Generative design of de novo AAV vectors with unique serological profiles

A variational autoencoder generated de novo AAV capsid designs where four candidates avoided neutralizing antibody neutralization (NT50 < 1:50) across all reactive human sera.

• Why it matters: Pre-existing neutralizing antibodies limit who can receive AAV gene replacement therapies, and prior engineering approaches often compromise AAV function before full antibody escape is reached.
• What they did: The team trained a variational autoencoder on natural AAV sequence constraints, synthesized and tested more than 255 designs in vitro across two design sets, including one probing uncertain sequence regions.
• The result: Across both campaigns, seven designs transduced human cells with >50% efficiency, and one showed 18% sequence identity to the nearest natural AAV sequence, enabling a de novo serotype with a unique serological profile.

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