Method of Treating or Retarding the Development of Blindness

Abstract

A method for treating an ocular disorder characterized by the defect or absence of a normal gene in the ocular cells of a human or animal subject involves administering to the subject by subretinal injection an effective amount of a recombinant adeno-associated virus carrying a nucleic acid sequence encoding the normal gene under the control of a promoter sequence which expresses the product of the gene in the ocular cells. The ocular cells are preferably retinal pigment epithelial (RPE) cells, and the gene is preferably an RPE-specific gene, e.g., RPE65. The promoter is one that can express the gene product in the RPE cells. Compositions for subretinal administration are useful in this method.

1 . A method for treating an ocular disorder characterized by the defect or absence of a normal gene in the ocular cells of a subject, said method comprising the step of:
 administering to said subject by subretinal injection an effective amount of a recombinant adeno-associated virus carrying a nucleic acid sequence encoding said normal gene under the control of a promoter sequence which expresses the product of said gene in said ocular cells.   
     
     
         2 . The method according to  claim 1 , wherein said ocular disorder is caused by a mutation in said normal retinal pigment epithelium-specific gene. 
     
     
         3 . The method according to  claim 2 , wherein said gene is RPE65. 4 The method according to  claim 2 , wherein said gene is the arylhydrocarbon-interacting receptor protein like 1 (AIPL1). The method according to  claim 2 , wherein said gene is the CRB 1 gene. 
     
     
         6 . The method according to  claim 2 , wherein said gene is the lecithin retinal acetyltransferase gene (LRAT) 
     
     
         7 . The method according to  claim 1 , wherein said ocular cells are retinal pigment epithelial cells. 
     
     
         8 . The method according to  claim 1 , wherein said ocular disorder is caused by a mutation in said normal photoreceptor-specific gene. 
     
     
         9 . The method according to  claim 8 , wherein said gene is the photoreceptor-specific homeo box gene (CRX). 
     
     
         10 . The method according to  claim 8 , wherein said gene is the retinal guanylate cyclase gene (GUCY2D). 
     
     
         11 . The method according to  claim 8 , wherein said gene encodes RPGR interacting protein 1 (RPGRIP1). 
     
     
         12 . The method according to  claim 1 , wherein said ocular cells are photoreceptor cells. 
     
     
         13 . The method according to  claim 1 , wherein said normal gene is obtained from the same subject species as the subject being treated. 
     
     
         14 . The method according to  claim 1 , wherein said promoter is a cell-specific promoter. 
     
     
         15 . The method according to  claim 8 , wherein said promoter is the chicken beta actin promoter/CMV enhancer. 
     
     
         16 . The method according to  claim 1 , wherein said effective amount comprises 1×10 9  to 2×10 12  rAAV infectious units in a volume of between 150 to 800 μl. 
     
     
         17 . A composition for treatment of an ocular disorder characterized by the defect or absence of a normal gene in the ocular cells of a subject, said composition comprising an effective amount of a recombinant adeno-associated virus carrying a nucleic acid sequence encoding said normal gene under the control of a promoter sequence which expresses the product of said gene in said ocular cells, formulated with a carrier and additional components suitable for subretinal injection. 
     
     
         18 . The composition according to  claim 17 , wherein said normal gene is a retinal pigment epithelium-specific gene. 
     
     
         19 . The composition according to  claim 18 , wherein said gene is RPE65. 
     
     
         20 . The composition according to  claim 18 , wherein said gene is the arylhydrocarbon-interacting receptor protein like 1 (AIPL1). 
     
     
         21 . The composition according to  claim 18 , wherein said gene is the CRB1 gene. 
     
     
         22 . The composition according to  claim 18 , wherein said gene is the lecithin retinal acetyltransferase gene (LRAT) 
     
     
         23 . The composition according to  claim 17 , wherein said normal gene is a photoreceptor-specific gene. 
     
     
         24 . The composition according to  claim 23 , wherein said gene is the photoreceptor-specific homeo box gene (CRX). 
     
     
         25 . The composition according to  claim 23 , wherein said gene is the retinal guanylate cyclase gene (GUCY2D). 
     
     
         26 . The composition according to  claim 23 , wherein said gene encodes RPGR interacting protein 1 (RPGREP1). 
     
     
         27 . A method for treating an ocular disorder characterized by the defect or absence of a normal gene in the retinal pigment epithelial (RPE) cells of a subject, said method comprising the step of:
 administering to said subject by subretinal injection an effective amount of a recombinant virus carrying a nucleic acid sequence encoding a normal retinal pigment epithelial (RPE) cell-specific gene under the control of a promoter sequence which expresses the product of said gene in said RPE cells.   
     
     
         28 . The method according to  claim 27 , wherein said recombinant virus is an adeno-associated virus. 
     
     
         29 . The method according to  claim 27 , wherein said gene is the RPE65 gene. 
     
     
         30 . A method for treating Leber congenital amaurosis in a subject comprising the step of administering to said subject by subretinal injection an effective amount of a recombinant virus carrying a nucleic acid sequence encoding a normal gene under the control of a promoter sequence which expresses the product of the gene in ocular cells, wherein said cells contain a mutated version of said gene and wherein expression of the normal gene provides to the cells the product necessary to restore or maintain vision in said subject. 
     
     
         31 . The method according to  claim 30 , wherein said ocular cells are selected from the group consisting of RPE cells and photoreceptor cells. 
     
     
         32 . The method according to  claim 30 , wherein said promoter is cell-specific. 
     
     
         33 . The method according to  claim 30 , wherein said recombinant virus is a recombinant AAV carrying the normal RPE65 gene.