AAV capsid bioengineering in primary human retina models.

Autor: Westhaus A; Translational Vectorology Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, Australia.; Infection, Immunity and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, UK.; Genethon, Evry, France., Eamegdool SS; Eye Genetics Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute and Sydney Children's Hospitals Network, The University of Sydney, Westmead, Australia., Fernando M; Stem Cell and Organoid Facility, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, Australia., Fuller-Carter P; Lions Eye Institute, Nedlands, Australia., Brunet AA; Centre for Ophthalmology and Visual Sciences, The University of Western Australia, Nedlands, Australia., Miller AL; Centre for Ophthalmology and Visual Sciences, The University of Western Australia, Nedlands, Australia., Rashwan R; Lions Eye Institute, Nedlands, Australia., Knight M; Translational Vectorology Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, Australia., Daniszewski M; Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia., Lidgerwood GE; Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia., Pébay A; Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia.; Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia., Hewitt A; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.; Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia., Santilli G; Infection, Immunity and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, UK., Thrasher AJ; Infection, Immunity and Inflammation Teaching and Research Department, Great Ormond Street Institute of Child Health, University College London, London, UK., Carvalho LS; Lions Eye Institute, Nedlands, Australia.; Centre for Ophthalmology and Visual Sciences, The University of Western Australia, Nedlands, Australia., Gonzalez-Cordero A; Stem Cell and Organoid Facility, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, Australia.; Stem Cell Medicine Group, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, Australia., Jamieson RV; Eye Genetics Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute and Sydney Children's Hospitals Network, The University of Sydney, Westmead, Australia., Lisowski L; Translational Vectorology Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, Australia. llisowski@cmri.org.au.; Australian Genome Therapeutics Centre, Children's Medical Research Institute and Sydney Children's Hospitals Network, Westmead, NSW, 2145, Australia. llisowski@cmri.org.au.; Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Warsaw, Poland. llisowski@cmri.org.au.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Dec 11; Vol. 13 (1), pp. 21946. Date of Electronic Publication: 2023 Dec 11.
DOI: 10.1038/s41598-023-49112-2
Abstrakt: Adeno-associated viral (AAV) vector-mediated retinal gene therapy is an active field of both pre-clinical as well as clinical research. As with other gene therapy clinical targets, novel bioengineered AAV variants developed by directed evolution or rational design to possess unique desirable properties, are entering retinal gene therapy translational programs. However, it is becoming increasingly evident that predictive preclinical models are required to develop and functionally validate these novel AAVs prior to clinical studies. To investigate if, and to what extent, primary retinal explant culture could be used for AAV capsid development, this study performed a large high-throughput screen of 51 existing AAV capsids in primary human retina explants and other models of the human retina. Furthermore, we applied transgene expression-based directed evolution to develop novel capsids for more efficient transduction of primary human retina cells and compared the top variants to the strongest existing benchmarks identified in the screening described above. A direct side-by-side comparison of the newly developed capsids in four different in vitro and ex vivo model systems of the human retina allowed us to identify novel AAV variants capable of high transgene expression in primary human retina cells.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: