Adeno-associated viral vectors for treatment of Niemann-Pick Disease type-C
Provided herein are gene therapy compositions and methods for treating, preventing, and/or curing NPC1. More specifically, the disclosure provides Adeno-associated virus (AAV) vectors for delivery of nucleic acids and nucleic acids (including AAV transfer cassettes) for treating, preventing, and/or curing NPC1.
1. An adeno-associated virus (AAV) vector comprising:
(i) a protein capsid comprising a capsid protein subunit comprising the sequence of SEQ ID NO: 180; and
(ii) a nucleic acid encapsidated by the protein capsid;
wherein the nucleic acid comprises a transfer cassette;
wherein the transfer cassette comprises, from 5′ to 3′:
a 5′ inverted terminal repeat (ITR);
a promoter;
a transgene that encodes a Niemann-Pick intracellular cholesterol transporter 1 (NPC1) protein;
a polyadenylation signal; and
a 3′ ITR.
2. The AAV vector of claim 1 , wherein the transfer cassette further comprises an intronic sequence.
3. The AAV vector of claim 2 , wherein the intronic sequence comprises the sequence of SEQ ID NO: 3010 or 3011.
4. The AAV vector of claim 1 , wherein the 5′ ITR comprises the sequence of SEQ ID NO: 3003.
5. The AAV vector of claim 1 , wherein the 3′ ITR comprises the sequence of SEQ ID NO: 3004.
6. The AAV vector of claim 1 , wherein the promoter is a chicken β-actin (CBA) promoter.
7. The AAV vector of claim 6 , wherein the CBA promoter comprises the sequence of SEQ ID NO: 3005.
8. The AAV vector of claim 1 , wherein the NPC1 protein is a human NPC1 protein.
9. The AAV vector of claim 8 , wherein the human NPC1 protein comprises the sequence of SEQ ID NO: 3001.
10. The AAV vector of claim 1 , wherein the transgene comprises the sequence of SEQ ID NO: 3002.
11. The AAV vector of claim 1 , wherein the polyadenylation signal is a SV40 polyadenylation signal.
12. The AAV vector of claim 11 , wherein the SV40 polyadenylation signal comprises the sequence of SEQ ID NO: 3012.
13. The AAV vector of claim 1 , wherein the transfer cassette further comprises an enhancer.
14. The AAV vector of claim 1 , wherein the transfer cassette comprises the sequence of SEQ ID NO: 3014.
15. The AAV vector of claim 1 , wherein the transfer cassette comprises the sequence of any one of SEQ ID NO: 3015-3019.
16. A composition comprising the AAV vector of claim 1 .
17. A cell comprising the AAV vector of claim 1 .
18. A method for treating a subject in need thereof comprising administering to the subject an effective amount of the AAV vector of claim 1 .
19. The method of claim 18 , wherein the subject has Neimann-Pick Disease Type C.
20. The method of claim 18 , wherein the subject is a human subject.