Gene Therapy for NMNAT1-Associated Retinal Degeneration
Methods and compositions for gene therapy of retinal degeneration related to mutations in nicotinaminde mononucleotide adenylyltransferase 1 (NMNAT1).
1 - 12 . (canceled)
13 . An adeno-associated virus (AAV) vector genome comprising from 5′ to 3′:
(i) a CASI promoter;
(ii) a human nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) coding sequence; and
(iii) a bovine growth hormone polyadenylation signal (bGHpA) sequence.
14 . The AAV vector genome of claim 13 , wherein the human NMNAT1 coding sequence has at least 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1.
15 . The AAV vector genome of claim 13 , wherein the human NMNAT1 coding sequence has at least 95% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1.
16 . The AAV vector genome of claim 13 , wherein the human NMNAT1 coding sequence encodes the amino acid sequence set forth in SEQ ID NO: 3.
17 . The AAV vector genome of claim 13 , wherein the human NMNAT1 coding sequence has at least 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1 and encodes the amino acid sequence set forth in SEQ ID NO: 3.
18 . The AAV vector genome of claim 13 , wherein the human NMNAT1 coding sequence has at least 95% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1 and encodes the amino acid sequence set forth in SEQ ID NO: 3.
19 . The AAV vector genome of claim 13 , wherein the CASI promoter drives expression in photoreceptor cells.
20 . The AAV vector genome of claim 13 , wherein the AAV vector genome is a single-stranded or self-complementary AAV vector genome.
21 . The AAV vector genome of claim 13 , wherein the AAV vector genome is a self-complementary AAV vector genome.
22 . A recombinant AAV (rAAV) comprising an AAV capsid and the AAV vector genome of claim 1 .
23 . The rAAV of claim 22 , wherein the AAV capsid is an AAV9 or Anc80 capsid.
24 . The rAAV of claim 22 , wherein the AAV capsid is an AAV9 capsid.
25 . A recombinant adeno-associated virus (rAAV) comprising an AAV9 capsid and an AAV vector genome comprising from 5′ to 3′:
(i) a CASI promoter;
(ii) a human nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) coding sequence, wherein the human NMNAT1 coding sequence has at least 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1 and encodes the amino acid sequence set forth in SEQ ID NO: 3; and
(iii) a bovine growth hormone polyadenylation signal (bGHpA) sequence.
26 . A pharmaceutical composition comprising the rAAV of claim 22 .
27 . A pharmaceutical composition comprising the rAAV of claim 25 .
28 . A method of increasing expression of NMNAT1 in the eye of a human subject, the method comprising delivering to an eye of the subject a therapeutically effective amount of the recombinant AAV of claim 22 .
29 . A method of treating a disease caused by one or more mutations in a nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) gene in a human subject, the method comprising delivering to an eye of the subject a therapeutically effective amount of the recombinant AAV of claim 22 .
30 . The method of claim 29 , wherein the disease is selected from the group consisting of retinal degeneration, Leber congenital amaurosis, early-onset severe retinal dystrophy, and loss of vision.
31 . A method of treating a disease caused by one or more mutations in a nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) gene in a human subject, the method comprising delivering to an eye of the subject a therapeutically effective amount of the recombinant AAV of claim 25 .