Raav-guanylate cyclase compositions and methods for treating leber's congenital amaurosis-1 (lca1)

Abstract

Disclosed are viral vector compositions comprising polynucleotide sequences that express one or more biologically-active mammalian guanylate cyclase proteins. Also disclosed are methods for their use in preventing, treating, and/or ameliorating at least one or more symptoms of a disease, disorder, abnormal condition, or dysfunction resulting at least in part from a guanylate cyclase deficiency in vivo. In particular embodiments, the use of recombinant adeno-associated viral (rAAV) vectors to treat or ameliorate symptoms of Leber's congenital amaurosis, as well as other conditions caused by an absence or reduction in the expression of a functional retinal-specific guanylate cyclase 1 (retGC1).

1 - 56 . (canceled) 
     
     
         57 . A recombinant adeno-associated viral (rAAV) vector comprising a photoreceptor-specific human rhodopsin kinase promoter operably linked to a nucleic acid encoding a mammalian guanylate cyclase polypeptide. 
     
     
         58 . The rAAV vector according to  claim 57 , wherein the mammalian guanylate cyclase polypeptide comprises an amino acid sequence at least about 90% identical to at least 80 contiguous amino acids of a sequence as set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11. 
     
     
         59 . The rAAV vector according to  claim 57 , wherein the mammalian guanylate cyclase polypeptide comprises an amino acid sequence at least about 92% identical to at least 100 contiguous amino acids of a sequence as set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, or SEQ ID NO: 11. 
     
     
         60 . The rAAV vector according to  claim 57 , wherein the guanylate cyclase polypeptide comprises an amino acid sequence at least about 95% identical to at least 120 contiguous amino acids of a sequence as set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11. 
     
     
         61 . The rAAV vector according to  claim 57 , wherein the guanylate cyclase polypeptide comprises an amino acid sequence at least about 98% identical to at least 140 contiguous amino acids of a sequence as set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11. 
     
     
         62 . The rAAV vector according to  claim 57 , wherein the guanylate cyclase polypeptide comprises an amino acid sequence at least about 98% identical to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11. 
     
     
         63 . The rAAV vector according to  claim 57 , wherein the rAAV vector is a recombinant adeno-associated virus serotype 1 (rAAV1) vector, a recombinant adeno-associated virus serotype 2 (rAAV2) vector, recombinant adeno-associated virus serotype 3 (rAAV3) vector, a recombinant adeno-associated virus serotype 4 (rAAV4) vector, a recombinant adeno-associated virus serotype 5 (rAAV5) vector, a recombinant adeno-associated virus serotype 6 (rAAV6) vector, a recombinant adeno-associated virus serotype 7 (rAAV7) vector, a recombinant adeno-associated virus serotype 8 (rAAV8) vector, or a recombinant adeno-associated virus serotype 9 (rAAV) vector. 
     
     
         64 . The rAAV vector according to  claim 57 , wherein the photoreceptor-specific human rhodopsin kinase promoter is at least 90% identical to SEQ ID NO: 12. 
     
     
         65 . The rAAV vector of  claim 57 , further comprising an enhancer operably linked to the photoreceptor-specific human rhodopsin kinase promoter. 
     
     
         66 . The rAAV vector of  claim 57 , further comprising a mammalian intron sequence operably linked to the photoreceptor-specific human rhodopsin kinase promoter. 
     
     
         67 . The rAAV vector according to  claim 57 , comprised within an infectious adeno-associated viral particle, virion, or a plurality of infectious AAV particles. 
     
     
         68 . A virion or an infectious viral particle comprising the rAAV vector of  claim 57 . 
     
     
         69 . A plurality of infectious viral particles prepared from the rAAV vector of  claim 57 . 
     
     
         70 . A composition comprising: the rAAV vector of  claim 57  and a pharmaceutically-acceptable buffer, carrier, vehicle, or diluent. 
     
     
         71 . The composition according to  claim 70 , further comprising a lipid, a liposome, a lipid complex, an ethosome, a niosome, a nanoparticle, a microparticle, a liposphere, a nanocapsule, or any combination thereof. 
     
     
         72 . The composition according to  claim 70 , formulated administration to the human eye. 
     
     
         73 . The composition according to  claim 70 , for use in therapy or prophylaxis of a human retinal dystrophy, disease, or disorder. 
     
     
         74 . The composition according to  claim 70 , for use in the therapy or prophylaxis of Leber congenital amaurosis-1 (LCA1). 
     
     
         75 . The composition according to  claim 70 , for use in a subject having a mutation in GUCY2D.