Compositions for improving cell viability and methods of use thereof

Abstract

This invention relates to methods and compositions for use improving cell viability, particularly neural cell viability, and more particularly to methods and compositions for use improving cell viability by reducing reactive oxygen metabolite-mediated oxidative damage in a cell, regulating redox homeostasis in a cell, or reducing mitochondrial dysfunction in a cell. The invention further relates to the administration of the bile acid tauroursodeoxycholic acid (TUDCA) in combination with phenylbutyric Acid (PBA) to improve cell viability, and treat at least one symptom associated with, prevent the time of onset of, or slow the development of a disease related to oxidative stress.

1 - 37 . (canceled) 
     
     
         38 . A method of treating a neurodegenerative disease, the method comprising administering to a subject in need thereof:
 a therapeutically effective amount of an amino acid conjugate of a bile acid, or a pharmaceutically acceptable salt thereof, and   a therapeutically effective amount of a phenylbutyric acid (PBA), or a pharmaceutically acceptable salt thereof.   
     
     
         39 . The method of  claim 38 , wherein the bile acid in the conjugate is selected from ursodeoxycholic acid (UDCA), chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, and iocholic acid. 
     
     
         40 . The method of  claim 38 , wherein the amino acid in the conjugate is selected from taurine, glycine, glutamine, asparagine, methionine, and carbocysteine. 
     
     
         41 . The method of  claim 40 , wherein the amino acid is taurine. 
     
     
         42 . The method of  claim 41 , wherein the amino acid conjugate of the bile acid is selected from tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid, and taurodeoxycholic acid, or a pharmaceutically acceptable salt thereof 
     
     
         43 . The method of  claim 40 , wherein the amino acid is glycine. 
     
     
         44 . The method of  claim 43 , wherein the amino acid conjugate of the bile acid is selected from glycoursodeoxycholic acid and glycocholic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The method of  claim 38 , wherein the amino acid conjugate is a compound of Formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R is —H or C 1 -C 4  alkyl; 
         R 1  is —CH 2 —SO 3 R 3  and R 2  is —H; or R 1  is —COOH and R 2  is —CH 2 —CH 2 —CONH 2 , —CH 2 —CONH 2,  —CH 2 —CH 2 —SCH 3  or —CH 2 —S—CH 2 —COOH; and 
         R 3  is —H or the residue of a basic amino acid. 
       
     
     
         46 . The method of  claim 45 , wherein the amino acid conjugate is tauroursodeoxycholic acid (TUDCA) having the Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         47 . The method of  claim 38 , wherein the phenylbutyric acid (PBA) is selected from 4-phenylbutyric acid (4-PBA), glyceryl(Tri-4-PBA), 2-(4-methoxyphenoxy) acetic acid (2-POAA-OMe), 2-(4-nitrophenoxy) acetic acid (2-POAA-NO 2 ), and 2-(2-naphathyloxy) acetic acid (2-NOAA), or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The method of  claim 47 , wherein the phenylbutyric acid (PBA) is a 4-phenylbutyric acid (4-PBA), or a pharmaceutically acceptable salt thereof. 
     
     
         49 . The method of  claim 38 , wherein the PBA or a pharmaceutically acceptable salt thereof comprises a sodium phenylbutyrate. 
     
     
         50 . The method of  claim 38 , wherein:
 the amino acid conjugate of the bile acid is tauroursodeoxycholic acid (TUDCA), or a pharmaceutically acceptable salt thereof; and   the phenylbutyric acid (PBA) is a 4-phenylbutyric acid (4-PBA), or a pharmaceutically acceptable salt thereof.   
     
     
         51 . The method of  claim 38 , wherein the therapeutically effective amount of the amino acid conjugate of the bile acid, or a pharmaceutically acceptable salt thereof, is from about 10 mg/kg to about 50 mg/kg, from about 20 mg/kg to about 40 mg/kg, or from about 10 mg/kg to about 30 mg/kg of body weight of the subject. 
     
     
         52 . The method of  claim 38 , wherein the therapeutically effective amount of the phenylbutyric acid (PBA), or a pharmaceutically acceptable salt thereof, is from about 10 mg/kg to about 400 mg/kg, from about 10 mg/kg to about 100 mg/kg, or from about 30 mg/kg to about 100 mg/kg of body weight of the subject. 
     
     
         53 . The method of  claim 38 , comprising administering:
 from about 10 mg/kg to about 50 mg/kg of body weight of the subject of an amino acid conjugate of a bile acid, or a pharmaceutically acceptable salt thereof, and   from about 10 mg/kg to about 400 mg/kg of body weight of the subject of a phenylbutyric acid (PBA), or a pharmaceutically acceptable salt thereof.   
     
     
         54 . The method of  claim 38 , wherein the amino acid conjugate of the bile acid, or a pharmaceutically acceptable salt thereof, and the phenylbutyric acid (PBA), or a pharmaceutically acceptable salt thereof, are administered to the subject separately. 
     
     
         55 . The method of  claim 38 , wherein the amino acid conjugate of the bile acid, or a pharmaceutically acceptable salt thereof, and the phenylbutyric acid (PBA), or a pharmaceutically acceptable salt thereof, are administered to the subject concurrently. 
     
     
         56 . The method of  claim 38 , wherein the amino acid conjugate of the bile acid is administered once a day, twice a day, or three times a day. 
     
     
         57 . The method of  claim 38 , wherein the phenylbutyric acid (PBA) is administered once a day, twice a day, or three times a day. 
     
     
         58 . The method of  claim 38 , wherein the administration is oral, nasal, parenteral, or transdermal administration. 
     
     
         59 . The method of  claim 38 , wherein the neurodegenerative disease is selected from Multiple Sclerosis (MS), Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), stroke, Pick's Disease, Multi-Infarct Dementia, Creutzfeldt-Jakob's Disease, Dementia with Lewy bodies, Mixed dementia, and Frontotemporal dementia. 
     
     
         60 . The method of  claim 59 , wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). 
     
     
         61 . The method of  claim 38 , wherein the subject is a mammal. 
     
     
         62 . The method of  claim 61 , wherein the subject is a human. 
     
     
         63 . A pharmaceutical composition comprising:
 a therapeutically effective amount of an amino acid conjugate of a bile acid, or a pharmaceutically acceptable salt thereof;   a therapeutically effective amount of a phenylbutyric acid (PBA), or a pharmaceutically acceptable salt thereof; and   a pharmaceutically acceptable carrier.