Viral vectors for the treatment of retinal dystrophy

Abstract

The present invention relates to viral vectors that are capable of delivering a heterologous gene to the retina and in particular delivering RLBP1 to RPE and Müller cells of the retina. The invention also relates nucleic acids useful for producing viral vectors, compositions comprising the viral vectors and uses of the compositions and viral vectors. The invention also relates to methods of delivering and/or expressing a heterologous gene to the retina, improving the rate of dark adaption in a subject and treating RLBP1-associated retinal dystrophy.

1 - 30 . (canceled) 
     
     
         31 . A method of treating RLBP1-associated retinal dystrophy comprising administering to a subject in need thereof an effective amount of a composition comprising an adeno-associated virus (AAV) vector, wherein the AAV vector comprises a vector genome comprising: a) retinaldehyde binding protein 1 (RLBP1) coding sequence; and b) an AAV capsid. 
     
     
         32 . The method of  claim 31 , wherein the AAV vector is adapted to direct the expression of the RLBP1 coding sequence in retinal pigment epithelial (RPE) cells and Müller cells of the retina. 
     
     
         33 . The method of  claim 31 , wherein the vector genome comprises in the 5′ to 3′ direction:
 a. a 5′ inverted terminal repeat (ITR); 
 b. a promoter; 
 c. RLBP1 coding sequence; and 
 d. a 3′ ITR. 
 
     
     
         34 . The method of  claim 33 , wherein the vector genome comprises a nucleic acid sequence, in the 5′ to 3′ direction, selected from the group consisting of:
 a. SEQ ID NOs: 2, 10, 5, 6, 8, and 9; 
 b. SEQ ID NOs: 2, 11, 5, 6, 8, 14, and 9; 
 c. SEQ ID NOs: 2, 22, 5, 6, 8, 23, and 9; and 
 d. SEQ ID NOs: 2, 3, 4, 5, 6, 8, 23, and 9. 
 
     
     
         35 . The method of  claim 33 , wherein the 5′ ITR comprises a non-resolvable ITR. 
     
     
         36 . The method of  claim 35 , wherein the non-resolvable ITR comprises a nucleic acid sequence as set forth in SEQ ID NO: 1. 
     
     
         37 . The method of  claim 36 , wherein the RLBP1 coding sequence comprises a nucleic acid sequence as set forth in SEQ ID NO: 6. 
     
     
         38 . The method of  claim 33 , wherein the promoter comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 3, 10, 11, and 22. 
     
     
         39 . The method of  claim 37 , wherein the vector genome comprises a nucleic acid sequence, in the 5′ to 3′ direction, of SEQ ID NOs: 1, 5, 6, 8, and 9. 
     
     
         40 . The method of  claim 39 , wherein the vector genome comprises a nucleic acid sequence, in the 5′ to 3′ direction, of SEQ ID NOs: 1, 3, 4, 5, 6, 8, and 9. 
     
     
         41 . The method of  claim 40 , wherein the vector genome comprises a nucleic acid sequence, in the 5′ to 3′ direction, of SEQ ID NOs: 36, 62, 63, 64, 65, 66, 1, 3, 4, 5, 6, 8, and 9. 
     
     
         42 . The method of  claim 31 , wherein the AAV capsid comprises an AAV serotype 8 capsid. 
     
     
         43 . The method of  claim 42 , wherein the AAV serotype 8 capsid is encoded by a nucleic acid sequence of SEQ ID NO: 20. 
     
     
         44 . The method of  claim 31 , wherein the AAV capsid comprises an AAV serotype 2 capsid or an AAV serotype 5 capsid. 
     
     
         45 . The method of  claim 31 , wherein the vector genome is comprised in a plasmid sequence comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 28, 29, 30, and 50. 
     
     
         46 . The method of  claim 31 , wherein the administering is via subretinal injection. 
     
     
         47 . The method of  claim 31 , wherein the administering is via intravitreal injection. 
     
     
         48 . The method of  claim 46 , wherein the subject is administered with the AAV vector at at least about 5×10 9  vg/eye. 
     
     
         49 . The method of  claim 31 , wherein the subjected has improved dark adaptation or a reduction in the rate of development of retinal atrophy as a result of the administering of the composition relative to a control subject. 
     
     
         50 . The method of  claim 31 , wherein the RLBP1-associated retinal dystrophy is retinitis pigmentosa.