US2004242704A1PendingUtilityA1

Stabilized mutant opsin proteins

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Assignee: UNIV WASHINGTON TECHTRANSFER IPriority: Mar 14, 2003Filed: Mar 15, 2004Published: Dec 2, 2004
Est. expiryMar 14, 2023(expired)· nominal 20-yr term from priority
Inventors:Krzysztof PalczewskiShalesh KaushalVladimir A. KuksaSyed M. Noorwez
A61K 31/435A61K 31/695A61K 31/11A61K 31/382A61K 31/07A61K 38/1709A61K 9/0048A61P 27/10A61P 27/02
61
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Claims

Abstract

Methods and compositions for stabilizing opsin protein in a vertebrate visual system are provided by administration of opsin-binding synthetic retinoids.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A method of restoring photoreceptor function in a vertebrate eye having a mutant opsin protein, comprising administering to the vertebrate an effective amount of an opsin-binding synthetic retinoid in a pharmaceutically acceptable vehicle, wherein the opsin-binding synthetic retinoid binds to and stabilizes the opsin protein in the eye.  
     
     
         2 . The method of  claim 1 , wherein the opsin-binding synthetic retinoid is an 11-cis-7-ring retinal or a 9-cis-7-ring retinal.  
     
     
         3 . The method of  claim 2 , wherein the synthetic retinoid is cycloheptatrienylidene 11-cis-locked retinal or cycloheptatrienylidene 9-cis-locked retinal.  
     
     
         4 . The method of  claim 1 , wherein the opsin-binding synthetic retinoid comprises a synthetic retinoid of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII.  
     
     
         5 . The method of  claim 4 , wherein the opsin-binding synthetic retinoid is a 9-cis-fused retinal.  
     
     
         6 . The method of  claim 1 , wherein the opsin-binding synthetic retinoid is locally administered to the eye.  
     
     
         7 . The method of  claim 6 , wherein the opsin-binding synthetic retinoid is locally administered by eye drops, intraocular injection or periocular injection.  
     
     
         8 . The method of  claim 1 , wherein the opsin-binding synthetic retinoid is orally administered to a subject comprising the vertebrate eye.  
     
     
         9 . The method of  claim 1 , wherein the mutant opsin protein is P23H mutant opsin protein.  
     
     
         10 . A method for stabilizing mutant opsin protein, comprising: 
 contacting with the mutant opsin protein with an opsin-binding synthetic retinoid for an amount of time sufficient for the formation of a stabilized opsin/synthetic retinoid complex.    
     
     
         11 . The method of  claim 10 , wherein the opsin-binding synthetic retinoid comprises a synthetic retinoid of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII.  
     
     
         12 . The method of  claim 11 , wherein the opsin-binding synthetic retinoid is a 9-cis-locked retinal or an 11-cis-locked retinal.  
     
     
         13 . The method of  claim 10 , wherein the mutant opsin protein is a P23H mutant opsin protein.  
     
     
         14 . The method of  claim 13 , wherein the opsin-binding synthetic retinoid is an 11-cis-7-ring retinal or a 9-cis-ring retinal.  
     
     
         15 . The method of  claim 14 , wherein the opsin-binding synthetic retinoid is cycloheptatrienylidene 11-cis-locked retinal or cycloheptatrienylidene 9-cis-locked retinal.  
     
     
         16 . A method of ameliorating loss of photoreceptor function in a vertebrate eye, comprising: 
 prophylactically administering an effective amount of an opsin-binding synthetic retinoid in a pharmaceutically acceptable vehicle to a vertebrate eye comprising a mutant opsin protein having a reduced affinity for 11-cis-retinal, wherein the synthetic retinoid binds to and stabilizes the mutant opsin protein.    
     
     
         17 . The method of  claim 16 , wherein the opsin-binding synthetic retinoid is orally administered to a vertebrate.  
     
     
         18 . The method of  claim 16 , wherein the opsin-binding synthetic retinoid is locally administered to the vertebrate eye.  
     
     
         19 . The method of  claim 16 , wherein the opsin-binding synthetic retinoid comprises a synthetic retinoid of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII.  
     
     
         20 . The method of  claim 19 , wherein the opsin-binding synthetic retinoid is a 9-cis-7-ring retinal or an 11-cis-7-ring retinal and the mutant opsin protein is a P23H mutant opsin protein.  
     
     
         21 . The method of  claim 20 , wherein the synthetic retinoid is cycloheptatrienylidene 11-cis-locked retinal or cycloheptatrienylidene 9-cis-locked retinal.  
     
     
         22 . The method of  claim 16 , wherein the mutant opsin protein has a mutation in the N-terminal plug  
     
     
         23 . An ophthalmologic composition comprising an opsin-binding synthetic retinoid in a pharmaceutically acceptable vehicle.  
     
     
         24 . The composition of  claim 23 , wherein the opsin-binding synthetic retinoid comprises a synthetic retinoid of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII.  
     
     
         25 . The composition of  claim 24 , wherein the opsin-binding synthetic retinoid is a 9-cis-7-ring retinal or an 11-cis-7-ring retinal.  
     
     
         26 . The composition of  claim 25 , wherein the opsin-binding synthetic retinoid is cycloheptatrienylidene 11-cis-locked retinal or cycloheptatrienylidene 9-cis-locked retinal.  
     
     
         27 . An oral dosage form comprising an opsin-binding synthetic retinoid in a pharmaceutically acceptable vehicle.  
     
     
         28 . The composition of  claim 27 , wherein the opsin-binding synthetic retinoid comprises a synthetic retinoid of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII.  
     
     
         29 . The composition of  claim 28 , wherein the opsin-binding synthetic retinoid is a 9-cis-7-ring retinal or an 11-cis-7-ring retinal.  
     
     
         30 . The composition of  claim 29 , wherein the opsin-binding synthetic retinoid is cycloheptatrienylidene 11-cis-locked retinal or cycloheptatrienylidene 9-cis-locked retinal.  
     
     
         31 . A method of identifying an opsin-binding synthetic retinoid to stabilize a mutant opsin protein, comprising: 
 providing an expression system for the expression of a mutant opsin protein;    contacting the mutant opsin protein with a synthetic retinoid for a time sufficient and in suitable conditions for the binding of the synthetic retinoid by the mutant opsin protein; and    detecting whether the mutant opsin protein binds the synthetic retinoid to form a stable mutant opsin protein/synthetic retinoid complex.    
     
     
         32 . The method of  claim 31 , wherein the expression system is a eukaryotic cell line expressing the mutant opsin protein.  
     
     
         33 . The method of  claim 32 , wherein the synthetic retinoid is administered to cell culture media in which the eukaryotic cell line is cultured.  
     
     
         34 . The method of  claim 31 , wherein the opsin-binding synthetic retinoid comprises a synthetic retinoid of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII.

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