Compositions and methods for the treatment and prevention of neurological disorders
The invention provides compositions and methods for treating neurological disorders, such as amyotrophic lateral sclerosis, frontotemporal degeneration, and Alzheimer's disease, among others. Using the compositions and methods described herein, a patient having a neurological disorder, such as a neurological disorder associated with TAR-DNA binding protein (TDP)-43 aggregation, may be administered an inhibitor of cytochrome P450 (CYP450) isoform 51A1 (CYP51A1), also referred to herein as lanosterol 14-alpha demethylase, so as to treat an underlying etiology of the disorder and/or to alleviate one or more symptoms of the disease. The inhibitor of CYP51A1 may be a small molecule, anti-CYP51A1 antibody or antigen-binding fragment thereof, or a compound, such as an interfering RNA molecule, that attenuates CYP51A1 expression. Patients that may be treated using the compositions and methods described herein include those that express a mutant TDP-43 isoform containing a mutation associated with TDP-43-promoted aggregation and toxicity.
1. A method of treating a neurological disorder associated with TDP-43 aggregation in a human patient, the method comprising administering to the patient a therapeutically effective amount of a CYP51A1 inhibitor represented by formula (XLIII):
wherein n is 2 or 3;
p is 0, 1, or 2;
q is 0, 1, or 2;
X is oxygen or S(O) t wherein t is 0, 1, or 2;
each R 1 is independently halo, lower alkyl, lower alkoxy, or trifluoromethyl;
each R 2 is independently halo or lower alkyl;
R 3 is nitro or —N(R 5 )R 6 , where R 5 is hydrogen or lower alkyl, and R 6 is hydrogen, lower alkyl, lower alkylsulfonyl or —C(Y)R 7 where Y is oxygen or sulfur and R 7 is hydrogen, lower alkyl, lower alkoxy or —N(R 8 )R 9 where R 8 is hydrogen or lower alkyl and R 9 is hydrogen, lower alkyl or lower alkoxycarbonyl; or R 5 and R 6 together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by —C(O)R 10 where R 10 is hydrogen, lower alkyl, lower alkoxy or amino; and
R 4 is hydrogen or optionally substituted lower alkyl;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , the method comprising:
(i) determining that the patient is susceptible to developing TAR-DNA binding protein (TDP)-43 aggregation; and
(ii) administering to the patient the therapeutically effective amount of the CYP51A1 inhibitor.
3. The method of claim 1 , wherein the patient has previously been determined to be susceptible to developing TDP- 43 aggregation.
4. The method of claim 1 , the method comprising:
(i) determining that the patient expresses a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation; and
(ii) administering to the patient the therapeutically effective amount of the CYP51A1 inhibitor.
5. The method of claim 1 , wherein the patient has previously been determined to express a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation.
6. The method of claim 5 , wherein the mutation is selected from the group consisting of Q331K, M337V, Q343R, N345K, R361S, and N390D.
7. The method of claim 1 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis.
8. The method of claim 1 , wherein the CYP51A1 inhibitor is azalanstat.