Methods of predicting clinical course and treating multiple sclerosis

Abstract

Provided are methods and kits for classifying a subject as being more likely to have benign multiple sclerosis (BMS) or as being more likely to have typical relapsing remitting multiple sclerosis (RRMS). Classification of multiple sclerosis disease course is performed by comparing a level of expression of at least one gene involved in the RNA polymerase I pathway in a cell of the subject to a reference expression data of said at least one gene obtained from a cell of at least one subject pre-diagnosed as having BMS and/or from a cell of at least one subject pre-diagnosed as having typical RRMS, thereby classifying the subject as being more likely to have BMS or as being more likely to have typical RRMS. Also provided are methods of diagnosing and treating multiple sclerosis and methods of monitoring treatment efficiency.

1 . A method of classifying a subject as being more likely to have benign multiple sclerosis (BMS) or as being more likely to have typical relapsing remitting multiple sclerosis (RRMS), the method comprising comparing a level of expression of at least one gene involved in the RNA polymerase I pathway in a cell of the subject to a reference expression data of said at least one gene obtained from a cell of at least one subject pre-diagnosed as having BMS and/or from a cell of at least one subject pre-diagnosed as having typical RRMS, thereby classifying the subject as being more likely to have BMS or as being more likely to have typical RRMS. 
     
     
         2 . A method of diagnosing a subject pre-diagnosed with multiple sclerosis (MS) as having benign multiple sclerosis (BMS) or typical relapsing remitting multiple sclerosis (RRMS), the method comprising:
 (a) classifying the subject as being more likely to have BMS or as being more likely to have typical RRMS according to the method of  claim 1 ,   (i) wherein when the subject is classified as being more likely to have said BMS then the subject is diagnosed as having BMS;   (ii) wherein when the subject is classified as being more likely to have said typical RRMS, then the subject is diagnosed as having typical RRMS; and   (c) informing the subject of the diagnosis,   thereby diagnosing the subject pre-diagnosed with the MS as having the BMS or the typical RRMS.   
     
     
         3 . A method of monitoring an efficiency of an anti multiple sclerosis (MS) drug in treating a subject diagnosed with a typical relapsing remitting multiple sclerosis (RRMS) course, the method comprising:
 (a) treating the subject with the anti MS drug; and   (b) comparing a level of expression of least one gene involved in the RNA polymerase I pathway in a cell of the subject following said treating with the anti MS drug to a level of expression of said at least one gene in a cell of the subject prior to said treating the subject with the anti MS drug,   (i) wherein a decrease above a predetermined threshold in said level of expression of said at least one gene following said treating with the anti MS drug relative to said level of expression of said at least one gene prior to said treating with the anti MS drug indicates that the anti MS drug is efficient for treating the subject;   (ii) wherein an increase above a predetermined threshold in said level of expression of said at least one gene following said treating with the anti MS drug relative to said level of expression of said at least one gene prior to said treating with the anti MS drug indicates that the anti MS drug is not efficient for treating the subject; or   (iii) wherein when a level of expression of said at least one gene following said treating with the anti MS drug is identical or changed below a predetermined threshold as compared to prior to said treating with the anti MS drug then the treatment is not efficient for treating the subject   thereby monitoring the efficiency of the anti multiple sclerosis (MS) drug in treating the subject diagnosed with the typical RRMS course.   
     
     
         4 . An in vitro method of predicting an efficiency of an anti multiple sclerosis (MS) drug for treatment of a subject diagnosed with a typical relapsing remitting multiple sclerosis (RRMS), the method comprising:
 (a) contacting cells of the subject with a therapeutically effective amount of the anti MS drug; and   (b) comparing a level of expression in said cells of at least one gene involved in the RNA polymerase I pathway following said contacting with the anti MS drug to a level of expression of said at least one gene in said cells prior to said contacting with the anti MS drug,   (i) wherein a decrease above a predetermined threshold in said level of expression of said at least one gene following said contacting with the anti MS drug relative to said level of expression of said at least one gene prior to said contacting with the anti MS drug indicates that the treatment is efficient for treating the subject;   (ii) wherein an increase above a predetermined threshold in said level of expression of said at least one gene following said contacting with the anti MS drug relative to said level of expression of said at least one gene prior to said contacting with the anti MS drug indicates that the treatment is not efficient for treating the subject; or   (iii) wherein when a level of expression of said at least one gene following said contacting with the anti MS drug is identical or changed below a predetermined threshold as compared to prior to said contacting with the anti MS drug then the treatment is not efficient for treating the subject   thereby predicting the efficiency of the anti MS drug for treatment of the subject diagnosed with the typical RRMS.   
     
     
         5 . A method of treating a subject diagnosed with multiple sclerosis, the method comprising
 (a) classifying the subject as being more likely to have BMS or typical RRMS according to the method of  claim 1 ,   (b) selecting a treatment regimen based on classification results of step (a); thereby treating the subject diagnosed with multiple sclerosis.   
     
     
         6 . A method of treating a subject diagnosed with multiple sclerosis, the method comprising:
 (a) diagnosing a typical relapsing remitting multiple sclerosis (RRMS) according to the method of  claim 2 ,   (b) administering to the subject a therapeutically effective amount of diterpenoid triepoxide Triptolide (TPT) or a derivative thereof, thereby treating the subject.   
     
     
         7 . A probeset comprising a plurality of oligonucleotides and no more than 50 oligonucleotides, wherein an oligonucleotide of said plurality of oligonucleotides specifically recognizes a polynucleotide of at least one gene involved in the RNA polymerase pathway. 
     
     
         8 . A kit for classifying a disease course in a subject diagnosed with multiple sclerosis (MS), comprising the probeset of  claim 7 . 
     
     
         9 . A method of selecting a drug for treating a typical relapsing remitting multiple sclerosis (RRMS) in a subject, the method comprising:
 contacting cells of a subject classified as having a typical RRMS with a plurality of drug molecules,   identifying at least one drug molecule which downregulates a level of expression of at least one gene involved in the RNA polymerase I pathway, said at least one drug molecule is suitable for treating the typical RRMS in the subject,   thereby selecting the drug for treating the typical RRMS in the subject.   
     
     
         10 . The method of  claim 1 , wherein a decrease above a predetermined threshold in said level of expression of said at least one gene in said cell of the subject relative to said reference expression data of said at least one gene obtained from said at least one subject having said typical RRMS classifies the subject as being more likely to have the BMS. 
     
     
         11 . The method of  claim 1 , wherein an increase above a predetermined threshold in said level of expression of said at least one gene in said cell of the subject relative to said reference expression data of said at least one gene obtained from said at least one subject having said BMS classifies the subject as being more likely to have the typical RRMS. 
     
     
         12 . The method of  claim 1 , wherein when a level of expression of said at least one gene in said cell of the subject is identical or changed below a predetermined threshold as compared to said reference expression data of said at least one gene obtained from said at least one subject having said BMS, then the subject is classified as being more likely to have the BMS. 
     
     
         13 . The method of  claim 1 , wherein when a level of expression of said at least one gene in said cell of the subject is identical or changed below a predetermined threshold as compared to said reference expression data of said at least one gene obtained from said at least one subject having said typical RRMS, then the subject is classified as being more likely to have the typical RRMS. 
     
     
         14 . The method of  claim 5 , wherein when the subject being more likely to have typical RRMS then said treatment regimen comprises administering to the subject an agent which downregulates the level of expression of said at least one gene involved in said RNA polymerase I pathway. 
     
     
         15 . The method of  claim 1 , wherein said at least one gene involved in said RNA polymerase 1 pathway is selected from the group consisting of POLR1D, LRPPRC, RRN3 and NCL. 
     
     
         16 . The method of  claim 1 , wherein said at least one gene involved in said RNA polymerase 1 pathway comprises the POLR1D, LRPPRC, RRN3 and NCL genes. 
     
     
         17 . The method of  claim 6 , wherein said agent is selected from the group consisting of an siRNA, an antisense, an antibody and a small molecule. 
     
     
         18 . The method of  claim 17 , wherein said small molecule is Cycloheximide. 
     
     
         19 . The method of  claim 6 , wherein said at least one gene is RRN3, and whereas said downregulating is effected using diterpenoid triepoxide Triptolide (TPT) or a derivative thereof. 
     
     
         20 . The method of  claim 6 , wherein said at least one gene is RRN3, and whereas said downregulating is effected using Cycloheximide. 
     
     
         21 . The kit of  claim 8 , further comprising a positive control for an expression level of said at least one gene involved in the RNA polymerase pathway. 
     
     
         22 . The probeset of  claim 7 , wherein each of said plurality of oligonucleotides is bound to a solid support. 
     
     
         23 . The probeset wherein said plurality of oligonucleotides are bound to said solid support in an addressable location. 
     
     
         24 . The method of  claim 1 , wherein said level of expression is determined using an RNA detection method. 
     
     
         25 . The method of  claim 1 , wherein said level of expression is determined using a protein detection method. 
     
     
         26 . The method of  claim 1 , wherein said cell is a blood cell. 
     
     
         27 . The method of  claim 5 , further comprising administering to the subject a therapeutically effective amount of an anti MS agent. 
     
     
         28 . The method of  claim 3 , wherein said anti-MS agent is selected from the group consisting of Diterpenoid triepoxide Triptolide (TPT), Adderall, Ambien, Avonex, Baclofen, Beta interferon, Betaseron, Celexa, Clonazepam, Copaxone, Corticosteroids, Cymbalta, Cytoxan, Dexamethasone, Effexor, Elavil, Gabapentin, Hydrocodone, Lexapro, Lyrica, Mitoxantrone, Naltrexone, Neurontin, Novantrone, Prednisone, Provigil, Rebif, Solumedrol, Symmetrel, Topamax, Tysabri, Wellbutrin, Xanax, Zanaflex, Zoloft, fingolimod, laquinimod, Mylinax (cladribine), teriflunomide, BG-12 (Biogen Idec's), firategrast (GSK/Mitsubishi Tanabe Pharma), ibudilast (MediciNova's), and CDP323 (Biogen/UCB). 
     
     
         29 . The probeset of  claim 7 , wherein said at least one gene involved in said RNA polymerase 1 pathway comprises the POLR1D, LRPPRC, RRN3 and NCL genes.