期刊
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
卷 21, 期 -, 页码 607-620出版社
CELL PRESS
DOI: 10.1016/j.omtm.2021.04.010
关键词
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资金
- Australian National Health and Medical Research Council (NHMRC) [APP1108311, APP1156431, APP1161583]
- Department of Science and Higher Education of Ministry of National Defense, Republic of Poland [k/10/8047/DNiSW/T -WIHE/3]
- National Science Centre, Republic of Poland (OPUS 13) [UMO-2017/25/B/NZ1/02790]
- Paediatrio Paediatric Precision Medicine Program [PPM1 K5116/RD274]
- LogicBio Therapeutics
The study investigates the differential interspecies transduction abilities among AAV variants, identifying a key residue at a specific position through domain swapping strategies, and proposes the generation of AAV surrogates using this insertion for toxicology and dosing studies in the murine liver model.
Recent successes in clinical gene therapy applications have intensified the interest in using adeno-associated viruses (AAVs) as vectors for gene delivery into human liver. An inherent intriguing characteristic of AAVs is that vector variants vary substantially in their ability to transduce hepatocytes from different species. This has historically limited the value of preclinical studies using rodent models for predicting the efficiency of AAV vectors in liver-targeted gene therapy clinical studies. In this work, we aimed to investigate the key determinants of the observed differential interspecies transduction abilities among AAV variants. We took advantage of domain swapping strategies between AAV-KP1, a newly identified variant with enhanced murine liver tropism, and AAV3b, which functions poorly in mice. The systematic in vivo comparison of AAV3b/AAV-KP1 chimeric variants allowed us to identify a threonine insertion at position 265 within variable region I (VR-I) as the key residue that confers murine hepatic transduction to human-derived clade B (AAV2-like) and clade C (AAV3b-like) variants. We propose to use this insertion to generate phylogenetically related AAV surrogates in support of toxicology and dosing studies in the murine liver model.
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