Compositions and methods for modulating transduction efficiency of adeno-associated viruses

Patent metadata

Field	Value
Publication number	US-12195745-B2
Application number	US-201917269955-A
Country	US
Kind code	B2
Filing date	Aug 21, 2019
Priority date	Aug 21, 2018
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

Abstract

Methods and compositions for modulating the transduction efficiency of an adeno-associated vims (AAV) into a cell or tissue are provided.

First claim

What is claimed is:

1. A method of modulating the transduction efficiency of an adeno-associated virus (AAV) into a cell, the method comprising
introducing a genetically-modified adeno-associated virus (AAV) into the cell, wherein the AAV capsid has been genetically modified to comprise a heterologous VP1 polypeptide sequence, wherein the heterologous VP1 polypeptide sequence requires the presence of a GPR108 receptor for transduction or does not require the presence of a GPR108 receptor for transduction of the cell, wherein the heterologous VP1 polypeptide or portion thereof comprises the sequence shown in SEQ ID NO: 18 or 19.

2. The method of claim 1 , wherein the heterologous VP1 polypeptide sequence requires the presence of a GPR108 receptor for transduction.

3. The method of claim 1 , wherein the heterologous VP1 polypeptide sequence does not require the presence of a GPR108 receptor for transduction of the cell.

4. A method of modifying the cell entry of an adeno-associated virus (AAV), the method comprising:
genetically engineering an AAV to be GPR108-independent, wherein the genetically engineered GPR108-independent AAV comprises a VP1 polypeptide sequence having the sequence SEQ ID NO: 18, or
genetically engineering an AAV to be GPR108-dependent, wherein the genetically engineered GPR108-dependent AAV comprises a VP1 polypeptide sequence having the sequence shown in SEQ ID NO:19,
thereby modifying the cell entry of the AAV.

5. The method of claim 1 , wherein the cell is in vivo.

6. The method of claim 1 , wherein the cell is selected from the group consisting of a liver cell, a kidney cell, a heart cell, a lung cell, an epithelial cell, an endothelial cell, a bone marrow cell, and a hematopoietic stem cell.

7. A method of increasing the uptake of a heterologous therapeutic agent into a cell, the method comprising contacting the cell with the heterologous therapeutic agent linked to an AAV VP1 polypeptide, wherein the VP1 polypeptide comprises the sequence shown in SEQ ID NO: 18.

8. The method of claim 7 , wherein the therapeutic agent is a protein or protein complex.

9. The method of claim 7 , wherein the therapeutic agent is further linked to a binding factor that binds to GPR108.

10. The method of claim 9 , wherein the binding factor that binds to GPR108 is selected from the group consisting of an antibody, an aptamer, and an antibody domain.

11. A composition comprising a heterologous therapeutic agent linked to a VP1 polypeptide comprising SEQ ID NO:18 or SEQ ID NO: 19.

12. The composition of claim 11 , wherein the heterologous therapeutic agent is a protein or protein complex.

13. An AAV capsid sequence comprising a heterologous VP1 sequence that comprises SEQ ID NO: 18.

14. An AAV capsid sequence comprising a heterologous VP1 sequence that comprises SEQ ID NO: 19.

Assignees

• Massachusetts Eye & Ear Infirmary
• Schepens Eye Res Inst

Inventors

• Vandenberghe Luk H
• Dudek Amanda
• Lasarte Nerea Zabaleta

Classifications

• C12N2750/14143

  viral genome or elements thereof as genetic vector · CPC title

• C12N2750/14122

  New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes · CPC title

• C12N2750/14121

  Viruses as such, e.g. new isolates, mutants or their genomic sequences · CPC title

• C12N7/00

  Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title