METHODS FOR DETERMINING WHETHER A PATIENT IS LIKELY TO BENEFIT FROM TREATMENT WITH A THERAPEUTIC FORMULATION

Abstract

The present invention relates to a method for determining whether a patient is likely to benefit from treatment with a therapeutic formulation, the method comprising the steps of: (a) determining the concentration of corticotropin releasing hormone (CRH) in a sample from a patient prior to administration of the therapeutic formulation; (b) determining the concentration of CRH in a sample from a patient subsequent to administration of the therapeutic formulation; and (c) comparing the concentration of CRH pre-administration with the concentration of CRH subsequent to administration; wherein an increase in patient CRH concentration subsequent to administration indicates that the patient is likely to benefit from treatment with the therapeutic formulation and wherein no increase or a decrease in patient CRH concentration subsequent to administration indicates that the patient is unlikely to benefit from treatment with the therapeutic formulation. The patient may have multiple sclerosis or systemic sclerosis. The therapeutic formulation may be derived from an ungulate such as a goat and may contain CRH, CRH-binding protein, pro-opiomelanocortin (POMC) and alpha-2 macroglobulin. Also provided are methods of treating a patient with a disorder such as multiple sclerosis or systemic sclerosis.

Claims

1. A method for determining whether a patient is likely to benefit from treatment with a therapeutic formulation, the method comprising the steps of: (a) determining the concentration of corticotropin releasing hormone (CRH) in a sample from a patient prior to administration of the therapeutic formulation; (b) determining the concentration of CRH in a sample from a patient subsequent to administration of the therapeutic formulation; and (c) comparing the concentration of CRH pre-administration with the concentration of CRH subsequent to administration; wherein an increase in patient CRH concentration subsequent to administration indicates that the patient is likely to benefit from treatment with the therapeutic formulation and wherein no increase or a decrease in patient CRH concentration subsequent to administration indicates that the patient is unlikely to benefit from treatment with the therapeutic formulation; wherein the therapeutic formulation comprises CRH.

2. The method according to claim 1, wherein step (b) is carried out within four hours of administration of the therapeutic formulation.

3. The method according to claim 1 or 2, wherein the therapeutic formulation is derived from an ungulate.

4. The method according to any one of the preceding claims, wherein the therapeutic formulation is derived from a goat.

5. The method according to any one of the preceding claims, wherein the therapeutic formulation is derived from a hyperimmune serum.

6. The method according to any one of the preceding claims, further comprising determining the concentration of PIIINP and/or IL-17 in a sample from a patient and comparing the concentration thereof pre-administration with the concentration thereof subsequent to administration, wherein an increase in said concentration subsequent to administration indicates that the patient is likely to benefit from treatment with the therapeutic formulation and wherein no increase or a decrease in said concentration subsequent to administration indicates that the patient is unlikely to benefit from treatment with the therapeutic formulation.

7. The method according to any one of the preceding claims, wherein the patient has multiple sclerosis.

8. The method according to claim 7 when dependent upon claim 6, wherein the method comprises measuring the concentration of CRH and IL-17 only.

9. The method according to any one of the preceding claims, wherein the patient has systemic sclerosis.

10. The method according to claim 9 when dependent upon claim 6, wherein the method comprises measuring the concentration of CRH and PIIINP only.

11. The method according to any one of the preceding claims, wherein the patient has one or more of the disorders selected from the following list: an inflammatory disorder such as rheumatoid arthritis; optic neuritis; motor neuron disease; autoimmune diseases; axonal or nerve damage; and cancers (including myelomas, melanomas and lymphomas); cardiovascular diseases; neural disorders, both demyelinating and non-demyelinating; cerebrovascular ischemic disease; Alzheimer's disease; Parkinson's disease; Huntingdon's chorea; mixed connective tissue diseases; scleroderma; anaphylaxis; septic shock; carditis and endocarditis; wound healing; contact dermatitis; occupational lung diseases; glomerulonephritis; transplant rejection; temporal arteritis; vasculitic diseases; hepatitis (in particular hepatitis C); burns; multiple system atrophy; epilepsy; muscular dystrophy; schizophrenia; bipolar disorder; depression; channelopathies; myasthenia gravis; pain due to malignant neoplasia; chronic fatigue syndrome; fibromyositis; irritable bowel syndrome; work related upper limb disorder; cluster headache; migraine; chronic daily headache; infections of the nervous system; nerve entrapment and focal injury; traumatic spinal cord injury; brachial plexopathy (idiopathic and traumatic, brachial neuritis, parsonage turner syndrome, neuralgic amyotrophy); radiculopathy; channelopathies; tic douloureux; lupus; psoriasis; eczema; thyroiditis; polymysotis; hereditary motor and sensor neuropathy of all types; Charcot-Marie-Tooth disease (CMT) types CMT1A, CMT1B, CMT2, CMT3 (Dejerine Sottas disease), CMT4 (Types A, B, C and D), X-linked Charcot-Marie-Tooth disease (CMTX); Hereditary Neuropathy with liability to pressure palsies (HNPP), also called Tomaculous neuropathy; Hereditary Motor and Sensory Neuropathy with Deafness-Lom (HMSNL); Proximal Hereditary Motor and Sensory Neuropathy/Neuronopathy (HMSNP); Hereditary Neuralgic Amyotrophy; Hereditary Sensory and Autonomic Neuropathies (HSAN1, HSAN2, HSAN3 (also called Riley-Day syndrome or familial dysautonomia), HSAN4, HSAN5); Familial Amyloid polyneuropathies (Type I, Type II, Type III, Type IV); Metachromatic Leukodystrophy; Krabbe's Disease; Fabry's Disease; Adrenoleukodystrophy; Refsum's disease (HMSN IV); Tangier Disease; Friedreich's ataxia; Spinal cerebellar ataxia (SCA) all typesSCA1, SCA2, SCA3, SCA4, SCA5, SCA6, SCA7, SCA8, SCA10, SCA11, SCA12, SCA13, SCA14, SCA16; Spinocerebellar Ataxia; Cockayne's syndrome; Giant axonal neuropathy; chronic inflammatory demyelinating polyneuropathy (CIDP); and Guillain-Barre syndrome.

12. The method according to any one of the preceding claims, wherein the patient is a non-ungulate and the therapeutic formulation contains an ungulate CRH.

13. The method according to any one of the preceding claims, wherein the patient is a human and the therapeutic formulation contains a non-human CRH.

14. The method according to claim 13, wherein the non-human CRH is an ungulate CRH.

15. A method of treating a patient having a disorder, the method comprising: i. obtaining the results of the method according to any one of the preceding claims; and ii. administering the therapeutic formulation to said patient when it is indicated that the patient is likely to benefit from treatment with said therapeutic formulation.

16. The method according to claim 15, wherein the disorder is one or more selected from the group consisting of: an inflammatory disorder such as rheumatoid arthritis; optic neuritis; motor neuron disease; autoimmune diseases; axonal or nerve damage; and cancers (including myelomas, melanomas and lymphomas); cardiovascular diseases; neural disorders, both demyelinating and non-demyelinating; cerebrovascular ischemic disease; Alzheimer's disease; Parkinson's disease; Huntingdon's chorea; mixed connective tissue diseases; scleroderma; anaphylaxis; septic shock; carditis and endocarditis; wound healing; contact dermatitis; occupational lung diseases; glomerulonephritis; transplant rejection; temporal arteritis; vasculitic diseases; hepatitis (in particular hepatitis C); burns; multiple system atrophy; epilepsy; muscular dystrophy; schizophrenia; bipolar disorder; depression; channelopathies; myasthenia gravis; pain due to malignant neoplasia; chronic fatigue syndrome; fibromyositis; irritable bowel syndrome; work related upper limb disorder; cluster headache; migraine; chronic daily headache; infections of the nervous system; nerve entrapment and focal injury; traumatic spinal cord injury; brachial plexopathy (idiopathic and traumatic, brachial neuritis, parsonage turner syndrome, neuralgic amyotrophy); radiculopathy; channelopathies; tic douloureux; lupus; psoriasis; eczema; thyroiditis; polymysotis; hereditary motor and sensor neuropathy of all types; Charcot-Marie-Tooth disease (CMT) types CMT1A, CMT1B, CMT2, CMT3 (Dejerine Sottas disease), CMT4 (Types A, B, C and D), X-linked Charcot-Marie-Tooth disease (CMTX); Hereditary Neuropathy with liability to pressure palsies (HNPP), also called Tomaculous neuropathy; Hereditary Motor and Sensory Neuropathy with Deafness-Lom (HMSNL); Proximal Hereditary Motor and Sensory Neuropathy/Neuronopathy (HMSNP); Hereditary Neuralgic Amyotrophy; Hereditary Sensory and Autonomic Neuropathies (HSAN1, HSAN2, HSAN3 (also called Riley-Day syndrome or familial dysautonomia), HSAN4, HSAN5); Familial Amyloid polyneuropathies (Type I, Type II, Type III, Type IV); Metachromatic Leukodystrophy; Krabbe's Disease; Fabry's Disease; Adrenoleukodystrophy; Refsum's disease (HMSN IV); Tangier Disease; Friedreich's ataxia; Spinal cerebellar ataxia (SCA) all typesSCA1, SCA2, SCA3, SCA4, SCA5, SCA6, SCA7, SCA8, SCA10, SCA11, SCA12, SCA13, SCA14, SCA16; Spinocerebellar Ataxia; Cockayne's syndrome; Giant axonal neuropathy; chronic inflammatory demyelinating polyneuropathy (CIDP); and Guillain-Barre syndrome.

17. The method according to claim 15 or 16, wherein the disorder is multiple sclerosis or systemic sclerosis.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0069] The present invention will now be described by way of example only with reference to the accompanying drawings, in which:

[0070] FIG. 1 shows the difference in mean CRH concentration within a patient group both before (CRH pre) and 4 hours after (CRH post) administration of a CRH formulation;

[0071] FIG. 2 shows the difference in mean scores of the 9-Hole Peg Test (9-HPT) within a patient group having multiple sclerosis both before (9 hole Peg pre) and 4 hours after (9 hole Peg post) administration of the CRH formulation;

[0072] FIG. 3 shows the difference in mean scores of the 9-HPT within a second patient group having multiple sclerosis both before (9-HPT pre_placebo) and 4 hours after (9-HPT post_placebo) administration of a placebo;

[0073] FIG. 4 shows the difference in mean scores of the Multiple Sclerosis Functional Composite (MSFC) within the patient group having multiple sclerosis both before (MSFC pre) and 4 hours after (MSFC post) administration of the CRH formulation;

[0074] FIG. 5 shows the difference in mean scores of the MSFC within the second patient group having multiple sclerosis both before (MSFC pre placebo) and 4 hours after (MSFC post placebo) administration of the placebo;

[0075] FIG. 6 shows the difference in Mean Rodnan Skin Score (MRSS) within a patient group having systemic sclerosis both before (MRSS CRH pre) and 4 hours after (M RSS CRH post) administration of the CRH formulation;

[0076] FIG. 7 shows the difference in MRSS within a patient group having systemic sclerosis both before (MRSS placebo pre) and 4 hours after (MRSS placebo post) administration of the placebo;

[0077] FIG. 8 shows the relationship between the change in CRH concentration 4 hours after administration of the CRH formulation (x-axis) and the difference in MRSS clinical score (y-axis) within a patient group having systemic sclerosis;

[0078] FIG. 9 shows the relationship between the change in IL-17 concentration 4 hours after administration of the CRH formulation (x-axis) and the difference in MSFC clinical score (y-axis) within a patient group having multiple sclerosis; and

[0079] FIG. 10 shows the relationship between the change in PIIINP concentration 4 hours after administration of the CRH formulation (x-axis) and the difference in MRSS clinical score (y-axis) within a patient group having systemic sclerosis.

EXAMPLES

[0080] Materials & Methods

[0081] The tests (MSFC and 9-HPT) carried out herein on patients diagnosed with multiple sclerosis are described in detail in Fischer et al, Mult. Scler. (1999), 5: 244; and in Fischer et al (2001), MSFC Administration and Scoring Manual, National Multiple Sclerosis Society; both of which are incorporated in their entirety by reference thereto.

[0082] The MRSS test carried out herein on patients diagnosed with systemic sclerosis is a widely-used 17-site skin assessment described by Furst et al, J. Rheumatol. (1998), January; 25(1): 84-88; incorporated in its entirety by reference thereto.

[0083] CRH concentration was measured throughout using the CRF EIA Kit from Phoenix Pharmaceuticals, Inc. (Catalog # EK-019-06). The complete protocol is provided with the kit and is described in detail in Kodomari et al, Neurochem Int. (2009), March-April; 54(3-4):222-8; Wang et al, PLoS One (2008), October 3; 3(10):e3320; Ng et al, Neonatology (2008), 94(3):170-5; Moeser et al, Am J Physiol Gastrointest Liver Physiol. (2007), August; 293(2):G413-21; all of which are incorporated in their entirety by reference thereto.

Example 1

Patient CRH Concentration Increases Following Administration of the CRH Formulation

[0084] A group of 35 patients was tested to establish their CRH concentration and subsequently administered 1 ml of the above-described CRH formulation by subcutaneous injection. Four hours after administration of the CRH formulation, the patients' CRH concentration was tested again.

[0085] The mean results for the pre- and post-administration CRH data are shown in FIG. 1. A paired T-test (data not shown) established (P=0.004) that the mean CRH concentration pre-administration is significantly less than the mean CRH concentration post-administration.

[0086] A test on a further (control) group of patients established (data not shown) that there is no significant increase in CRH concentration following administration of a placebo.

Example 2

[0087] Administration of the CRH Formulation Leads to a Significant Improvement in Patients with Multiple Sclerosis

[0088] Following administration of the CRH formulation, the patient group and the control group were tested using the 9 Hole Peg Test (9-HPT) and the Multiple Sclerosis Functional Composite (MSFC) test. These tests were carried out both prior to administration and four hours after administration of the CRH formulation or the placebo, as appropriate.

[0089] The mean results of the 9-HPT for the patient group administered the CRH formulation are shown in FIG. 2. It was established (P=0.48, data not shown) that the data results follow a normal distribution. A paired T-test (data not shown) established (P=0.013) that there is a significant improvement in test results for the 9-HPT following administration of the CRH formulation.

[0090] The mean results of the 9-HPT for the control group are shown in FIG. 3. A paired T-test (data not shown) established (P=0.09) that there is no significant difference in test results for the 9-HPT following administration of the placebo.

[0091] The mean results of the MSFC test for the patient group administered the CRH formulation are shown in FIG. 4. A paired T-test (data not shown) established (P=0.045) that there is a significant improvement in test results for the MSFC test following administration of the CRH formulation.

[0092] The mean results of the MSFC test for the control group are shown in FIG. 5. A paired T-test (data not shown) established (P=0.461) that there is no significant difference in test results for the MSFC test following administration of the placebo.

Example 3

[0093] Administration of the CRH Formulation Leads to a Significant Improvement in Patients with Systemic Sclerosis

[0094] A further group of subjects suffering from systemic sclerosis was divided into a patient group to be administered the CRH formulation and a control group to be administered a placebo.

[0095] An MRSS assessment was carried out on both groups prior to administration. A further MRSS assessment was carried out on both groups 4 hours after administration.

[0096] The mean results of the MRSS assessment for the patient group administered the CRH formulation are shown in FIG. 6. It was established (data not shown) that the results follow a normal distribution (P=0.754). A paired T-test (data not shown) established (P=0.034) that there is a significant improvement in test results for the MRSS assessment following administration of the CRH formulation.

[0097] The mean results of the MRSS assessment for the control group are shown in FIG. 7. A paired T-test (data not shown) established (P=0.837) that there is no significant improvement in test results for the MRSS assessment following administration of the placebo.

Example 4

[0098] Increase in CRH Following Administration of the CRH Formulation Correlates with an Improvement in Patients

[0099] The data provided above show that there is an increase in CRH and that there is an improvement in patient test results following administration of the CRH formulation. It was investigated whether the two results are significantly correlated.

[0100] The relative increase in CRH concentration pre- and post-administration of the CRH formulation was plotted against the relative improvement in MSFC scores pre- and post-administration of the CRH formulation. An Analysis of Variance (ANOVA) test established (data not shown) that there is a significant (P=0.005) relationship between the increase in CRH concentration and the improvement in MSFC.

[0101] The relative increase in CRH concentration pre- and post-administration of the CRH formulation was plotted against the relative improvement in MRSS scores pre- and post-administration of the CRH formulation. The results are shown in FIG. 8.

[0102] An Analysis of Variance (ANOVA) test established (data not shown) that there is a significant (P=0.03) relationship between the increase in CRH concentration and the improvement in MRSS.

Example 5

Administration of the CRH Formulation Leads to an Increase in Concentration of Other Biomarkers

[0103] The above patient groups were also tested for their concentration of IL-17 and PIINP both pre- and post-administration of the CRH formulation. The relative change in concentration of these biomarkers was compared with the relative improvement in the MSFC test (for IL-17) and MRSS assessment (for PIIINP).

[0104] The relative increase in IL-17 concentration pre- and post-administration of the CRH formulation was plotted against the relative improvement in MSFC scores pre- and post-administration of the CRH formulation. The results are shown in FIG. 9.

[0105] An Analysis of Variance (ANOVA) test established (data not shown) that there is a significant (P=0.008) relationship between the increase in IL-17 concentration and the improvement in MSFC.

[0106] The relative increase in PIINP concentration pre- and post-administration of the CRH formulation was plotted against the relative improvement in MRSS scores pre- and post-administration of the CRH formulation. The results are shown in FIG. 10.

[0107] An Analysis of Variance (ANOVA) test established (data not shown) that there is a significant (P=0.023) relationship between the increase in PIIINP concentration and the improvement in MRSS.

CLAUSES

[0108] 1. A method for determining whether a patient is likely to benefit from treatment with CRH, the method comprising the steps of: [0109] (a) determining the concentration of CRH in a sample from a patient prior to administration of a formulation containing CRH; [0110] (b) determining the concentration of CRH in a sample from a patient subsequent to administration of a formulation containing CRH; and [0111] (c) comparing the concentration of CRH pre-administration with the concentration of CRH subsequent to administration; [0112] wherein an increase in patient CRH concentration subsequent to administration indicates that the patient is likely to benefit from treatment with CRH and wherein no increase or a decrease in patient CRH concentration subsequent to administration indicates that the patient is unlikely to benefit from treatment with CRH. [0113] 2. The method according to clause 1, wherein step (b) is carried out within four hours of administration of the formulation containing CRH. [0114] 3. The method according to clause 1 or 2, wherein the formulation containing CRH is derived from an ungulate. [0115] 4. The method according to any one of the preceding clauses, wherein the formulation containing CRH is derived from a goat. [0116] 5. The method according to any one of the preceding clauses, wherein the formulation containing CRH is derived from a hyperimmune serum. [0117] 6. The method according to any one of the preceding clauses, further comprising determining the concentration of PIIINP and/or IL-17 in a sample from a patient and comparing the concentration thereof pre-administration with the concentration thereof subsequent to administration, wherein an increase in said concentration subsequent to administration indicates that the patient is likely to benefit from treatment with CRH and wherein no increase or a decrease in said concentration subsequent to administration indicates that the patient is unlikely to benefit from treatment with CRH. [0118] 7. The method according to any one of the preceding clauses, wherein the patient has multiple sclerosis. [0119] 8. The method according to clause 7 when dependent upon clause 6, wherein the method comprises measuring the concentration of CRH and IL-17 only. [0120] 9. The method according to any one of the preceding clauses, wherein the patient has systemic sclerosis. [0121] 10. The method according to clause 9 when dependent upon clause 6, wherein the method comprises measuring the concentration of CRH and PIIINP only. [0122] 11. The method according to any one of the preceding clauses, wherein the patient has one or more of the conditions selected from the following list: an inflammatory disorder such as rheumatoid arthritis; optic neuritis; motor neuron disease; autoimmune diseases; axonal or nerve damage; and cancers (including myelomas, melanomas and lymphomas); cardiovascular diseases; neural disorders, both demyelinating and non-demyelinating; cerebrovascular ischemic disease; Alzheimer's disease; Parkinson's disease; Huntingdon's chorea; mixed connective tissue diseases; scleroderma; anaphylaxis; septic shock; carditis and endocarditis; wound healing; contact dermatitis; occupational lung diseases; glomerulonephritis; transplant rejection; temporal arteritis; vasculitic diseases; hepatitis (in particular hepatitis C); burns; multiple system atrophy; epilepsy; muscular dystrophy; schizophrenia; bipolar disorder; depression; channelopathies; myasthenia gravis; pain due to malignant neoplasia; chronic fatigue syndrome; fibromyositis; irritable bowel syndrome; work related upper limb disorder; cluster headache; migraine; chronic daily headache; infections of the nervous system; nerve entrapment and focal injury; traumatic spinal cord injury; brachial plexopathy (idiopathic and traumatic, brachial neuritis, parsonage turner syndrome, neuralgic amyotrophy); radiculopathy; channelopathies; tic douloureux; lupus; psoriasis; eczema; thyroiditis; polymysotis; hereditary motor and sensor neuropathy of all types; Charcot-Marie-Tooth disease (CMT) types CMT1A, CMT1B, CMT2, CMT3 (Dejerine Sottas disease), CMT4 (Types A, B, C and D), X-linked Charcot-Marie-Tooth disease (CMTX); Hereditary Neuropathy with liability to pressure palsies (HNPP), also called Tomaculous neuropathy; Hereditary Motor and Sensory Neuropathy with Deafness-Lom (HMSNL); Proximal Hereditary Motor and Sensory Neuropathy/Neuronopathy (HMSNP); Hereditary Neuralgic Amyotrophy; Hereditary Sensory and Autonomic Neuropathies (HSAN1, HSAN2, HSAN3 (also called Riley-Day syndrome or familial dysautonomia), HSAN4, HSAN5); Familial Amyloid polyneuropathies (Type I, Type II, Type III, Type IV); Metachromatic Leukodystrophy; Krabbe's Disease; Fabry's Disease; Adrenoleukodystrophy; Refsum's disease (HMSN IV); Tangier Disease; Friedreich's ataxia; Spinal cerebellar ataxia (SCA) all typesSCA1, SCA2, SCA3, SCA4, SCA5, SCA6, SCA7, SCAB, SCA10, SCA11, SCA12, SCA13, SCA14, SCA16, Spinocerebellar Ataxia; Cockayne's syndrome; Giant axonal neuropathy; chronic inflammatory demyelinating polyneuropathy (CIDP); and Guillain-Barre syndrome. [0123] 12. The method according to any one of the preceding clauses, wherein the patient is a non-ungulate and the formulation contains an ungulate CRH. [0124] 13. The method according to any one of the preceding clauses, wherein the patient is a human and the formulation contains a non-human CRH. [0125] 14. The method according to clause 13, wherein the non-human CRH is an ungulate CRH. [0126] 15. A method of treating a patient having a disease, the method comprising: [0127] (a) obtaining the results of the method according to any one of the preceding clauses; and [0128] (b) administering a formulation containing CRH to said patient when it is indicated that the patient is likely to benefit from treatment with CRH. [0129] 16. The method according to clause 15, wherein the disease is one or more selected from the group consisting of: an inflammatory disorder such as rheumatoid arthritis; optic neuritis; motor neuron disease; autoimmune diseases; axonal or nerve damage; and cancers (including myelomas, melanomas and lymphomas); cardiovascular diseases; neural disorders, both demyelinating and non-demyelinating; cerebrovascular ischemic disease; Alzheimer's disease; Parkinson's disease; Huntingdon's chorea; mixed connective tissue diseases; scleroderma; anaphylaxis; septic shock; carditis and endocarditis; wound healing; contact dermatitis; occupational lung diseases; glomerulonephritis; transplant rejection; temporal arteritis; vasculitic diseases; hepatitis (in particular hepatitis C); burns; multiple system atrophy; epilepsy; muscular dystrophy; schizophrenia; bipolar disorder; depression; channelopathies; myasthenia gravis; pain due to malignant neoplasia; chronic fatigue syndrome; fibromyositis; irritable bowel syndrome; work related upper limb disorder; cluster headache; migraine; chronic daily headache; infections of the nervous system; nerve entrapment and focal injury; traumatic spinal cord injury; brachial plexopathy (idiopathic and traumatic, brachial neuritis, parsonage turner syndrome, neuralgic amyotrophy); radiculopathy; channelopathies; tic douloureux; lupus; psoriasis; eczema; thyroiditis; polymysotis; hereditary motor and sensor neuropathy of all types; Charcot-Marie-Tooth disease (CMT) types CMT1A, CMT1B, CMT2, CMT3 (Dejerine Sottas disease), CMT4 (Types A, B, C and D), X-linked Charcot-Marie-Tooth disease (CMTX); Hereditary Neuropathy with liability to pressure palsies (HNPP), also called Tomaculous neuropathy; Hereditary Motor and Sensory Neuropathy with Deafness-Lom (HMSNL); Proximal Hereditary Motor and Sensory Neuropathy/Neuronopathy (HMSNP); Hereditary Neuralgic Amyotrophy; Hereditary Sensory and Autonomic Neuropathies (HSAN1, HSAN2, HSAN3 (also called Riley-Day syndrome or familial dysautonomia), HSAN4, HSAN5); Familial Amyloid polyneuropathies (Type I, Type II, Type III, Type IV); Metachromatic Leukodystrophy; Krabbe's Disease; Fabry's Disease; Adrenoleukodystrophy; Refsum's disease (HMSN IV); Tangier Disease; Friedreich's ataxia; Spinal cerebellar ataxia (SCA) all typesSCA1, SCA2, SCA3, SCA4, SCA5, SCA6, SCA7, SCA8, SCA10, SCA11, SCA12, SCA13, SCA14, SCA16, Spinocerebellar Ataxia; Cockayne's syndrome; Giant axonal neuropathy; chronic inflammatory demyelinating polyneuropathy (CIDP); and Guillain-Barre syndrome. [0130] 17. The method according to clause 15 or 16, wherein the disease is multiple sclerosis or systemic sclerosis.

[0131] All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in biochemistry and biotechnology or related fields are intended to be within the scope of the following claims.