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

作者：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 · 发表于：Molecular Therapy — Methods & Clinical Development · 年份：2021 · DOI：10.1016/j.omtm.2021.11.011 · 被引用次数：45 · 研究领域：Virus-based gene therapy research、Viral Infections and Immunology Research、Herpesvirus Infections and Treatments

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.