RP2 and RPGR vectors for treating X-linked retinitis pigmentosa
Disclosed are adeno-associated virus (AAV) vectors comprising a nucleotide sequence encoding RP2 or RPGR-ORF15 and related pharmaceutical compositions. Also disclosed are methods of treating or preventing X-linked retinitis pigmentosa, increasing photoreceptor number in a retina of a mammal, and increasing visual acuity of a mammal using the vectors and pharmaceutical compositions.
1. An adeno-associated virus (AAV) vector comprising a nucleic acid comprising
(a) a nucleotide sequence encoding RP2 or a functional fragment thereof;
(b) a human β-globin polyadenylation signal or a functional fragment thereof;
(c) a cytomegalovirus (CMV)/human β-globin intron;
(d) a human rhodopsin kinase promoter comprising the nucleotide sequence of SEQ ID NO: 10; and
(e) an AAV2 Inverted Terminal Repeat (ITR) or a functional fragment thereof;
wherein the nucleotide sequence encoding RP2 or functional fragment thereof is under the transcriptional control of the rhodopsin kinase promoter.
2. The vector of claim 1 , comprising the nucleotide sequence of SEQ ID NO: 7.
3. The vector of claim 1 , comprising the nucleotide sequence of SEQ ID NO: 9.
4. The vector according to claim 1 , wherein the vector is self-complementary.
5. The vector according to claim 1 , wherein the vector is an AAV8 or AAV9 vector.
6. A pharmaceutical composition comprising the vector of claim 1 , further comprising a pharmaceutically acceptable carrier.
7. A method of treating or preventing X-linked retinitis pigmentosa (XLRP) in a mammal in need thereof, the method comprising administering to the mammal the vector of claim 1 in an amount effective to treat or prevent XLRP in the mammal.
8. A method of increasing photoreceptor number in a retina of a mammal, the method comprising administering to the mammal the vector of claim 1 in an amount effective to increase photoreceptor number in the retina of the mammal.
9. A method of increasing visual acuity of a mammal, the method comprising administering to the mammal the vector claim 1 in an amount effective to increase visual acuity in the mammal.
10. A method of decreasing retinal detachment in a mammal, the method comprising administering to the mammal the vector of claim 1 in an amount effective to decrease retinal detachment in the mammal.
11. A method of increasing the electrical response of a photoreceptor in a mammal, the method comprising administering to the mammal the vector of claim 1 in an amount effective to increase the electrical response of the photoreceptor in the mammal.
12. A method of increasing expression of RP2 in a retina of a mammal, the method comprising administering to the mammal the vector of claim 1 in an amount effective to increase expression of RP2 in the retina of the mammal.
13. The method of claim 12 , comprising administering the vector comprising the nucleotide sequence encoding RP2 at a dose of about 5×10 6 to about 5×10 12 vector genomes (vg) per eye.
14. The method of claim 12 , wherein the mammal is a human.
15. The vector according to claim 1 , comprising the nucleotide sequence of SEQ ID NO: 12.
16. The vector according to claim 1 , comprising the nucleotide sequence of SEQ ID NO: 13.
17. The vector according to claim 1 , comprising the nucleotide sequence of SEQ ID NO: 1.
18. The vector according to claim 1 , wherein the nucleotide sequence encodes an amino acid sequence comprising SEQ ID NO: 2.
19. An adeno-associated virus (AAV) vector comprising a nucleic acid comprising
(a) a nucleotide sequence encoding RP2 or a functional fragment thereof;
(b) a human β-globin polyadenylation signal or a functional fragment thereof;
(c) a cytomegalovirus (CMV)/human β-globin intron comprising the nucleotide sequence of SEQ ID NO: 9;
(d) a human rhodopsin kinase promoter; and
(e) an AAV2 Inverted Terminal Repeat (ITR) or a functional fragment thereof;
wherein the nucleotide sequence encoding RP2 or functional fragment thereof is under the transcriptional control of the rhodopsin kinase promoter.
20. The vector according to claim 19 , wherein the vector is an AAV8 or AAV9 vector.
21. A pharmaceutical composition comprising the vector of claim 19 , further comprising a pharmaceutically acceptable carrier.
22. An adeno-associated virus (AAV) vector comprising a nucleic acid comprising
(a) a nucleotide sequence encoding RP2 or a functional fragment thereof;
(b) a human β-globin polyadenylation signal or a functional fragment thereof;
(c) a cytomegalovirus (CMV)/human β-globin intron;
(d) a human rhodopsin kinase promoter; and
(e) an AAV2 Inverted Terminal Repeat (ITR) or a functional fragment thereof;
wherein the nucleotide sequence encoding RP2 or functional fragment thereof is under the transcriptional control of the rhodopsin kinase promoter and the AAV vector comprises a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO: 14.
23. The vector according to claim 22 , comprising a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 14.
24. The vector according to claim 22 , comprising the nucleotide sequence of SEQ ID NO: 14.
25. The vector according to claim 22 , wherein the vector is an AAV8 or AAV9 vector.