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 cells are retinal pigment epithelial cells or photoreceptor cells.  
   
   
       3 . The method according to  claim 1 , wherein said ocular disorder is caused by a mutation in a normal retinal pigment epithelium-specific gene or normal photoreceptor-specific gene.  
   
   
       4 . The method according to  claim 3 , wherein said ocular disorder is caused by a mutation in said normal retinal pigment epithelium-specific gene and said gene is selected, from the group consisting of RPE65, the arylhydrocarbon-interacting receptor protein like 1 (AIPL 1), CRB1 gene, and lecithin retinal acetyltransferase gene (LRAT).  
   
   
       5 . The method according to  claim 3 , wherein said ocular disorder is caused by a mutation in said normal photoreceptor-specific gene and said gene is the photoreceptor-specific homeo box gene (CRX) or retinal guanylate cyclase gene (GUCY2D).  
   
   
       6 . The method according to  claim 5 , wherein said gene encodes RPGR interacting protein 1 (RPGRIP1).  
   
   
       7 . The method according to  claim 1 , wherein said normal gene is obtained from the same subject species as the subject being treated.  
   
   
       8 . The method according to  claim 1 , wherein said promoter is a cell-specific promoter.  
   
   
       9 . The method according to  claim 1 , wherein said promoter is the chicken beta actin promoter/CMV enhancer.  
   
   
       10 . 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.  
   
   
       11 . The composition according to  claim 10 , wherein said normal gene is a retinal pigment epithelium-specific gene or photoreceptor-specific gene.  
   
   
       12 . The composition according to  claim 11 , wherein said normal gene is a retinal pigment epithelium-specific gene and is selected from the group consisting of RPE65, arylhydrocarbon-interacting receptor protein like 1 (AIPL1), the CRB1 gene, and the lecithin retinal acetyltransferase gene (LRAT).  
   
   
       13 . The composition-according to  claim 11 , wherein said normal gene is a photoreceptor-specific selected from the group consisting of the photoreceptor-specific homeo box gene (CRX) and the retinal guanylate cyclase gene (GUCY2D).  
   
   
       14 . The composition according to  claim 10 , wherein said gene encodes RPGR interacting protein 1 (RPGRIP1).  
   
   
       15 . 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.    
   
   
       16 . The method according to  claim 15 , wherein said recombinant virus is an adeno-associated virus and said gene is the RPE65 gene.  
   
   
       17 . 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.  
   
   
       18 . The method according to  claim 17 , wherein said ocular cells are selected from the group consisting of RPE cells and photoreceptor cells.  
   
   
       19 . The method according to  claim 17 , wherein said promoter is cell-specific.  
   
   
       20 . The method according to  claim 17 , wherein said recombinant virus is a recombinant AAV carrying the normal RPE65 gene.