Compositions and methods for enhanced parvovirus transduction
View Patent ↗The present invention provides methods and compositions for enhanced transduction of an adeno-associated virus (AAV) vector comprising a heterologous nucleic acid of interest wherein the AAV vector genome is oversized relative to a wild type AAV genome by employing a proteasome inhibitor.
1. A composition comprising:
(a) an adeno-associated virus (AAV) vector comprising an AAV vector genome comprising a heterologous nucleic acid encoding a protein selected from the group consisting of Factor VIII (FVIII), dystrophin, mini-dystrophin and cystic fibrosis transmembrane regulator protein (CFTR), wherein the AAV vector genome is oversized relative to a wild type AAV genome; and
(b) bortezomib.
2. The composition of claim 1 , wherein the size of the AAV vector genome is greater than about 5.0 kb.
3. The composition of claim 1 , wherein the AAV vector genome is a double-stranded AAV vector genome.
4. The composition of claim 1 , wherein the AAV vector is a split transgene AAV vector.
5. The composition of claim 1 , wherein the heterologous nucleic acid comprises a coding sequence that has been optimized for enhanced expression.
6. The composition of claim 1 , wherein the heterologous nucleic acid comprises noncoding sequences that have been optimized for enhanced expression.
7. The composition of claim 1 , wherein the AAV vector genome has been optimized for enhanced expression.
8. A pharmaceutical formulation comprising a composition according to claim 1 in a pharmaceutically acceptable carrier.
9. A method of delivering the heterologous nucleic acid to a cell, comprising contacting the cell with the composition of claim 1 .
10. The method of claim 9 , wherein the cell is a muscle cell, a liver cell, a cell in a joint or a cell in a osteochondral site.
11. A method of delivering the heterologous nucleic acid to a subject, comprising administering to the subject the composition of claim 1 .
12. The method of claim 11 , wherein the subject is a human.
13. A method of delivering a heterologous nucleic acid to a subject, comprising administering to the subject an AAV vector comprising an AAV vector genome comprising a heterologous nucleic acid encoding a protein selected from the group consisting of FVIII, dystrophin, mini-dystrophin and CFTR, wherein the AAV vector genome is oversized relative to a wild type AAV genome; and bortezomib, wherein the AAV vector is administered to the subject before, and/or after administration of the bortezomib with or without concurrent administration of the bortezomib.