Methods for the treatment and prevention of age-related retinal dysfunction

Abstract

A method of treating or preventing age-related retinal dysfunction involves administering to a patient a pharmaceutically effective amount of a synthetic retinal derivative repeatedly over a duration of at least about 3 months. Effective synthetic retinal derivatives include 9-cis-retinyl esters, 11-cis-retinyl esters, derivatives and congeners thereof, and combinations thereof. Suitable ester substituents include carboxylates of C 1 -C 10 monocarboxylic acids and C 2 -C 22 polycarboxylic acids.

1 . A method of treating or preventing age-related retinal dysfunction in a subject comprising administering to said subject a pharmaceutically effective amount of a synthetic retinal derivative, wherein said synthetic retinal derivative is administered to said subject for a period of at least three months. 
     
     
         2 . The method of  claim 1 , wherein said synthetic retinal derivative is administered to said subject for a period of from about six to about ten months. 
     
     
         3 . The method of  claim 1 , wherein said synthetic retinal derivative is administered about once every day or once every other day; about four times a week, three times a week, or two times a week; or about once every two, three, four, five, six, seven, eight, or nine weeks. 
     
     
         4 . The method of  claim 1 , wherein said synthetic retinal derivative is a compound of any one of Formulas I-XVI as disclosed in PCT/US2005/021812 (WO 2006/002097) or a compound of any one of Formulas I-XII as disclosed in PCT/US2005/021812 (WO 2004/082622). 
     
     
         5 . The method of  claim 4 , wherein:
 (a) said synthetic retinal derivative is a 9-cis-retinyl ester and/or an 11-cis-retinyl ester; and   (b) the ester substituent of said synthetic retinal derivative comprises a carboxylate radical of a C 1 -C 10  monocarboxylic acid, a C 3  to C 10  polycarboxylic acid, or a C 2  to C 22  polycarboxylic acid.   
     
     
         6 . The method of  claim 5 , wherein said synthetic retinal derivative is selected from the group consisting of: 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, 11-cis-retinyl acetate, 11-cis-retinyl succinate, 11-cis-retinyl citrate, 11-cis-retinyl ketoglutarate, 11-cis-retinyl fumarate, 11-cis-retinyl malate and 11-cis-retinyl oxaloacetate. 
     
     
         7 . The method of  claim 1 , wherein said age-related retinal dysfunction is manifested by one or more of the following clinical conditions: an impairment in rod-mediated dark adaptation after light exposure, an impairment in night vision, an impairment in contrast sensitivity, and age-related macular degeneration (AMD). 
     
     
         8 . The method of  claim 1 , wherein said synthetic retinal derivative is administered via a method selected from gavage, orally, and locally to a subject's eye. 
     
     
         9 . The method of  claim 8 , wherein said synthetic retinal derivative is locally administered via eye drops, an intraocular injectable solution or a periocular injectable solution. 
     
     
         10 . The method of  claim 1 , wherein said synthetic retinal derivative is administered less than once a day and wherein the dosage per administration is greater than the effective daily dose. 
     
     
         11 . A method of improving rhodopsin regeneration ratio in a mammal comprising administering to said mammal a pharmaceutically effective amount of a synthetic retinal derivative, wherein said synthetic retinal derivative is administered to said mammal for a period of at least three months. 
     
     
         12 . The method of  claim 11 , wherein said synthetic retinal derivative is administered to said subject for a period of at least six months to about 10 months. 
     
     
         13 . The method of  claim 11 , wherein said synthetic retinal derivative is administered to said subject about once every day or once every other day; about four times a week, three times a week, or two times a week; or about once every two, three, four, five, six, seven, eight, or nine weeks. 
     
     
         14 . The method of  claim 11 , wherein said synthetic retinal derivative is a compound of any one of Formulas I-XVI as disclosed in PCT/US2005/021812 (WO 2006/002097) or a compound of any one of Formulas I-XII as disclosed in PCT/US2005/021812 (WO 2004/082622). 
     
     
         15 . The method of  claim 14 , wherein:
 (a) said synthetic retinal derivative is a 9-cis-retinyl ester and/or an 11-cis-retinyl ester; and   (b) the ester substituent of said synthetic retinal derivative comprises a carboxylate radical of a C 1 -C 10  monocarboxylic acid, a C 3  to C 10  polycarboxylic acid, or a C 2  to C 22  polycarboxylic acid.   
     
     
         16 . The method of  claim 11 , wherein said synthetic retinal derivative is selected from the group consisting of: 9-cis-retinyl acetate, 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate, 9-cis-retinyl oxaloacetate, 11-cis-retinyl acetate, 11-cis-retinyl succinate, 11-cis-retinyl citrate, 11-cis-retinyl ketoglutarate, 11-cis-retinyl fumarate, 11-cis-retinyl malate and 11-cis-retinyl oxaloacetate. 
     
     
         17 . The method of  claim 11 , wherein said age-related retinal dysfunction is manifested by one or more of the following clinical conditions: an impairment in rod-mediated dark adaptation after light exposure, an impairment in night vision, an impairment in contrast sensitivity, and age-related macular degeneration (AMD). 
     
     
         18 . The method of  claim 11 , wherein said synthetic retinal derivative is administered via a method selected from gavage, orally, and locally to a subject's eye. 
     
     
         19 . The method of  claim 18 , wherein said synthetic retinal derivative is administered locally via eye drops, an intraocular injectable solution or a periocular injectable solution. 
     
     
         20 . The method of  claim 11 , wherein said synthetic retinal derivative is administered less than once a day and wherein the dosage per administration is greater than the effective daily dose.