USE OF JAK INHIBITORS FOR THE TREATMENT OF PAINFUL CONDITIONS INVOLVING NAV1.7 CHANNELS

Abstract

An increasing body of evidence suggests that Nav1.7 encoded by SCN9A gene may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain. The inventors now report an efficient treatment for severe cases of primary erythromelagia linked to a specific SCN9A mutation. In particular the inventors demonstrated that the inhibition of JAK2 produces a rightward shift in the voltage dependent activation of mutant Nav1.7 channels, thereby normalizing the function of mutant Nav1.7 channels. On this basis, the inventors treated a patient suffering from PE with very severe refractory pain with a JAK2 inhibitor (ruxolitinib) and showed the therapy leads to considerable reduction of pain. Accordingly, the present invention relates to the use of JAK inhibitors for the treatment of painful conditions involving Nav1.7 channels.

Claims

1. A method of treating a painful condition involving Nav1.7 channels in a patient in need thereof comprising administering a therapeutically effective amount of a JAK inhibitor.

2. The method of claim 1 wherein the painful condition is a nociceptive pain, a neuropathic pain, an inflammatory pain, a pathological pain, an acute pain, a subacute pain, a chronic pain, mechanical pain, chemical pain, a somatic pain, a visceral pain, deep somatic pain, superficial somatic pain, somatoform pain, allodynia, hyperalgesia, or a pain associated with a nerve injury.

3. The method of claim 2 wherein the nociceptive pain includes visceral pain, deep somatic pain and superficial somatic pain.

4. The method of claim 1 wherein the painful condition is caused by a gain of function mutation in SCN9A.

5. The method of claim 7 the mutation is selected from the group consisting of Q10R, F216S, S241T, N395K, E406K, I859T, L869F, L869H, F1460V, A1643E and A1643T in SEQ ID NO: 1.

6. The method of claim 4 wherein the painful condition is primary erythermalgia.

7. The method of claim 1 wherein the JAK inhibitor is ruxolitinib.

8. The method of claim 1 wherein JAK inhibitor is a selective JAK2 inhibitor.

9. The method of claim 8 wherein the selective JAK2 inhibitor is selected from the group consisting of Fedratinib, Gandotinib, Lestaurtinib, and Pacritinib.

10. The method of claim 1 wherein the JAK inhibitor is administered to the patient in a form of a topical formulation.

Description

FIGURES

[0039] FIG. 1. AG490 normalizes the properties of I848T mutant Nav1.7 channels. Normalized conductance-voltage curves for WT mNav1.7 (open circles) and I848T mutants pretreated (blue symbols) or not (red symbols) with 10 μM AG490 (10 min). Curves were fitted by using a first-order Boltzmann relation. V.sub.1/2=−31.44±1 mV (I848T), −22.13±0.5 mV (WT), −26.32±0.6 mV (I848T+AG490). *P=0.032, I848T+AG490 vs. I848T; data shown as means±SEM (n=5−6). Inset: Nav1.7 currents were evoked by depolarizing pulses from −80 to 20 mV, while the cell was hold at −100 mV.

EXAMPLE

[0040] A number of studies on primary erythermalgia have elucidated a close relationship between gain of function of Nav1.7 and hyperexcitability of peripheral nociceptive neurons. To characterize the functional impact of the I848T mutation, mutant Nav1.7 cDNA was expressed in Human embryonic kidney (HEK) 293 cells, and Nav1.7 current was recorded using the whole-cell patch clamp technique (See Methods).

[0041] The current-voltage relationships of wild type and mutant I848T Nav1.7 channels were recorded. Cells were held at −100 mV and stepped to a range of potentials (−80 to 20 mV with 5 mV increment) for 50 ms to record the current amplitude that was induced at each voltage step (inset in FIG. 1). The current-voltage curve of I848T mutant showed that there is a hyperpolarizing shift in the voltage dependent activation for mutant channels with no apparent shift in reversal potential (not shown). To obtain activation curves, normalized conductance was fitted with Boltzmann equation, and the half maximal activation potential (V.sub.1/2) of each channel was calculated (FIG. 1). I848T mutant channels display a significant (P<0.05) hyperpolarizing shift in activation V.sub.1/2 (I848T: −31.44±1 mV, n=5) compared with wild type channels (WT: −22.13±0.5 mV, n=5). The slope factors of activation curves are similar. We examined the voltage dependence of I848T mutant channel activation in HEK cells pre-treated with AG490 (10 μM), a specific inhibitor of the Janus tyrosine kinase 2 (JAK2), for 10 min. AG490 induced a positive shift in the activation curve of mutant channels, giving a half-activation voltage of −26.32±0.6 mV (n=6).

[0042] Collectively, these results indicate that the inhibition of JAK2 by AG490 produces a rightward shift in the voltage dependent activation of mutant Nav1.7 channels, thereby normalizing the function of mutant Nav1.7 channels.

[0043] Thanks to these fundamental data, we decided to treat a patient suffering from PE with very severe refractory pain.

[0044] Our patient, a man in his 30s suffered from intractable pain in feet due to PE (gain of function mutation c.2543T>C in the SCN9A gene) leading to major impact on his general condition (malnutrition, depressive syndrome, insomnia, social isolation, severe skin lesion due to prolonged immersion in cold water or ice). He scored 6/10 on the “Douleur Neuropathique 4” (DN4) questionnaire and 9/10 on the Visual Analog Scale for pain (VAS). All conventional treatments had been tried (opioids, anti-epileptic and anti-depressants drugs, ketamine, mexiletine, calcium channel blockers, beta-blockers, clonidine, botulinum toxin, capsaicin plaster, methadone, etc. . . . ) with no efficacy. He described intense “pain attacks” during which he experienced pulsatile pain and felt “stabs”. During these painful episodes, edemas of the hands and feet are observed with redness and local warmth.

[0045] After one month of treatment with Ruxolitinib 10 mg t.i.d, VAS pain was evaluated at 0/10 most of the time with some seizures where the intensity of the pain reaches 2/10. We observed the disappearance of edemas during seizures as well as redness and local heat. Only persists, according to the patient a small area of redness next to the external malleoli.

[0046] In conclusion, this is the first report of an efficient treatment for severe cases of primary erythromelagia linked to a specific SCN9A mutation. We have the perspective to treat other adults patients but also children considering the potential severity since childhood with a real “no-life” for the patients and severe secondary complications (delay to growth, psychological and physical alteration, denutrition . . . ) related to pain. Our objective is also to have a better understanding of the modulation of the pain with JAK inhibitors, very useful for other painful conditions involving Na.sub.v1.7 channels

REFERENCES

[0047] Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. [0048] Dib-Hajj S D, Rush A M, Cummins T R, Hisama F M, Novella S, Tyrrell L, et al. (2005). Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain 128:1847-54. [0049] Hao J, Padilla F, Dandonneau M, Lavebratt C, Lesage F, Delmas, P. (2013). Kv1.1 channels act as mechanical brake in the senses of touch and pain. Neuron 77:899-914 [0050] Waxman S. and Dib-Hajj S D, (2005). Molecular basis for an inherited pain syndrome, Trends in Molecular Medicine, 11(12), 555-562. [0051] Friberg D, Chen T, Tarr G, van Rij A. Erythromelalgia? A clinical study of people who experience red, hot, painful feet in the community. International journal of vascular medicine. 2013; 2013:864961. [0052] Tang Z, Chen Z, Tang B, Jiang H. Primary erythromelalgia: a review. Orphanet journal of rare diseases. Sep. 30, 2015; 10:127. [0053] Skeik N, Rooke T W, Davis M D, et al. Severe case and literature review of primary erythromelalgia: novel SCN9A gene mutation. Vascular medicine (London, England). February 2012; 17(1):44-49. [0054] Bennett D L, Woods C G. Painful and painless channelopathies. The Lancet. Neurology. June 2014; 13(6):587-599. [0055] Herzog R I, Cummins T R, Waxman S G. Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. Journal of neurophysiology. September 2001; 86(3):1351-1364. [0056] Dib-Hajj S D, Yang Y, Black J A, Waxman S G. The Na(V)1.7 sodium channel: from molecule to man. Nature reviews. Neuroscience. January 2013; 14(1):49-62. [0057] Dib-Hajj S D, Cummins T R, Black J A, Waxman S G. From genes to pain: Na v 1.7 and human pain disorders. Trends in neurosciences. November 2007; 30(11):555-563.