Aav capsid variants and uses thereof

Patent metadata

Field	Value
Publication number	US-2025388626-A1
Application number	US-202318877793-A
Country	US
Kind code	A1
Filing date	Jul 5, 2023
Priority date	Jul 6, 2022
Publication date	Dec 25, 2025
Grant date	—

Abstract

The disclosure relates to compositions and methods for the preparation, use, and/or formulation of adeno-associated virus capsid protein variants.

First claim

We claim:

1 . An AAV5 capsid variant comprising the amino acid sequence of positions 193-724 of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises the amino acid S at position 578 and E at position 579, numbered according to SEQ ID NO: 982.

2 . An AAV5 capsid variant comprising the amino acid sequence of positions 137-724 of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises the amino acid S at position 578 and E at position 579, numbered according to SEQ ID NO: 982.

3 . An AAV5 capsid variant comprising the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises an S at position 578 and an E at position 579, numbered according to SEQ ID NO: 982.

4 . The AAV5 capsid variant of any one of claims 1-3 , which further comprises one, two, or all of an amino acid other than A at position 581, T at position 582, and/or G at position 583, numbered according to SEQ ID NO: 138.

5 . The AAV capsid variant of any one of claims 1-4 , which further comprises one, two, or all of the amino acid T at position 581, K at position 582, and W at position 583, numbered according to SEQ ID NO: 982.

6 . An AAV5 capsid variant comprising the amino acid sequence of positions 193-724 of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises the amino acid S at position 578, E at position 579, T at position 581, K at position 582, and W at position 583, numbered according to SEQ ID NO: 982.

7 . An AAV5 capsid variant comprising the amino acid sequence of positions 137-724 of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises the amino acid S at position 578, E at position 579, T at position 581, K at position 582, and W at position 583, numbered according to SEQ ID NO: 982.

8 . An AAV5 capsid variant comprising the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises the amino acid S at position 578, E at position 579, T at position 581, K at position 582, and W at position 583, numbered according to SEQ ID NO: 982.

9 . The AAV5 capsid variant of any one of claims 1 or 4-6 , which comprises the amino acid sequence of positions 193-724 of SEQ ID NO: 982.

10 . The AAV5 capsid variant of any one of claims 1, 2, or 4-7 , which comprises the amino acid sequence of positions 137-724 of SEQ ID NO: 982.

11 . The AAV5 capsid variant of any one of claims 1-10 , which comprises the amino acid sequence of SEQ ID NO: 982.

12 . The AAV5 capsid variant of any one of claims 1-11 , wherein the nucleotide sequence encoding the AAV5 capsid variant comprises SEQ ID NO: 984, or a nucleotide sequence at least 95% identical thereto.

13 . The AAV5 capsid variant of any one of claims 1-12 , wherein the AAV5 capsid variant has one, two, three, four, or all of the following properties:
(i) has an increased tropism for a muscle cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 139; (ii) transduces a muscle region, optionally wherein the level of transduction is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15-fold greater as compared to a reference sequence of SEQ ID NO: 138 or 139, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 3; (iii) delivers an increased level of a payload to a muscle cell or region, optionally wherein the level of the payload is increased by at least 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 3); (iv) delivers an increased level of viral genomes to a muscle cell or region, optionally wherein the level of viral genomes is increased by at least 2, 2.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 12.6, 12.7, or 13-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 3); and/or (v) has an decreased tropism for a liver cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID SEQ ID NO: 139

14 . The AAV5 capsid variant of any one of claims 1-13 , wherein the AAV5 capsid variant has one, two, three, four, or all of the following properties:
(i) has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID SEQ ID NO: 139; (ii) transduces a brain cell or region, e.g., (e.g., the caudate, motor cortex, putamen, thalamus, and/or cerebellum), optionally wherein the level of transduction is at least 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 2.6, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46-fold greater as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 3; (iii) enriched at least about 4.5, 5, 10, 20, 21, 25, 28, 30, 40, 50, 55, 60, 70, 80, 81, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 203, or 205-fold, in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1 or 2; (iv) delivers an increased level of a payload to a brain cell or region, optionally wherein the level of the payload is increased by at least 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 2.6, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 3), optionally wherein the brain region is a caudate or motor cortex; and/or (v) delivers an increased level of viral genomes to a brain cell or region, optionally wherein the level of viral genomes is increased by at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 3), optionally wherein the brain region is a caudate or a motor cortex.

15 . A polynucleotide encoding the AAV5 capsid variant of any one of claims 1-14 .

16 . The polynucleotide of claim 15 , which comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence at least 95% identical thereto.

17 . A peptide comprising:
(a) the amino acid sequence of SEQ ID NO: 943; (b) an amino acid sequence comprising at least 4 or 5 consecutive amino acids from SEQ ID NO: 943; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of SEQ ID NO: 943; or (d) an amino sequence comprising one, two, or three but no more than f

Assignees

• Voyager Therapeutics Inc

Inventors

• Nonnenmacher Mathieu Emmanuel
• Lin Jing
• Wang Hongxing
• Hou Jinzhao
• Wang Wei
• Li Jiangyu

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

• C12N15/86 Primary

  Viral vectors · CPC title

• C07K14/005 Primary

  from viruses · CPC title

• A61K48/005

  characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered · CPC title