NRF2 Screening Assays and Related Methods and Compositions

Abstract

Provided are certain methods of screening, identifying, and evaluating neuroprotective compounds useful for treatment of neurological diseases, such as, e.g., multiple sclerosis (MS). The compounds described upregulate the cellular cytoprotective pathway regulated by Nrf2. Also provided are certain methods of utilizing such compounds in therapy for neurological disease, particularly, for slowing or reducing demyelination, axonal loss, or neuronal and oligodendrocyte death.

1 .- 17 . (canceled) 
     
     
         18 . A method of treating multiple sclerosis in a human subject in need thereof comprising
 orally administering to the subject about 480 mg dimethyl fumarate per day,   wherein the dimethyl fumarate is administered in the form of tablets or capsules, and   wherein the tablets or capsules are provided with a gastric-resistant coating which, once having passed the stomach, is dissolved within a few minutes by the juice present in the small intestine and releases the dimethyl fumarate from the tablets or capsules.   
     
     
         19 . The method of  claim 18 , wherein the tablets or capsules do not contain a salt of a monoalkyl fumarate. 
     
     
         20 . The method of  claim 18 , wherein the drug for treating multiple sclerosis in said tablets or capsules consists essentially of dimethyl fumarate. 
     
     
         21 . The method of  claim 18  wherein the dimethyl fumarate is administered in the form of tablets. 
     
     
         22 . The method of  claim 19  wherein the dimethyl fumarate is administered in the form of tablets. 
     
     
         23 . The method of  claim 20  wherein the dimethyl fumarate is administered in the form of tablets. 
     
     
         24 . The method of  claim 18  wherein the dimethyl fumarate is administered in the form of capsules. 
     
     
         25 . The method of  claim 19  wherein the dimethyl fumarate is administered in the form of capsules. 
     
     
         26 . The method of  claim 20  wherein the dimethyl fumarate is administered in the form of capsules. 
     
     
         27 . The method of  claim 18  wherein the dimethyl fumarate is administered in the form of microtablets in capsules. 
     
     
         28 . The method of  claim 19  wherein the dimethyl fumarate is administered in the form of microtablets in capsules. 
     
     
         29 . The method of  claim 20  wherein the dimethyl fumarate is administered in the form of microtablets in capsules. 
     
     
         30 . The method of  claim 18  wherein the 480 mg dimethyl fumarate per day is administered in a single dose. 
     
     
         31 . The method of  claim 19  wherein the 480 mg dimethyl fumarate per day is administered in a single dose. 
     
     
         32 . The method of  claim 20  wherein the 480 mg dimethyl fumarate per day is administered in a single dose. 
     
     
         33 . The method of  claim 27  wherein the 480 mg dimethyl fumarate per day is administered in a single dose. 
     
     
         34 . The method of  claim 28  wherein the 480 mg dimethyl fumarate per day is administered in a single dose. 
     
     
         35 . The method of  claim 29  wherein the 480 mg dimethyl fumarate per day is administered in a single dose. 
     
     
         36 . The method of  claim 18  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations. 
     
     
         37 . The method of  claim 19  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations. 
     
     
         38 . The method of  claim 20  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations. 
     
     
         39 . The method of  claim 18  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of equal doses. 
     
     
         40 . The method of  claim 19  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of equal doses. 
     
     
         41 . The method of  claim 20  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of equal doses. 
     
     
         42 . The method of  claim 27  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of equal doses. 
     
     
         43 . The method of  claim 28  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of equal doses. 
     
     
         44 . The method of  claim 29  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of equal doses. 
     
     
         45 . The method of  claim 39  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of two equal doses. 
     
     
         46 . The method of  claim 40  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of two equal doses. 
     
     
         47 . The method of  claim 41  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of two equal doses. 
     
     
         48 . The method of  claim 18  wherein the multiple sclerosis is relapsing-remitting multiple sclerosis. 
     
     
         49 . The method of  claim 19  wherein the multiple sclerosis is relapsing-remitting multiple sclerosis. 
     
     
         50 . The method of  claim 20  wherein the multiple sclerosis is relapsing-remitting multiple sclerosis. 
     
     
         51 . The method of  claim 18  wherein the method further comprises administering at least one immunosuppressive or immunomodulatory compound that does not upregulate the Nrf2 pathway. 
     
     
         52 . The method of  claim 19  wherein the method further comprises administering at least one immunosuppressive or immunomodulatory compound that does not upregulate the Nrf2 pathway. 
     
     
         53 . The method of  claim 20  wherein the method further comprises administering at least one immunosuppressive or immunomodulatory compound that does not upregulate the Nrf2 pathway. 
     
     
         54 . The method of  claim 18  wherein the tablets or capsules further comprise another active compound providing additional or enhanced therapeutic function. 
     
     
         55 . The method of  claim 19  wherein the tablets or capsules further comprise another active compound providing additional or enhanced therapeutic function. 
     
     
         56 . The method of  claim 20  wherein the tablets or capsules further comprise another active compound providing additional or enhanced therapeutic function. 
     
     
         57 . The method of  claim 21  wherein the tablets are micro-tablets. 
     
     
         58 . The method of  claim 22  wherein the tablets are micro-tablets. 
     
     
         59 . The method of  claim 23  wherein the tablets are micro-tablets. 
     
     
         60 . The method of  claim 18  wherein the 480 mg dimethyl fumarate is not used with other therapeutic agents. 
     
     
         61 . The method of  claim 19  wherein the 480 mg dimethyl fumarate is not used with other therapeutic agents. 
     
     
         62 . The method of  claim 20  wherein the 480 mg dimethyl fumarate is not used with other therapeutic agents. 
     
     
         63 . The method of  claim 60  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of two equal doses, and the multiple sclerosis is relapse-remitting multiple sclerosis. 
     
     
         64 . The method of  claim 61  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of two equal doses, and the multiple sclerosis is relapse-remitting multiple sclerosis. 
     
     
         65 . The method of  claim 62  wherein the 480 mg dimethyl fumarate per day is administered in separate administrations of two equal doses, and the multiple sclerosis is relapse-remitting multiple sclerosis.