Methods for Treating and Preventing Multiple Sclerosis

Abstract

We have discovered that LRG-47 (also called p47 GTPase), plays a central role in the pathogenesis of multiple sclerosis, and that inhibition of LRG-47 activity by anti-LRG-47 antibodies or of LRG-47 expression by siRNA dramatically reduce the pathology and symptoms of multiple sclerosis. Certain embodiments of the invention are directed to the therapeutic use of anti-LRG-47 antibodies (mouse or rabbit or other antibodies that are humanized or human antibodies to LRG-47, preferably antibodies made against human LRG-47) or siRNA or antisense nucleotides that specifically hybridize with the gene or mRNA or cDNA encoding human LRG-47 to treat or prevent multiple sclerosis and other autoimmune diseases that are T-cell-mediated. Other embodiments are directed to methods for the diagnosis of multiple sclerosis or to determining the aggressiveness of multiple sclerosis by determining the amount of human LRG-47 or LRG-47 mRNA in a biological sample from the patient.

1 .- 25 . (canceled) 
     
     
         26 . A method for treating or preventing multiple sclerosis in a patient, comprising administering a therapeutically effective amount of an isolated anti-LRG-47 antibody or biologically active fragment or variant thereof or a compound that reduces LRG-47 expression. 
     
     
         27 . The method of  claim 26 , wherein the isolated antibody is polyclonal anti-human LRG-47 antibody 138AB or a biologically active fragment or variant thereof. 
     
     
         28 . The method of  claim 26 , wherein the isolated anti-LRG-47 antibody is a humanized antibody selected from the group comprising LRG-47 (A-19) antibody, LRG-47 (M-95) antibody, LRG-47 (M-16) antibody, and LRG-47 (P-20) antibody, or biologically active fragment or variant thereof. 
     
     
         29 . The method of  claim 26 , wherein the isolated antibody is a monoclonal, polyclonal, chimeric, humanized or bispecific antibody. 
     
     
         30 . The method of  claim 26 , wherein the compound that reduces LRG-47 expression is an antisense nucleic acid or siRNA. 
     
     
         31 . The method of  claim 30 , wherein the antisense nucleic acid is sufficiently complementary to the human gene or mRNA encoding LRG-47 to hybridize to it thereby reducing expression of LRG-47. 
     
     
         32 . The method of  claim 31 , wherein the human gene encoding LRG-47 is identified by SEQ ID NO: 1. 
     
     
         33 . The method of  claim 30 , wherein the siRNA comprises SEQ ID NOs: 5 and 6. 
     
     
         34 . A method for treating or preventing multiple sclerosis in a patient, comprising:
 a. determining a pre-treatment level of human LRG-47 protein in a pre-treatment biological sample taken from the patient,   b. administering an amount of a compound that reduces human LRG-47 expression levels in patient cells,   c. determining a post-treatment level of human LRG-47 protein in a post-treatment biological sample taken from the patient,   d. comparing the pre-treatment and post-treatment levels of LRG-47 protein in the respective biological samples, and   e. determining that treatment is effective if the post-treatment level of human LRG-47 is significantly lower than the pre-treatment level.   
     
     
         35 . The method of  claim 34 , further comprising:
 f. if the difference between the pre-treatment and post-treatment levels of human LRG-47 is not significantly different, then increasing the amount or frequency of administration of the compound until the post-treatment level of human LRG-47 is significantly lower than the pre-treatment level.   
     
     
         36 . The method of  claim 34 , wherein the compound is an antisense nucleic acid or siRNA. 
     
     
         37 . The method of  claim 36 , wherein the antisense nucleic acid is sufficiently complementary to the human gene or mRNA encoding LRG-47 to hybridize to it thereby reducing expression of the LRG-47 protein. 
     
     
         38 . The method of  claim 37 , wherein the human gene encoding LRG-47 is identified by SEQ ID NO: 1. 
     
     
         39 . The method of  claim 34 , wherein the siRNA comprises SEQ ID NOs: 5 and 6. 
     
     
         40 . The method of  claim 34 , wherein the biological sample is a member selected from the group comprising a nerve sample, serum, blood, plasma, cerebral spinal fluid, fibroblasts, leukocytes, skin, and urine. 
     
     
         41 . The anti-human LRG-47 antibody 138AB or a biologically active fragment or variant thereof. 
     
     
         42 . A pharmaceutical composition comprising an isolated anti-LRG-47 antibody that is a member selected from the group comprising the anti-human LRG-47 antibody 138AB, humanized LRG-47 (A-19) antibody, humanized LRG-47 (M-95) antibody, humanized LRG-47 (M-16) antibody, and humanized LRG-47 (P-20) antibody or a biologically active fragment or variant thereof. 
     
     
         43 . A method for diagnosing a patient who is at risk of developing multiple sclerosis, comprising
 a. determining the level of human LRG-47 protein in a biological sample taken from the patient and in a corresponding sample taken from a control subject that is not affected with multiple sclerosis,   b. comparing the level of human LRG-47 protein in the biological samples and forming a diagnosis that the patient is at risk of developing multiple sclerosis if the level of human LRG-47 protein in the patient sample is significantly higher than the level of human LRG-47 protein in the control sample.   
     
     
         44 . The method of  claim 43 , further comprising the step of
 c. determining that the patient has multiple sclerosis if the patient shows other objective or subjective indicia of multiple sclerosis.   
     
     
         45 . The method as in  claim 43 , wherein the biological sample is a member selected from the group comprising a nerve sample, serum, blood, plasma, cerebral spinal fluid, fibroblasts, leukocytes, skin, and urine. 
     
     
         46 . The method as in  claim 45 , wherein the biological sample is a member selected from the group comprising a nerve sample, serum, blood, plasma, cerebral spinal fluid, fibroblasts, leukocytes, skin, and urine. 
     
     
         47 . The method as in  claim 42 , wherein the anti-human LRG-47 antibody 138AB is humanized.