgcatgtgtcagagg ttttcaccgtcatcaccgaaacgcgcgagacgaaagggcctcgtgatacg cctatttttataggttaatgtcatgataataatggtttcttagacgtcag gtggcacttttcggggaaatgtgcgcggaacccctatttgtttatttttc taaatacattcaaatatgtatccgctcatgagacaataaccctgataaat gcttcaataatattgaaaaaggaagagtatgagtattcaacatttccgtg tcgcccttattcccttttttgcggcattttgccttcctgtttttgctcac ccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcacg agtgggttacatcgaactggatctcaacagcggtaagatccttgagagtt ttcgccccgaagaacgttttccaatgatgagcacttttaaagttctgcta tgtggcgcggtattatcccgtattgacgccgggcaagagcaactcggtcg ccgcatacactattctcagaatgacttggttgagtactcaccagtcacag aaaagcatcttacggatggcatgacagtaagagaattatgcagtgctgcc ataaccatgagtgataacactgcggccaacttacttctgacaacgatcgg aggaccgaaggagctaaccgcttttttgcacaacatgggggatcatgtaa ctcgccttgatcgttgggaaccggagctgaatgaagccataccaaacgac gagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgcaaact attaactggcgaactacttactctagcttcccggcaacaattaatagact ggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccg gctggctggtttattgctgataaatctggagccggtgagcgtgggtctcg cggtatcattgcagcactggggccagatggtaagccctcccgtatcgtag ttatctacacgacggggagtcaggcaactatggatgaacgaaatagacag atcgctgagataggtgcctcactgattaagcattggtaactgtcagacca agtttactcatatatactttagattgatttaaaacttcatttttaattta aaaggatctaggtgaagatcctttttgataatctcatgaccaaaatccct taacgtgagttttcgttccactgagcgtcagaccccgtagaaaagatcaa aggatcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaa caaaaaaaccaccgctaccagcggtggtttgtttgccggatcaagagcta ccaactctttttccgaaggtaactggcttcagcagagcgcagataccaaa tactgtccttctagtgtagccgtagttaggccaccacttcaagaactctg tagcaccgcctacatacctcgctctgctaatcctgttaccagtggctgct gccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagtt accggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagc ccagcttggagcgaacgacctacaccgaactgagatacctacagcgtgag ctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggtatcc ggtaagcggcagggtcggaacaggagagcgcacgagggagcttccagggg gaaacgcctggtatctttatagtcctgtcgggtttcgccacctctgactt gagcgtcgatttttgtgatgctcgtcaggggggcggagcctatggaaaaa cgccagcaacgcggcctttttacggttcctggccttttgctggccttttg ctcacatgt

TABLE-US-00035 Nucleotide sequence of Tet-On-dCAS9VP64 construct  (SEQ ID NO: 35) ATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTAC CACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCT ATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTATCAGTGA TAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTATCAGTGATAGAGAAA AGTGAAAGTCGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTGAAAG TCGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGCTC GGTACCCACCGGTGTCGACTCTAGAgccaccATGCCCAAGAAGAAGAGGA AGGTGGGAAGGGGGATGGACAAGAAGTACTCCATTGGGCTCGCTATCGGC ACAAACAGCGTCGGCTGGGCCGTCATTACGGACGAGTACAAGGTGCCGAG CAAAAAATTCAAAGTTCTGGGCAATACCGATCGCCACAGCATAAAGAAGA ACCTCATTGGCGCCCTCCTGTTCGACTCCGGGGAGACGGCCGAAGCCACG CGGCTCAAAAGAACAGCACGGCGCAGATATACCCGCAGAAAGAATCGGAT CTGCTACCTGCAGGAGATCTTTAGTAATGAGATGGCTAAGGTGGATGACT CTTTCTTCCATAGGCTGGAGGAGTCCTTTTTGGTGGAGGAGGATAAAAAG CACGAGCGCCACCCAATCTTTGGCAATATCGTGGACGAGGTGGCGTACCA TGAAAAGTACCCAACCATATATCATCTGAGGAAGAAGCTTGTAGACAGTA CTGATAAGGCTGACTTGCGGTTGATCTATCTCGCGCTGGCGCATATGATC AAATTTCGGGGACACTTCCTCATCGAGGGGGACCTGAACCCAGACAACAG CGATGTCGACAAACTCTTTATCCAACTGGTTCAGACTTACAATCAGCTTT TCGAAGAGAACCCGATCAACGCATCCGGAGTTGACGCCAAAGCAATCCTG AGCGCTAGGCTGTCCAAATCCCGGCGGCTCGAAAACCTCATCGCACAGCT CCCTGGGGAGAAGAAGAACGGCCTGTTTGGTAATCTTATCGCCCTGTCAC TCGGGCTGACCCCCAACTTTAAATCTAACTTCGACCTGGCCGAAGATGCC AAGCTTCAACTGAGCAAAGACACCTACGATGATGATCTCGACAATCTGCT GGCCCAGATCGGCGACCAGTACGCAGACCTTTTTTTGGCGGCAAAGAACC TGTCAGACGCCATTCTGCTGAGTGATATTCTGCGAGTGAACACGGAGATC ACCAAAGCTCCGCTGAGCGCTAGTATGATCAAGCGCTATGATGAGCACCA CCAAGACTTGACTTTGCTGAAGGCCCTTGTCAGACAGCAACTGCCTGAGA AGTACAAGGAAATTTTCTTCGATCAGTCTAAAAATGGCTACGCCGGATAC ATTGACGGCGGAGCAAGCCAGGAGGAATTTTACAAATTTATTAAGCCCAT CTTGGAAAAAATGGACGGCACCGAGGAGCTGCTGGTAAAGCTTAACAGAG AAGATCTGTTGCGCAAACAGCGCACTTTCGACAATGGAAGCATCCCCCAC CAGATTCACCTGGGCGAACTGCACGCTATCCTCAGGCGGCAAGAGGATTT CTACCCCTTTTTGAAAGATAACAGGGAAAAGATTGAGAAAATCCTCACAT TTCGGATACCCTACTATGTAGGCCCCCTCGCCCGGGGAAATTCCAGATTC GCGTGGATGACTCGCAAATCAGAAGAGACCATCACTCCCTGGAACTTCGA GGAAGTCGTGGATAAGGGGGCCTCTGCCCAGTCCTTCATCGAAAGGATGA CTAACTTTGATAAAAATCTGCCTAACGAAAAGGTGCTTCCTAAACACTCT CTGCTGTACGAGTACTTCACAGTTTATAACGAGCTCACCAAGGTCAAATA CGTCACAGAAGGGATGAGAAAGCCAGCATTCCTGTCTGGAGAGCAGAAGA AAGCTATCGTGGACCTCCTCTTCAAGACGAACCGGAAAGTTACCGTGAAA CAGCTCAAAGAAGACTATTTCAAAAAGATTGAATGTTTCGACTCTGTTGA AATCAGCGGAGTGGAGGATCGCTTCAACGCATCCCTGGGAACGTATCACG ATCTCCTGAAAATCATTAAAGACAAGGACTTCCTGGACAATGAGGAGAAC GAGGACATTCTTGAGGACATTGTCCTCACCCTTACGTTGTTTGAAGATAG GGAGATGATTGAAGAACGCTTGAAAACTTACGCTCATCTCTTCGACGACA AAGTCATGAAACAGCTCAAGAGGCGCCGATATACAGGATGGGGGCGGCTG TCAAGAAAACTGATCAATGGGATCCGAGACAAGCAGAGTGGAAAGACAAT CCTGGATTTTCTTAAGTCCGATGGATTTGCCAACCGGAACTTCATGCAGT TGATCCATGATGACTCTCTCACCTTTAAGGAGGACATCCAGAAAGCACAA GTTTCTGGCCAGGGGGACAGTCTTCACGAGCACATCGCTAATCTTGCAGG TAGCCCAGCTATCAAAAAGGGAATACTGCAGACCGTTAAGGTCGTGGATG AACTCGTCAAAGTAATGGGAAGGCATAAGCCCGAGAATATCGTTATCGAG ATGGCCCGAGAGAACCAAACTACCCAGAAGGGACAGAAGAACAGTAGGGA AAGGATGAAGAGGATTGAAGAGGGTATAAAAGAACTGGGGTCCCAAATCC TTAAGGAACACCCAGTTGAAAACACCCAGCTTCAGAATGAGAAGCTCTAC CTGTACTACCTGCAGAACGGCAGGGACATGTACGTGGATCAGGAACTGGA CATCAATCGGCTCTCCGACTACGACGTGGCTGCTATCGTGCCCCAGTCTT TTCTCAAAGATGATTCTATTGATAATAAAGTGTTGACAAGATCCGATAAA gcTAGAGGGAAGAGTGATAACGTCCCCTCAGAAGAAGTTGTCAAGAAAAT GAAAAATTATTGGCGGCAGCTGCTGAACGCCAAACTGATCACACAACGGA AGTTCGATAATCTGACTAAGGCTGAACGAGGTGGCCTGTCTGAGTTGGAT AAAGCCGGCTTCATCAAAAGGCAGCTTGTTGAGACACGCCAGATCACCAA GCACGTGGCCCAAATTCTCGATTCACGCATGAACACCAAGTACGATGAAA ATGACAAACTGATTCGAGAGGTGAAAGTTATTACTCTGAAGTCTAAGCTG GTCTCAGATTTCAGAAAGGACTTTCAGTTTTATAAGGTGAGAGAGATCAA CAATTACCACCATGCGCATGATGCCTACCTGAATGCAGTGGTAGGCACTG CACTTATCAAAAAATATCCCAAGCTTGAATCTGAATTTGTTTACGGAGAC TATAAAGTGTACGATGTTAGGAAAATGATCGCAAAGTCTGAGCAGGAAAT AGGCAAGGCCACCGCTAAGTACTTCTTTTACAGCAATATTATGAATTTTT TCAAGACCGAGATTACACTGGCCAATGGAGAGATTCGGAAGCGACCACTT ATCGAAACAAACGGAGAAACAGGAGAAATCGTGTGGGACAAGGGTAGGGA TTTCGCGACAGTCCGGAAGGTCCTGTCCATGCCGCAGGTGAACATCGTTA AAAAGACCGAAGTACAGACCGGAGGCTTCTCCAAGGAAAGTATCCTCCCG AAAAGGAACAGCGACAAGCTGATCGCACGCAAAAAAGATTGGGACCCCAA GAAATACGGCGGATTCGATTCTCCTACAGTCGCTTACAGTGTACTGGTTG TGGCCAAAGTGGAGAAAGGGAAGTCTAAAAAACTCAAAAGCGTCAAGGAA CTGCTGGGCATCACAATCATGGAGCGATCAAGCTTCGAAAAAAACCCCAT CGACTTTCTCGAGGCGAAAGGATATAAAGAGGTCAAAAAAGACCTCATCA TTAAGCTTCCCAAGTACTCTCTCTTTGAGCTTGAAAACGGCCGGAAACGA ATGCTCGCTAGTGCGGGCGAGCTGCAGAAAGGTAACGAGCTGGCACTGCC CTCTAAATACGTTAATTTCTTGTATCTGGCCAGCCACTATGAAAAGCTCA AAGGGTCTCCCGAAGATAATGAGCAGAAGCAGCTGTTCGTGGAACAACAC AAACACTACCTTGATGAGATCATCGAGCAAATAAGCGAATTCTCCAAAAG AGTGATCCTCGCCGACGCTAACCTCGATAAGGTGCTTTCTGCTTACAATA AGCACAGGGATAAGCCCATCAGGGAGCAGGCAGAAAACATTATCCACTTG TTTACTCTGACCAACTTGGGCGCGCCTGCAGCCTTCAAGTACTTCGACAC CACCATAGACAGAAAGCGGTACACCTCTACAAAGGAGGTCCTGGACGCCA CACTGATTCATCAGTCAATTACGGGGCTCTATGAAACAAGAATCGACCTC TCTCAGCTCGGTGGAGACAGCAGGGCTGACCCCAAGAAGAAGAGGAAGGT GGAGGCCAGCGGTTCCGGACGGGCTGACGCATTGGACGATTTTGATCTGG ATATGCTGGGAAGTGACGCCCTCGATGATTTTGACCTTGACATGCTTGGT TCGGATGCCCTTGATGACTTTGACCTCGACATGCTCGGCAGTGACGCCCT TGATGATTTCGACCTGGACATGCTGATTAACTCT

TABLE-US-00036 Nucleotide sequence of optimised AAV- Tet-On-dCAS9 VP64 vector (SEQ ID NO: 36) cctgcaggcagctgcgcgctcg ctcgctcactgaggccgcccgggcaaagcccgggcgtcgggcgacctttg gtcgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaac tccatcactaggggttcctgcggcctCTAGACCAGTTTGGTTAGATCTCG AGTTTACCACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACC ACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTA TCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTATCAGTGAT AGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTATCAGTGATAGAGAAAA GTGAAAGTCGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTGAAAGT CGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGCTCG GTACCCACCGGTGTCGACTCTAGAgccaccATGCCCAAGAAGAAGAGGAA GGTGGGAAGGGGGATGGACAAGAAGTACTCCATTGGGCTCGCTATCGGCA CAAACAGCGTCGGCTGGGCCGTCATTACGGACGAGTACAAGGTGCCGAGC AAAAAATTCAAAGTTCTGGGCAATACCGATCGCCACAGCATAAAGAAGAA CCTCATTGGCGCCCTCCTGTTCGACTCCGGGGAGACGGCCGAAGCCACGC GGCTCAAAAGAACAGCACGGCGCAGATATACCCGCAGAAAGAATCGGATC TGCTACCTGCAGGAGATCTTTAGTAATGAGATGGCTAAGGTGGATGACTC TTTCTTCCATAGGCTGGAGGAGTCCTTTTTGGTGGAGGAGGATAAAAAGC ACGAGCGCCACCCAATCTTTGGCAATATCGTGGACGAGGTGGCGTACCAT GAAAAGTACCCAACCATATATCATCTGAGGAAGAAGCTTGTAGACAGTAC TGATAAGGCTGACTTGCGGTTGATCTATCTCGCGCTGGCGCATATGATCA AATTTCGGGGACACTTCCTCATCGAGGGGGACCTGAACCCAGACAACAGC GATGTCGACAAACTCTTTATCCAACTGGTTCAGACTTACAATCAGCTTTT CGAAGAGAACCCGATCAACGCATCCGGAGTTGACGCCAAAGCAATCCTGA GCGCTAGGCTGTCCAAATCCCGGCGGCTCGAAAACCTCATCGCACAGCTC CCTGGGGAGAAGAAGAACGGCCTGTTTGGTAATCTTATCGCCCTGTCACT CGGGCTGACCCCCAACTTTAAATCTAACTTCGACCTGGCCGAAGATGCCA AGCTTCAACTGAGCAAAGACACCTACGATGATGATCTCGACAATCTGCTG GCCCAGATCGGCGACCAGTACGCAGACCTTTTTTTGGCGGCAAAGAACCT GTCAGACGCCATTCTGCTGAGTGATATTCTGCGAGTGAACACGGAGATCA CCAAAGCTCCGCTGAGCGCTAGTATGATCAAGCGCTATGATGAGCACCAC CAAGACTTGACTTTGCTGAAGGCCCTTGTCAGACAGCAACTGCCTGAGAA GTACAAGGAAATTTTCTTCGATCAGTCTAAAAATGGCTACGCCGGATACA TTGACGGCGGAGCAAGCCAGGAGGAATTTTACAAATTTATTAAGCCCATC TTGGAAAAAATGGACGGCACCGAGGAGCTGCTGGTAAAGCTTAACAGAGA AGATCTGTTGCGCAAACAGCGCACTTTCGACAATGGAAGCATCCCCCACC AGATTCACCTGGGCGAACTGCACGCTATCCTCAGGCGGCAAGAGGATTTC TACCCCTTTTTGAAAGATAACAGGGAAAAGATTGAGAAAATCCTCACATT TCGGATACCCTACTATGTAGGCCCCCTCGCCCGGGGAAATTCCAGATTCG CGTGGATGACTCGCAAATCAGAAGAGACCATCACTCCCTGGAACTTCGAG GAAGTCGTGGATAAGGGGGCCTCTGCCCAGTCCTTCATCGAAAGGATGAC TAACTTTGATAAAAATCTGCCTAACGAAAAGGTGCTTCCTAAACACTCTC TGCTGTACGAGTACTTCACAGTTTATAACGAGCTCACCAAGGTCAAATAC GTCACAGAAGGGATGAGAAAGCCAGCATTCCTGTCTGGAGAGCAGAAGAA AGCTATCGTGGACCTCCTCTTCAAGACGAACCGGAAAGTTACCGTGAAAC AGCTCAAAGAAGACTATTTCAAAAAGATTGAATGTTTCGACTCTGTTGAA ATCAGCGGAGTGGAGGATCGCTTCAACGCATCCCTGGGAACGTATCACGA TCTCCTGAAAATCATTAAAGACAAGGACTTCCTGGACAATGAGGAGAACG AGGACATTCTTGAGGACATTGTCCTCACCCTTACGTTGTTTGAAGATAGG GAGATGATTGAAGAACGCTTGAAAACTTACGCTCATCTCTTCGACGACAA AGTCATGAAACAGCTCAAGAGGCGCCGATATACAGGATGGGGGCGGCTGT CAAGAAAACTGATCAATGGGATCCGAGACAAGCAGAGTGGAAAGACAATC CTGGATTTTCTTAAGTCCGATGGATTTGCCAACCGGAACTTCATGCAGTT GATCCATGATGACTCTCTCACCTTTAAGGAGGACATCCAGAAAGCACAAG TTTCTGGCCAGGGGGACAGTCTTCACGAGCACATCGCTAATCTTGCAGGT AGCCCAGCTATCAAAAAGGGAATACTGCAGACCGTTAAGGTCGTGGATGA ACTCGTCAAAGTAATGGGAAGGCATAAGCCCGAGAATATCGTTATCGAGA TGGCCCGAGAGAACCAAACTACCCAGAAGGGACAGAAGAACAGTAGGGAA AGGATGAAGAGGATTGAAGAGGGTATAAAAGAACTGGGGTCCCAAATCCT TAAGGAACACCCAGTTGAAAACACCCAGCTTCAGAATGAGAAGCTCTACC TGTACTACCTGCAGAACGGCAGGGACATGTACGTGGATCAGGAACTGGAC ATCAATCGGCTCTCCGACTACGACGTGGCTGCTATCGTGCCCCAGTCTTT TCTCAAAGATGATTCTATTGATAATAAAGTGTTGACAAGATCCGATAAAg cTAGAGGGAAGAGTGATAACGTCCCCTCAGAAGAAGTTGTCAAGAAAATG AAAAATTATTGGCGGCAGCTGCTGAACGCCAAACTGATCACACAACGGAA GTTCGATAATCTGACTAAGGCTGAACGAGGTGGCCTGTCTGAGTTGGATA AAGCCGGCTTCATCAAAAGGCAGCTTGTTGAGACACGCCAGATCACCAAG CACGTGGCCCAAATTCTCGATTCACGCATGAACACCAAGTACGATGAAAA TGACAAACTGATTCGAGAGGTGAAAGTTATTACTCTGAAGTCTAAGCTGG TCTCAGATTTCAGAAAGGACTTTCAGTTTTATAAGGTGAGAGAGATCAAC AATTACCACCATGCGCATGATGCCTACCTGAATGCAGTGGTAGGCACTGC ACTTATCAAAAAATATCCCAAGCTTGAATCTGAATTTGTTTACGGAGACT ATAAAGTGTACGATGTTAGGAAAATGATCGCAAAGTCTGAGCAGGAAATA GGCAAGGCCACCGCTAAGTACTTCTTTTACAGCAATATTATGAATTTTTT CAAGACCGAGATTACACTGGCCAATGGAGAGATTCGGAAGCGACCACTTA TCGAAACAAACGGAGAAACAGGAGAAATCGTGTGGGACAAGGGTAGGGAT TTCGCGACAGTCCGGAAGGTCCTGTCCATGCCGCAGGTGAACATCGTTAA AAAGACCGAAGTACAGACCGGAGGCTTCTCCAAGGAAAGTATCCTCCCGA AAAGGAACAGCGACAAGCTGATCGCACGCAAAAAAGATTGGGACCCCAAG AAATACGGCGGATTCGATTCTCCTACAGTCGCTTACAGTGTACTGGTTGT GGCCAAAGTGGAGAAAGGGAAGTCTAAAAAACTCAAAAGCGTCAAGGAAC TGCTGGGCATCACAATCATGGAGCGATCAAGCTTCGAAAAAAACCCCATC GACTTTCTCGAGGCGAAAGGATATAAAGAGGTCAAAAAAGACCTCATCAT TAAGCTTCCCAAGTACTCTCTCTTTGAGCTTGAAAACGGCCGGAAACGAA TGCTCGCTAGTGCGGGCGAGCTGCAGAAAGGTAACGAGCTGGCACTGCCC TCTAAATACGTTAATTTCTTGTATCTGGCCAGCCACTATGAAAAGCTCAA AGGGTCTCCCGAAGATAATGAGCAGAAGCAGCTGTTCGTGGAACAACACA AACACTACCTTGATGAGATCATCGAGCAAATAAGCGAATTCTCCAAAAGA GTGATCCTCGCCGACGCTAACCTCGATAAGGTGCTTTCTGCTTACAATAA GCACAGGGATAAGCCCATCAGGGAGCAGGCAGAAAACATTATCCACTTGT TTACTCTGACCAACTTGGGCGCGCCTGCAGCCTTCAAGTACTTCGACACC ACCATAGACAGAAAGCGGTACACCTCTACAAAGGAGGTCCTGGACGCCAC ACTGATTCATCAGTCAATTACGGGGCTCTATGAAACAAGAATCGACCTCT CTCAGCTCGGTGGAGACAGCAGGGCTGACCCCAAGAAGAAGAGGAAGGTG GAGGCCAGCGGTTCCGGACGGGCTGACGCATTGGACGATTTTGATCTGGA TATGCTGGGAAGTGACGCCCTCGATGATTTTGACCTTGACATGCTTGGTT CGGATGCCCTTGATGACTTTGACCTCGACATGCTCGGCAGTGACGCCCTT GATGATTTCGACCTGGACATGCTGATTAACTCTAGATAAGaattcAATAA AAGATCTTTATTTTCATTAGATCTGTGTGTTGGTTTTTTGTGTgcggccg caggaacccctagtgatggagttggccactccctctctgcgcgctcgctc gctcactgaggccgggcgaccaaaggtcgcccgacgcccgggctttgccc gggcggcctcagtgagcgagcgagcgcgcagctgcctgcaggggcgcctg atgcggtattttctccttacgcatctgtgcggtatttcacaccgcatacg tcaaagcaaccatagtacgcgccctgtagcggcgcattaagcgcggcggg tgtggtggttacgcgcagcgtgaccgctacacttgccagcgccctagcgc ccgctctttcgctttcttcccttcctttctcgccacgttcgccggctttc cccgtcaagctctaaatcgggggctccctttagggttccgatttagtgct ttacggcacctcgaccccaaaaaacttgatttgggtgatggttcacgtag tgggccatcgccctgatagacggtttttcgccctttgacgttggagtcca cgttctttaatagtggactcttgttccaaactggaacaacactcaaccct atctcgggctattcttttgatttataagggattttgccgatttcggccta ttggttaaaaaatgagctgatttaacaaaaatttaacgcgaattttaaca aaatattaacgtttacaattttatggtgcactctcagtacaatctgctct gatgccgcatagttaagccagccccgacacccgccaacacccgctgacgc gccctgacgggcttgtctgctcccggcatccgcttacagacaagctgtga ccgtctccgggagctgcatgtgtcagaggttttcaccgtcatcaccgaaa cgcgcgagacgaaagggcctcgtgatacgcctatttttataggttaatgt catgataataatggtttcttagacgtcaggtggcacttttcggggaaatg tgcgcggaacccctatttgtttatttttctaaatacattcaaatatgtat ccgctcatgagacaataaccctgataaatgcttcaataatattgaaaaag gaagagtatgagtattcaacatttccgtgtcgcccttattcccttttttg cggcattttgccttcctgtttttgctcacccagaaacgctggtgaaagta aaagatgctgaagatcagttgggtgcacgagtgggttacatcgaactgga tctcaacagcggtaagatccttgagagttttcgccccgaagaacgttttc caatgatgagcacttttaaagttctgctatgtggcgcggtattatcccgt attgacgccgggcaagagcaactcggtcgccgcatacactattctcagaa tgacttggttgagtactcaccagtcacagaaaagcatcttacggatggca tgacagtaagagaattatgcagtgctgccataaccatgagtgataacact gcggccaacttacttctgacaacgatcggaggaccgaaggagctaaccgc ttttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaac cggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcct gtagcaatggcaacaacgttgcgcaaactattaactggcgaactacttac tctagcttcccggcaacaattaatagactggatggaggcggataaagttg caggaccacttctgcgctcggcccttccggctggctggtttattgctgat aaatctggagccggtgagcgtggaagccgcggtatcattgcagcactggg gccagatggtaagccctcccgtatcgtagttatctacacgacggggagtc aggcaactatggatgaacgaaatagacagatcgctgagataggtgcctca ctgattaagcattggtaactgtcagaccaagtttactcatatatacttta gattgatttaaaacttcatttttaatttaaaaggatctaggtgaagatcc tttttgataatctcatgaccaaaatcccttaacgtgagttttcgttccac tgagcgtcagaccccgtagaaaagatcaaaggatcttcttgagatccttt ttttctgcgcgtaatctgctgcttgcaaacaaaaaaaccaccgctaccag cggtggtttgtttgccggatcaagagctaccaactctttttccgaaggta actggcttcagcagagcgcagataccaaatactgtccttctagtgtagcc gtagttaggccaccacttcaagaactctgtagcaccgcctacatacctcg ctctgctaatcctgttaccagtggctgctgccagtggcgataagtcgtgt cttaccgggttggactcaagacgatagttaccggataaggcgcagcggtc gggctgaacggggggttcgtgcacacagcccagcttggagcgaacgacct acaccgaactgagatacctacagcgtgagctatgagaaagcgccacgctt cccgaagggagaaaggcggacaggtatccggtaagcggcagggtcggaac aggagagcgcacgagggagcttccagggggaaacgcctggtatctttata gtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgtgatgc tcgtcaggggggcggagcctatggaaaaacgccagcaacgcggccttttt acggttcctggccttttgctggccttttgctcacatgt

TABLE-US-00037 Nucleotide sequence of sgRNA KCNA1 (SEQ ID NO: 37)  AGTCAATGATCACATCCTCC

TABLE-US-00038 Nucleotide sequence of sgRNA LacZ (control) (SEQ I D NO: 38) TGCGAATACGCCCACGCGAT

TABLE-US-00039 Nucleotide sequence of optimised AAV- sgRNA KCNA1- cFos-rTTA-EGFP vector (SEQ ID NO: 39) ctgcgcgctcgc tcgctcactgaggccgcccgggcaaagcccgggcgtcgggcgacctttgg tcgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaact ccatcactaggggttcctgcggccgcacgcgtTTAACGAGGGCCTATTTC CCATGATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGATA ATTAGAATTAATTTGACTGTAAACACAAAGATATTAGTACAAAATACGTG ACGTAGAAAGTAATAATTTCTTGGGTAGTTTGCAGTTTTAAAATTATGTT TTAAAATGGACTATCATATGCTTACCGTAACTTGAAAGTATTTCGATTTC TTGGCTTTATATATCTTGTGGAAAGGACGAAACACCGagtcaatgatcac atcctccGTTTTAGAGCTAGAAATAGCAAGTTAAAATAAGGCTAGTCCGT TATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTTTTTTGTTAACATCGA TtCTCGAGTTCGCTATTACGCCAGTTTTATTGCGGCCGCAGCTTTCCTTT AGGAACAGAGGCTTCGAGCCTTTAAGGCTGCGTACTTGCTTCTCCTAATA CCAGAGACTCAAAAAAAAAAAAAAAGTTCCAGATTGCTGGACAATGACCC GGGTCTCATCCCTTGACCCTGGGAACCGGGTCCACATTGAATCAGGTGCG AATGTTCGCTCGCCTTCTCTGCCTTTCCCGCCTCCCCTCCCCCGGCCGCG GCCCCGGTTCCCCCCCTGCGCTGCACCCTCAGAGTTGGCTGCAGCCGGCG AGCTGTTCCCGTCAATCCCTCCCTCCTTTACACAGGATGTCCATATTAGG ACATCTGCGTCAGCAGGTTTCCACGGCCGGTCCCTGTTGTTCTGGGGGGG GGACCATCTCCGAAATCCTACACGCGGAAGGTCTAGGAGACCCCCTAAGA TCCCAAATGTGAACACTCATAGGTGAAAGATGTATGCCAAGACGGGGGTT GAAAGCCTGGGGCGTAGAGTTGACGACAGAGCGCCCGCAGAGGGCCTTGG GGCGCGCTTCCCCCCCCTTCCAGTTCCGCCCAGTGACGTAGGAAGTCCAT CCATTCACAGCGCTTCTATAAAGGCGCCAGCTGAGGCGCCTACTACTCCA ACCGCGACTGCAGCGAGCAACTGAGAAGACTGGATAGAGCCGGCGGTTCC GCGAACGAGCAGTGACCGCGCTCCCACCCAGCTCTGCTCTGCAGCTCCCA CCAGTGTCTGGCCGCATCGATTCTAGAATTCGCTGTCTGCGAGGGCCAGC TGTTGGGGTGAGTACTCCCTCTCAAAAGCGGGCATGACTTCTGCGCTAAG ATTGTCAGTTTCCAAAAACGAGGAGGATTTGATATTCACCTGGCCCGCGG TGATGCCTTTGAGGGTGGCCGCGTCCATCTGGTCAGAAAAGACAATCTTT TTGTTGTCAAGCTTGAGGTGTGGCAGGCTTGAGATCTGGCCATACACTTG AGTGACAATGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCA GGTCCAACTGCAGCCCAAGCGGAGGATCCATGTCTAGACTGGACAAGAGC AAAGTCATAAACGGCGCTCTGGAATTACTCAATGGAGTCGGTATCGAAGG CCTGACGACAAGGAAACTCGCTCAAAAGCTGGGAGTTGAGCAGCCTACCC TGTACTGGCACGTGAAGAACAAGCGGGCCCTGCTCGATGCCCTGCCAATC GAGATGCTGGACAGGCATCATACCCACTTCTGCCCCCTGGAAGGCGAGTC ATGGCAAGACTTTCTGCGGAACAACGCCAAGTCATTCCGCTGTGCTCTCC TCTCACATCGCGACGGGGCTAAAGTGCATCTCGGCACCCGCCCAACAGAG AAACAGTACGAAACCCTGGAAAATCAGCTCGCGTTCCTGTGTCAGCAAGG CTTCTCCCTGGAGAACGCACTGTACGCTCTGTCCGCCGTGGGCCACTTTA CACTGGGCTGCGTATTGGAGGAACAGGAGCATCAAGTAGCAAAAGAGGAA AGAGAGACACCTACCACCGATTCTATGCCCCCACTTCTGAGACAAGCAAT TGAGCTGTTCGACCGGCAGGGAGCCGAACCTGCCTTCCTTTTCGGCCTGG AACTAATCATATGTGGCCTGGAGAAACAGCTAAAGTGCGAAAGCGGCGGG CCGGCCGACGCCCTTGACGATTTTGACTTAGACATGCTCCCAGCCGATGC CCTGACGACTTTGACCTTGATATGCTGCCTGCTGACGCTCTTGACGATTT TGACCTTGACATGCTCCCCGGGTTCGAAGCtGAgGGTCGGGGCTCTCTGC TCACATGTGGCGACGTCGAGGAGAATCCCGGACCGGCCCCgGGTGTACAA atggtgagcaagggcgaggagctgttcaccggggtggtgcccatcctggt cgagctggacggcgacgtaaacggccacaagttcagcgtgtccggcgagg gcgagggcgatgccacctacggcaagctgaccctgaagttcatctgcacc accggcaagctgcccgtgccctggcccaccctcgtgaccaccctgaccta cggcgtgcagtgcttcagccgctaccccgaccacatgaagcagcacgact tcttcaagtccgccatgcccgaaggctacgtccaggagcgcaccatcttc ttcaaggacgacggcaactacaagacccgcgccgaggtgaagttcgaggg cgacaccctggtgaaccgcatcgagctgaagggcatcgacttcaaggagg acggcaacatcctggggcacaagctggagtacaactacaacagccacaac gtctatatcatggccgacaagcagaagaacggcatcaaggtgaacttcaa gatccgccacaacatcgaggacggcagcgtgcagctcgccgaccactacc agcagaacacccccatcggcgacggccccgtgctgctgcccgacaaccac tacctgagcacccagtccgccctgagcaaagaccccaacgagaagcgcga tcacatggtcctgctggagttcgtgaccgccgccgggatcactctcggca tggacgagctgtacaagtaaACCGGTGCTAGCtaaTctagagTCGACAAT CAACCTCATcgataccgagcgctgctcgagagatctacgggtggcatccc tgtgacccctccccagtgcctctcctggccctggaagttgccactccagt gcccaccagccttgtcctaataaaattaagttgcatcattttgtctgact aggtgtccttctataatattatggggtggaggggggtggtatggagcaag gggcaagttgggaagacaacctgtagggcctgcggggtctattgggaacc aagctggagtgcagtggcacaatcttggctcactgcaatctccgcctcct gggttcaagcgattctcctgcctcagcctcccgagttgttgggattccag gcatgcatgaccaggctcagctaatttttgtttttttggtagagacgggg tttcaccatattggccaggctggtctccaactcctaatctcaggtgatct acccaccttggcctcccaaattgctgggattacaggcgtgaaccactgct cccttccctgtccttctgattttgtaggtaaccacgtgcggaccgagcgg ccgcaggaacccctagtgatggagttggccactccctctctgcgcgctcg ctcgctcactgaggccgggcgaccaaaggtcgcccgacgcccgggctttg cccgggcggcctcagtgagcgagcgagcgcgcagctgcctgcaggggcgc ctgatgcggtattttctccttacgcatctgtgcggtatttcacaccgcat acgtcaaagcaaccatagtacgcgccctgtagcggcgcattaagcgcggc gggtgtggtggttacgcgcagcgtgaccgctacacttgccagcgccctag cgcccgctcctttcgctttcttcccttcctttctcgccacgttcgccggc tttccccgtcaagctctaaatcgggggctccctttagggttccgatttag tgctttacggcacctcgaccccaaaaaacttgatttgggtgatggttcac gtagtgggccatcgccctgatagacggtttttcgccctttgacgttggag tccacgttctttaatagtggactcttgttccaaactggaacaacactcaa ccctatctcgggctattcttttgatttataagggattttgccgatttcgg cctattggttaaaaaatgagctgatttaacaaaaatttaacgcgaatttt aacaaaatattaacgtttacaattttatggtgcactctcagtacaatctg ctctgatgccgcatagttaagccagccccgacacccgccaacacccgctg acgcgccctgacgggcttgtctgctcccggcatccgcttacagacaagct gtgaccgtctccgggagctgcatgtgtcagaggttttcaccgtcatcacc gaaacgcgcgagacgaaagggcctcgtgatacgcctatttttataggtta atgtcatgataataatggtttcttagacgtcaggtggcacttttcgggga aatgtgcgcggaacccctatttgtttatttttctaaatacattcaaatat gtatccgctcatgagacaataaccctgataaatgcttcaataatattgaa aaaggaagagtatgagtattcaacatttccgtgtcgcccttattcccttt tttgcggcattttgccttcctgtttttgctcacccagaaacgctggtgaa agtaaaagatgctgaagatcagttgggtgcacgagtgggttacatcgaac tggatctcaacagcggtaagatccttgagagttttcgccccgaagaacgt tttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatc ccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctc agaatgacttggttgagtactcaccagtcacagaaaagcatcttacggat ggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataa cactgcggccaacttacttctgacaacgatcggaggaccgaaggagctaa ccgcttttttgcacaacatgggggatcatgtaactcgccttgatcgttgg gaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgat gcctgtagcaatggcaacaacgttgcgcaaactattaactggcgaactac ttactctagcttcccggcaacaattaatagactggatggaggcggataaa gttgcaggaccacttctgcgctcggcccttccggctggctggtttattgc tgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcac tggggccagatggtaagccctcccgtatcgtagttatctacacgacgggg agtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgc ctcactgattaagcattggtaactgtcagaccaagtttactcatatatac tttagattgatttaaaacttcatttttaatttaaaaggatctaggtgaag atcctttttgataatctcatgaccaaaatcccttaacgtgagttttcgtt ccactgagcgtcagaccccgtagaaaagatcaaaggatcttcttgagatc ctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaaccaccgcta ccagcggtggtttgtttgccggatcaagagctaccaactctttttccgaa ggtaactggcttcagcagagcgcagataccaaatactgtccttctagtgt agccgtagttaggccaccacttcaagaactctgtagcaccgcctacatac ctcgctctgctaatcctgttaccagtggctgctgccagtggcgataagtc gtgtcttaccgggttggactcaagacgatagttaccggataaggcgcagc ggtcgggctgaacggggggttcgtgcacacagcccagcttggagcgaacg acctacaccgaactgagatacctacagcgtgagctatgagaaagcgccac gcttcccgaagggagaaaggcggacaggtatccggtaagcggcagggtcg gaacaggagagcgcacgagggagcttccagggggaaacgcctggtatctt tatagtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgtg atgctcgtcaggggggcggagcctatggaaaaacgccagcaacgcggcct ttttacggttcctggccttttgctggccttttgctca

TABLE-US-00040 Nucleotide sequence of optimised AAV- sgRNA LacZ-c Fos-rTTA-EGFP vector (SEQ ID NO: 40) cctgcaggcagct gcgcgctcgctcgctcactgaggccgcccgggcaaagcccgggcgtcggg cgacctttggtcgcccggcctcagtgagcgagcgagcgcgcagagaggga gtggccaactccatcactaggggttcctgcggccgcacgcgtTTAACGAG GGCCTATTTCCCATGATTCCTTCATATTTGCATATACGATACAAGGCTGT TAGAGAGATAATTAGAATTAATTTGACTGTAAACACAAAGATATTAGTAC AAAATACGTGACGTAGAAAGTAATAATTTCTTGGGTAGTTTGCAGTTTTA AAATTATGTTTTAAAATGGACTATCATATGCTTACCGTAACTTGAAAGTA TTTCGATTTCTTGGCTTTATATATCTTGTGGAAAGGACGAAACACCGTGC GAATACGCCCACGCGATGTTTTAGAGCTAGAAATAGCAAGTTAAAATAAG GCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTTTTTTG TTAACATCGATtTCCCACGGGGTCTCGAGTTCGCTATTACGCCAGTTTTA TTGCGGCCGCAGCTTTCCTTTAGGAACAGAGGCTTCGAGCCTTTAAGGCT GCGTACTTGCTTCTCCTAATACCAGAGACTCAAAAAAAAAAAAAAAGTTC CAGATTGCTGGACAATGACCCGGGTCTCATCCCTTGACCCTGGGAACCGG GTCCACATTGAATCAGGTGCGAATGTTCGCTCGCCTTCTCTGCCTTTCCC GCCTCCCCTCCCCCGGCCGCGGCCCCGGTTCCCCCCCTGCGCTGCACCCT CAGAGTTGGCTGCAGCCGGCGAGCTGTTCCCGTCAATCCCTCCCTCCTTT ACACAGGATGTCCATATTAGGACATCTGCGTCAGCAGGTTTCCACGGCCG GTCCCTGTTGTTCTGGGGGGGGGACCATCTCCGAAATCCTACACGCGGAA GGTCTAGGAGACCCCCTAAGATCCCAAATGTGAACACTCATAGGTGAAAG ATGTATGCCAAGACGGGGGTTGAAAGCCTGGGGCGTAGAGTTGACGACAG AGCGCCCGCAGAGGGCCTTGGGGCGCGCTTCCCCCCCCTTCCAGTTCCGC CCAGTGACGTAGGAAGTCCATCCATTCACAGCGCTTCTATAAAGGCGCCA GCTGAGGCGCCTACTACTCCAACCGCGACTGCAGCGAGCAACTGAGAAGA CTGGATAGAGCCGGCGGTTCCGCGAACGAGCAGTGACCGCGCTCCCACCC AGCTCTGCTCTGCAGCTCCCACCAGTGTCTGGCCGCATCGATTCTAGAAT TCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGC GGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATT TGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCGTCCATC TGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGAGGTGTGGCAGGCT TGAGATCTGGCCATACACTTGAGTGACAATGACATCCACTTTGCCTTTCT CTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGCCCAAGCGGAGGATCC ATGTCTAGACTGGACAAGAGCAAAGTCATAAACGGCGCTCTGGAATTACT CAATGGAGTCGGTATCGAAGGCCTGACGACAAGGAAACTCGCTCAAAAGC TGGGAGTTGAGCAGCCTACCCTGTACTGGCACGTGAAGAACAAGCGGGCC CTGCTCGATGCCCTGCCAATCGAGATGCTGGACAGGCATCATACCCACTT CTGCCCCCTGGAAGGCGAGTCATGGCAAGACTTTCTGCGGAACAACGCCA AGTCATTCCGCTGTGCTCTCCTCTCACATCGCGACGGGGCTAAAGTGCAT CTCGGCACCCGCCCAACAGAGAAACAGTACGAAACCCTGGAAAATCAGCT CGCGTTCCTGTGTCAGCAAGGCTTCTCCCTGGAGAACGCACTGTACGCTC TGTCCGCCGTGGGCCACTTTACACTGGGCTGCGTATTGGAGGAACAGGAG CATCAAGTAGCAAAAGAGGAAAGAGAGACACCTACCACCGATTCTATGCC CCCACTTCTGAGACAAGCAATTGAGCTGTTCGACCGGCAGGGAGCCGAAC CTGCCTTCCTTTTCGGCCTGGAACTAATCATATGTGGCCTGGAGAAACAG CTAAAGTGCGAAAGCGGCGGGCCGGCCGACGCCCTTGACGATTTTGACTT AGACATGCTCCCAGCCGATGCCCTTGACGACTTTGACCTTGATATGCTGC CTGCTGACGCTCTTGACGATTTTGACCTTGACATGCTCCCCGGGTTCGAA GCtGAgGGTCGGGGCTCTCTGCTCACATGTGGCGACGTCGAGGAGAATCC CGGACCGGCCCCgGGTGTACAAatggtgagcaagggcgaggagctgttca ccggggtggtgcccatcctggtcgagctggacggcgacgtaaacggccac aagttcagcgtgtccggcgagggcgagggcgatgccacctacggcaagct gaccctgaagttcatctgcaccaccggcaagctgcccgtgccctggccca ccctcgtgaccaccctgacctacggcgtgcagtgcttcagccgctacccc gaccacatgaagcagcacgacttcttcaagtccgccatgcccgaaggcta cgtccaggagcgcaccatcttcttcaaggacgacggcaactacaagaccc gcgccgaggtgaagttcgagggcgacaccctggtgaaccgcatcgagctg aagggcatcgacttcaaggaggacggcaacatcctggggcacaagctgga gtacaactacaacagccacaacgtctatatcatggccgacaagcagaaga acggcatcaaggtgaacttcaagatccgccacaacatcgaggacggcagc gtgcagctcgccgaccactaccagcagaacacccccatcggcgacggccc cgtgctgctgcccgacaaccactacctgagcacccagtccgccctgagca aagaccccaacgagaagcgcgatcacatggtcctgctggagttcgtgacc gccgccgggatcactctcggcatggacgagctgtacaagtaaACCGGTGC TAGCtaaTctagagTCGACAATCAACCTCATcgataccgagcgctgctcg agagatctacgggtggcatccctgtgacccctccccagtgcctctcctgg ccctggaagttgccactccagtgcccaccagccttgtcctaataaaatta agttgcatcattttgtctgactaggtgtccttctataatattatggggtg gaggggggtggtatggagcaaggggcaagttgggaagacaacctgtaggg cctgcggggtctattgggaaccaagctggagtgcagtggcacaatcttgg ctcactgcaatctccgcctcctgggttcaagcgattctcctgcctcagcc tcccgagttgttgggattccaggcatgcatgaccaggctcagctaatttt tgtttttttggtagagacggggtttcaccatattggccaggctggtctcc aactcctaatctcaggtgatctacccaccttggcctcccaaattgctggg attacaggcgtgaaccactgctcccttccctgtccttctgattttgtagg taaccacgtgcggaccgagcggccgcaggaacccctagtgatggagttgg ccactccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaag gtcgcccgacgcccgggctttgcccgggcggcctcagtgagcgagcgagc gcgcagctgcctgcaggggcgcctgatgcggtattttctccttacgcatc tgtgcggtatttcacaccgcatacgtcaaagcaaccatagtacgcgccct gtagcggcgcattaagcgcggcgggtgtggtggttacgcgcagcgtgacc gctacacttgccagcgccctagcgcccgctcctttcgctttcttcccttc ctttctcgccacgttcgccggctttccccgtcaagctctaaatcgggggc tccctttagggttccgatttagtgctttacggcacctcgaccccaaaaaa cttgatttgggtgatggttcacgtagtgggccatcgccctgatagacggt ttttcgccctttgacgttggagtccacgttctttaatagtggactcttgt tccaaactggaacaacactcaaccctatctcgggctattcttttgattta taagggattttgccgatttcggcctattggttaaaaaatgagctgattta acaaaaatttaacgcgaattttaacaaaatattaacgtttacaattttat ggtgcactctcagtacaatctgctctgatgccgcatagttaagccagccc cgacacccgccaacacccgctgacgcgccctgacgggcttgtctgctccc ggcatccgcttacagacaagctgtgaccgtctccgggagctgcatgtgtc agaggttttcaccgtcatcaccgaaacgcgcgagacgaaagggcctcgtg atacgcctatttttataggttaatgtcatgataataatggtttcttagac gtcaggtggcacttttcggggaaatgtgcgcggaacccctatttgtttat ttttctaaatacattcaaatatgtatccgctcatgagacaataaccctga taaatgcttcaataatattgaaaaaggaagagtatgagtattcaacattt ccgtgtcgcccttattcccttttttgcggcattttgccttcctgtttttg ctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggt gcacgagtgggttacatcgaactggatctcaacagcggtaagatccttga gagttttcgccccgaagaacgttttccaatgatgagcacttttaaagttc tgctatgtggcgcggtattatcccgtattgacgccgggcaagagcaactc ggtcgccgcatacactattctcagaatgacttggttgagtactcaccagt cacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtg ctgccataaccatgagtgataacactgcggccaacttacttctgacaacg atcggaggaccgaaggagctaaccgcttttttgcacaacatgggggatca tgtaactcgccttgatcgttgggaaccggagctgaatgaagccataccaa acgacgagcgtgacaccacgatgcctgtagcaatggcaacaacgttgcgc aaactattaactggcgaactacttactctagcttcccggcaacaattaat agactggatggaggcggataaagttgcaggaccacttctgcgctcggccc ttccggctggctggtttattgctgataaatctggagccggtgagcgtggg tctcgcggtatcattgcagcactggggccagatggtaagccctcccgtat cgtagttatctacacgacggggagtcaggcaactatggatgaacgaaata gacagatcgctgagataggtgcctcactgattaagcattggtaactgtca gaccaagtttactcatatatactttagattgatttaaaacttcattttta atttaaaaggatctaggtgaagatcctttttgataatctcatgaccaaaa tcccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaag atcaaaggatcttcttgagatcctttttttctgcgcgtaatctgctgctt gcaaacaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaag agctaccaactctttttccgaaggtaactggcttcagcagagcgcagata ccaaatactgtccttctagtgtagccgtagttaggccaccacttcaagaa ctctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtgg ctgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacga tagttaccggataaggcgcagcggtcgggctgaacggggggttcgtgcac acagcccagcttggagcgaacgacctacaccgaactgagatacctacagc gtgagctatgagaaagcgccacgcttcccgaagggagaaaggcggacagg tatccggtaagcggcagggtcggaacaggagagcgcacgagggagcttcc agggggaaacgcctggtatctttatagtcctgtcgggtttcgccacctct gacttgagcgtcgatttttgtgatgctcgtcaggggggcggagcctatgg aaaaacgccagcaacgcggcctttttacggttcctggccttttgctggcc ttttgctcacatgt