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 the NPC1 protein;
a polyadenylation signal; and
a 3′ ITR.
2 . The AAV vector of claim 1 , wherein the transfer cassette comprises an intronic sequence.
3 . The AAV vector of claim 2 , wherein the intronic sequence comprises the sequence of SEQ ID NO: 10.
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 the CBA promoter.
7 . The AAV vector of claim 1 , wherein the promoter comprises the sequence of SEQ ID NO: 3005.
8 . The AAV vector of claim 1 , wherein the NPC1 protein is the human NPC1 protein.
9 . The AAV vector of claim 1 , wherein the 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 the SV40 polyadenylation signal.
12 . The AAV vector of claim 1 , wherein the polyadenylation signal comprises the sequence of SEQ ID NO: 3012.
13 . The AAV vector of claim 1 , wherein the cassette comprises an enhancer.
14 . The AAV vector of claim 1 , wherein the AAV transfer cassette comprises the sequence of SEQ ID NO: 3014
15 . The AAV vector of claim 1 , wherein the AAV transfer cassette comprises the sequence of any one of SEQ ID NO: 3015-3019.
16 . An adeno-associated virus (AAV) vector comprising:
(i) a protein capsid comprising a capsid protein subunit comprising the sequence of SEQ ID NO: 180, or a sequence comprising about 1 to about 25 amino acid mutations relative to 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 which encodes the NPC1 protein;
a polyadenylation signal; and
a 3′ ITR.
17 . A composition comprising the AAV vector of any one of claims 1 - 16 .
18 . A cell comprising the AAV vector of any one of claims 1 - 16 .
19 . A method for treating a subject in need thereof comprising administering to the subject an effective amount of the AAV vector of any one of claims 1 - 16 , the composition of claim 17 , or the cell of claim 18 .
20 . The method of claim 19 , wherein the subject has Neimann-Pick Disease Type C.
21 . The method of claim 19 or 20 , wherein the subject is a human subject.