Single amino acid insertion allows functional transduction of murine hepatocytes with human liver tropic AAV capsids
| العنوان: | Single amino acid insertion allows functional transduction of murine hepatocytes with human liver tropic AAV capsids |
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| المؤلفون: | Matthieu Drouyer, Sophia H.Y. Liao, Laurence O. W. Wilson, Grober Baltazar, Leszek Lisowski, Erhua Zhu, Ian E. Alexander, Marti Cabanes-Creus, Clement Luong, Renina Gale Navarro, Suzanne Scott |
| المصدر: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 21, Iss, Pp 607-620 (2021) |
| بيانات النشر: | American Society of Gene & Cell Therapy, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Genetic enhancement, viruses, AAV capsid, Computational biology, adeno-associated virus, Gene delivery, Biology, QH426-470, medicine.disease_cause, Viral vector, 03 medical and health sciences, Transduction (genetics), 0302 clinical medicine, medicine, Genetics, Vector (molecular biology), vectorology, Molecular Biology, Adeno-associated virus, preclinical model, Tropism, bioengineering, QH573-671, viral vector, surrogate capsids, gene therapy, 030104 developmental biology, Capsid, 030220 oncology & carcinogenesis, Molecular Medicine, Original Article, Cytology |
| الوصف: | 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. Graphical abstract A threonine insertion at position 265 within VR-I confers murine hepatic transduction to human-derived clade B (AAV2-like) and clade C (AAV3b-like) AAV variants. This insertion can be used to generate phylogenetically related surrogates of clinical AAVs in support of toxicology and dosing studies in the murine models of human liver. |
| اللغة: | English |
| تدمد: | 2329-0501 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da86da39103bb7233e4ce023c4d8fa11 http://europepmc.org/articles/PMC8142051 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....da86da39103bb7233e4ce023c4d8fa11 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23290501 |
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