Compositions and methods for treating lysosomal disorders

Abstract

One aspect of the invention provides a method for treatment of a lysosomal storage disorder. The method may include administering to a subject in need of such treatment a composition including a therapeutically effective amount of an agent that mediates upregulation of Transcription Factor EB. In one embodiment, the composition includes a fibrate, such as gemfibrozil or fenofibrate. In another embodiment, the composition also includes all-trans retinoic acid or vitamin A.

1 . A method for treatment of a lysosomal storage disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of composition comprising an agent that mediates upregulation of Transcription Factor EB. 
     
     
         2 . The method of  claim 1 , wherein the agent is a statin. 
     
     
         3 . The method of  claim 2 , wherein the statin is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and a combination thereof. 
     
     
         4 . The method of  claim 1 , wherein the agent is selected from the group consisting of an analgesic, an antipyretic, aspirin, a cinnamon metabolite, cinnamic acid, sodium phenylbutyrate and sodium benzoate. 
     
     
         5 . The method of  claim 1 , wherein the agent is a lipid-lowering drug. 
     
     
         6 . The method of  claim 5 , wherein the lipid-lowering drug is a fibrate. 
     
     
         7 . The method of  claim 6 , wherein the fibrate is gemfibrozil or fenofibrate. 
     
     
         8 . The method of  claim 1 , wherein the composition further comprises a therapeutically effective amount of all-trans retinoic acid or vitamin A. 
     
     
         9 . The method of  claim 8 , wherein the composition comprises the fibrate and all-trans retinoic acid or vitamin A. 
     
     
         10 . The method of  claim 9 , wherein the composition comprises a synergistic combination of the fibrate and the all-trans retinoic acid or vitamin A. 
     
     
         11 . The method of  claim 1 , wherein
 the lysosomal storage disorder is a neurodegenerative disorder selected from the group consisting of neuronal ceroid lipofuscinosis, Alzheimer's disease, Huntington's disease, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, including Parkinson's plus diseases such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB).   
     
     
         12 . The method of  claim 1 , wherein the lysosomal storage disorder is a disorder of the autophagy pathway and wherein the agent increases lysosomal biogenesis. 
     
     
         13 . The method of  claim 1 , wherein the lysosomal storage disorder is selected from the group consisting of Tay-Sach's disease, Fabry disease, Niemann-Pick disease, Gaucher disease, Hunter Syndrome, Alpha-mannosidosis, Aspartylglucosaminuria, Cholesteryl ester storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis, Danon disease, Farber disease, Fucosidosis, and Galactosialidosis. 
     
     
         14 . The method of  claim 1 , wherein Transcription Factor EB is upregulated by increasing Transcription Factor EB mRNA levels increasing Transcription Factor EB protein levels or activating a PPARa-RXRa heterodimer. 
     
     
         15 - 20 . (canceled) 
     
     
         21 . A drug combination comprising: a statin and all-trans retinoic acid or vitamin A. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 4 , wherein the agent is aspirin. 
     
     
         25 . The method of  claim 1 , wherein the lysosomal storage disorder is selected from the group consisting of Tay-Sach's disease, Fabry disease, Niemann-Pick disease, Gaucher disease, Hunter Syndrome, Alpha-mannosidosis, Aspartylglucosaminuria, Cholesteryl ester storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis, Danon disease, Farber disease, Fucosidosis, Galactosialidosis and Batten disease including late infantile Batten disease and juvenile Batten disease. 
     
     
         26 . The method of  claim 1 , wherein the therapeutically effective amount of the fibrate is lower when the fibrate is administered in combination with all-trans retinoic acid or vitamin A. 
     
     
         27 . A method for treatment of a lysosomal storage disorder, comprising administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of an agent, wherein the agent restores Transcription Factor EB activity. 
     
     
         28 . The method of  claim 27 , wherein the agent is a statin. 
     
     
         29 . The method of  claim 28 , wherein the statin is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and a combination thereof. 
     
     
         30 . The method of  claim 27 , wherein the agent is selected from the group consisting of an analgesic, an antipyretic, aspirin, a cinnamon metabolite, cinnamic acid, sodium phenylbutyrate and sodium benzoate. 
     
     
         31 . The method of  claim 27 , wherein the agent is a lipid-lowering drug. 
     
     
         32 . The method of  claim 31 , wherein the lipid-lowing drug is a fibrate. 
     
     
         33 . The method of  claim 32 , wherein the fibrate is gemfibrozil or fenofibrate. 
     
     
         34 . The method of  claim 32 , wherein the therapeutically effective amount of the fibrate is lower when the fibrate is administered in combination with all-trans retinoic acid or vitamin A. 
     
     
         35 . The method of  claim 27 , wherein the lysosomal storage disorder is selected from the group consisting of Tay-Sach's disease, Fabry disease, Niemann-Pick disease, Gaucher disease, Hunter Syndrome, Alpha-mannosidosis, Aspartylglucosaminuria, Cholesteryl ester storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis, Danon disease, Farber disease, Fucosidosis, Galactosialidosis and Batten disease including late infantile Batten disease and juvenile Batten disease.