Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8
| Autor: | Sophia H.Y. Liao, Suzanne Scott, Erhua Zhu, Loan Hanh Nguyen, Adrian Westhaus, Adrian J. Thrasher, Grober Baltazar, Renina Gale Navarro, Anais K. Amaya, Marti Cabanes-Creus, Leszek Lisowski, Matthieu Drouyer, Laurence O. W. Wilson, Ian E. Alexander, Matthias Hebben |
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| Rok vydání: | 2022 |
| Předmět: |
bioengineered vectors
viruses Transgene xenograft model Computational biology QH426-470 Gene delivery Vectors in gene therapy Biology recombinant vectors Transduction (genetics) Genetics Molecular Biology Tropism bioengineering QH573-671 Mechanism (biology) AAV adeno-associated vectors Directed evolution gene therapy preclinical liver model Capsid Molecular Medicine Original Article Cytology liver-tropic |
| Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 24, Iss, Pp 88-101 (2022) |
| ISSN: | 2329-0501 |
| DOI: | 10.1016/j.omtm.2021.11.011 |
| Popis: | 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. Graphical Abstract Using DNA-family shuffling and directed evolution, AAV variable regions (VRs) responsible for efficient human hepatocyte transduction in vivo were identified. Dissection of these regions via domain-swapping strategies defined key transferable domains that markedly enhanced primary human hepatocyte uptake and transgene expression of AAV7 and AAV8. |
| Databáze: | OpenAIRE |
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