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Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8.

Marti Cabanes-Creus·Renina Gale Navarro·Erhua Zhu·Grober Baltazar·Sophia H Y Liao·Matthieu Drouyer·Anais K Amaya·Suzanne Scott·Loan Hanh Nguyen·Adrian Westhaus·Matthias Hebben·Laurence O W Wilson·Adrian J Thrasher·Ian E Alexander·Leszek Lisowski
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Abstract

Recent clinical successes have intensified interest in using adeno-associated virus (AAV) vectors for therapeutic gene delivery. The liver is a key clinical target, given its critical physiological functions and involvement in a wide range of genetic diseases. Here, we report the bioengineering of a set of next-generation AAV vectors, named AAV-SYDs (where "SYD" stands for Sydney, Australia), with increased human hepato-tropism in a liver xenograft mouse model repopulated with primary human hepatocytes. We followed a two-step process that staggered directed evolution and domain-swapping approaches. Using DNA-family shuffling, we first mapped key AAV capsid regions responsible for efficient human hepatocyte transduction in vivo. Focusing on these regions, we next applied domain-swapping strategies to identify and study key capsid residues that enhance primary human hepatocyte uptake and transgene expression. Our findings underscore the potential of AAV-SYDs as liver gene therapy vectors and provide insights into the mechanism responsible for their enhanced transduction profile.

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AAVadeno-associated vectorsbioengineered vectorsbioengineeringgene therapyliver-tropicpreclinical liver modelrecombinant vectorsxenograft modelJournal Article

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Marti Cabanes-Creus, Renina Gale Navarro, Erhua Zhu, Grober Baltazar, Sophia H Y Liao, Matthieu Drouyer, Anais K Amaya, Suzanne Scott, Loan Hanh Nguyen, Adrian Westhaus, Matthias Hebben, Laurence O W Wilson, Adrian J Thrasher, Ian E Alexander, Leszek Lisowski. 2021-11-25. Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8.. https://doi.org/10.1016/j.omtm.2021.11.011

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