Aav capsid variants and uses thereof
AssigneeVoyager Therapeutics, Inc.
InventorsMathieu Emmanuel Nonnenmacher, Tyler Christopher Moyer, Jiangyu Li, Brett Hoffman, Tatiana Knox, Ishan Sanjeev Shah, Dan Richard Laks
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Abstract
The disclosure relates to compositions and methods for the preparation, use, and/or formulation of adeno-associated virus capsid protein variants.
Claims66
An AAV capsid variant, comprising an amino acid sequence comprising SPH, wherein the SPH is present at positions 454-456, 455-457, 457-459, 458-460, or 459-461, numbered according to SEQ ID NO:
- 138, wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:
- 138.
An AAV capsid variant comprising an amino acid sequence having the following formula:
- X1X2SPHX3, wherein X3 does not comprise a basic amino acid, e.g., is not K or R;
- wherein the amino acid sequence is present in loop IV, wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:
- 138.
An AAV capsid variant comprising an amino acid sequence having the following formula:
- X1X2SPHX3, wherein X3 is P, Y, G, S, W, T, A, N, L, Q, M, I, V, or H;
- wherein the amino acid sequence is present in loop IV, wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:
- 138.
An AAV capsid variant comprising the amino acid sequence of any one of SEQ ID NOs:
- 1100-1571, 1573-1658, or 1659-1735, wherein the amino acid sequence is present immediately subsequent to position 453 or 455, numbered according to SEQ ID NO:
- 138 or 981, wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:
- 138.
An AAV capsid variant comprising the amino acid sequence of any one of SEQ ID NOs:
- 1102, 1138, 1140, 1209, 1286, 1291, 1296, 1297, 1305, 1311, 1320, 1321, 1338, 1347, 1349, 1358, 1365, 1379, 1382, 1384, 1387, 1390, 1391, 1396, 1406, 1407, 1409, 1410, 1411, 1423, 1427, 1431, 1434, 1440-1571, or 1573-1731, wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to SEQ ID NO:
- 138 or 982, wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:
- 138.
An AAV capsid variant comprising the amino acid sequence of any one of SEQ ID NOs:
- 1379, 1387, 1391, 1396, 1406, 1409, 1410, 1431, 1440-1444, 1446-1461, 1463-1470, 1472, 1474, 1475, 1477-1479, 1481-1484, 1488-1491, 1494, 1497-1499, 1514, 1515, 1520, 1521, 1529, 1540, 1544, 1546, 1548, 1550, or 1556, wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to SEQ ID NO:
- 138 or 982, wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:
- 138.
An AAV capsid variant comprising the amino acid sequence of any one of SEQ ID NOs:
- 1100-1439, wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO:
- 138 or 981, wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:
- 138.
An AAV capsid variant comprising the amino acid sequence of any one of SEQ ID NOs:
- 1100-1283, wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO:
- 138 or 981, wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:
- 138.
An AAV capsid variant comprising an amino acid sequence comprising:
- (a) at least 4, 5, or 6 consecutive amino acids of any one of the sequences in Tables 1, 48, or 49;
- (b) at least 4, 5, or 6 consecutive amino acids of any one of SEQ ID NOs:
- 1100-1571, 1573-1664, or 1732-1735;
- (c) at least 4, 5, 6, or 7 consecutive amino acids of any one of SEQ ID NOs:
- 1665-1685;
- or
- (c) at least 4, 5, 6, 7, 8 or 9 consecutive amino acids of any one of SEQ ID NOs:
- 1686-1731, optionally wherein the amino acid sequence is present:
- (i) in hypervariable loop IV;
- (ii) immediately subsequent to position 453 or 455, numbered according to SEQ ID NO:
- 138.
The AAV capsid variant of any one of the preceding claims, which comprises one, two, or all of the following properties:
- (i) is capable of binding to a glycosylphosphatidylinositol (GPI) anchored protein, e.g., alkaline phosphatase (ALPL);
- (ii) demonstrates preferential transduction in a cell comprising a glycosylphosphatidylinositol (GPI) anchored protein, e.g., alkaline phosphatase (ALPL), relative to a cell that does not comprise a glycosylphosphatidylinositol (GPI) anchored protein, e.g., as measured by an assay, e.g., an assay of Example 4;
- and/or
- (iii) is enriched at least 292, 250, 230, 220, 215, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 105, 100, 90, 95, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, or 2-fold in a cell comprising a glycosylphosphatidylinositol (GPI) anchored protein, e.g., alkaline phosphatase (ALPL), e.g., relative to levels present prior to transduction, e.g., as measured by an assay, e.g., an assay of Example 4.
The AAV capsid variant of any one of the preceding claims, which further comprises:
- (i) a modification, e.g., an insertion, substitution (e.g., conservative substitution), and/or deletion, in loop I, II, VI and/or VIII;
- and/or
- (ii) a substitution at position K449, e.g., a K449R substitution, numbered according to SEQ ID NO:
- 138.
A peptide comprising the amino acid sequence of any one of SEQ ID NOs:
- 1100-1571 or 1573-1735.
A peptide comprising an amino acid sequence comprising:
- (a) at least 4, 5, or 6 consecutive amino acids of any one of the sequences in Tables 1, 48, or 49;
- (b) at least 4, 5, or 6 consecutive amino acids of any one of SEQ ID NOs:
- 1100-1571, 1573-1664, or 1732-1735;
- (c) at least 4, 5, 6, or 7 consecutive amino acids of any one of SEQ ID NOs:
- 1665-1685;
- or
- (c) at least 4, 5, 6, 7, 8 or 9 consecutive amino acids of any one of SEQ ID NOs:
- 1686-1731.
The AAV capsid variant, polynucleotide, peptide, or AAV particle of any one of the preceding claims which is isolated, e.g., recombinant.
Dependencies are inferred from the claim text.