Recombinant adeno-associated virus capsids resistant to pre-existing human neutralizing antibodies
AssigneeThe Board of Trustees of the Leland Stanford Junior University
InventorsMark A. Kay, Nicole K. Paulk
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Abstract
The present invention relates to variant AAV capsid polypeptides, wherein the variant capsid polypeptides exhibit an enhanced neutralization profile, increased transduction and/or tropism in human liver tissue or hepatocyte cells (i.e., human hepatocyte cells), or both, as compared non-variant parent capsid polypeptides.
Claims50
An adeno-associated virus (AAV) vector comprising a nucleic acid sequence encoding a variant AAV capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits increased transduction or tropism in human liver tissue or hepatocyte cells as compared to a non-variant parent capsid polypeptide, wherein said variant AAV capsid polypeptide sequence comprises a sequence selected from the group consisting of AAV-NP84 (SEQ ID NO:2), AAV-NP59 (SEQ ID NO:4), AAV-NP40 (SEQ ID NO:6), and AAV-NP30 (SEQ ID NO:8).
An adeno-associated virus (AAV) vector comprising a nucleic acid sequence encoding a variant AAV capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits an enhanced neutralization profile as compared to a non-variant parent capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits increased transduction of human liver organoids in 3-dimensional cultures in vitro as compared to a non-variant parent capsid polypeptide, wherein said variant AAV capsid polypeptide sequence comprises a sequence selected from the group consisting of AAV-NP84 (SEQ ID NO:2), AAV-NP59 (SEQ ID NO:4), AAV-NP40 (SEQ ID NO:6), and AAV-NP30 (SEQ ID NO:8).
An adeno-associated virus (AAV) vector comprising a nucleic acid sequence encoding a variant AAV capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits an enhanced neutralization profile as compared to a non-variant parent capsid polypeptide, wherein said vector further comprises a nucleic acid sequence comprising a therapeutic expression cassette, wherein said expression cassette is a CRISPR/CAS expression system, wherein said variant AAV capsid polypeptide sequence comprises a sequence selected from the group consisting of AAV-NP84 (SEQ ID NO:2), AAV-NP59 (SEQ ID NO:4), AAV-NP40 (SEQ ID NO:6), and AAV-NP30 (SEQ ID NO:8).
An adeno-associated virus (AAV) vector comprising a nucleic acid sequence encoding a variant AAV capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits an enhanced neutralization profile as compared to a non-variant parent capsid polypeptide, wherein said variant AAV capsid polypeptide sequence comprises a sequence selected from the group consisting of AAV-NP84 (SEQ ID NO:2), AAV-NP59 (SEQ ID NO:4), AAV-NP40 (SEQ ID NO:6), and AAV-NP30 (SEQ ID NO:8).
An adeno-associated virus (AAV) vector comprising a nucleic acid sequence encoding a variant AAV capsid polypeptide, wherein said nucleic acid sequence encoding said variant AAV capsid polypeptide comprises a sequence selected from the group consisting of AAV-NP84 (SEQ ID NO:1), AAV-NP59 (SEQ ID NO:3), AAV-NP40 (SEQ ID NO:5), and AAV-NP30 (SEQ ID NO:7).
An adeno-associated virus (AAV) vector comprising a nucleic acid sequence encoding a variant AAV capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits increased transduction or tropism in human liver tissue or hepatocyte cells as compared to a non-variant parent capsid polypeptide, wherein said variant AAV capsid polypeptide exhibits increased transduction of human liver organoids in 3-dimensional cultures in vitro as compared to a non-variant parent capsid polypeptide, wherein said variant AAV capsid polypeptide sequence comprises a sequence selected from the group consisting of AAV-NP84 (SEQ ID NO:2), AAV-NP59 (SEQ ID NO:4), AAV-NP40 (SEQ ID NO:6), and AAV-NP30 (SEQ ID NO:8.
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