한빛사논문
- 조회501
Gijung Kwak 1,2, Olesia Gololobova 3, Neeraj Sharma 4, Colin Caine 5, Marina Mazur 6, Kathleen Mulka 3, Natalie E West 7, George M Solomon 6, Garry R Cutting 4, Kenneth W Witwer 3, Steven M Rowe 6, Michael Paulaitis 1, George Aslanidi 5,8,9, Jung Soo Suk 1,2,10
1Center for Nanomedicine at Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
3Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
5Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
6Gregory Fleming James Cystic Fibrosis Research Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
7Department of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
8Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
9Institute for Molecular Virology, University of Minnesota, Minneapolis, USA, Minnesota.
10Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
CORRESPONDING AUTHOR : Jung Soo Suk
Abstract
Adeno-associated virus (AAV) vector has shown multiple clinical breakthroughs, but its clinical implementation in inhaled gene therapy remains elusive due to difficulty in transducing lung airway cells. We demonstrate here AAV serotype 6 (AAV6) associated with extracellular vesicles (EVs) and secreted from vector-producing HEK-293 cells during vector preparation (EVAAV6) as a safe and highly efficacious gene delivery platform for inhaled gene therapy applications. Specifically, we discovered that EVAAV6 provided markedly enhanced reporter transgene expression in mucus-covered air-liquid interface (ALI) cultures of primary human bronchial and nasal epithelial cells as well as in mouse lung airways compared to standard preparations of AAV6 alone. Of note, AAV6 has been previously shown to outperform other clinically tested AAV serotypes, including those approved by the FDA for treating non-lung diseases, in transducing ALI cultures of primary human airway cells. We provide compelling experimental evidence that the superior performance of EVAAV6 is attributed to the ability of EV to facilitate mucus penetration and cellular entry/transduction of AAV6. The tight and stable linkage between AAV6 and EVs appears essential to exploit the benefits of EVs given that a physical mixture of individually prepared EVs and AAV6 failed to mediate EV-AAV6 interactions or to enhance gene transfer efficacy.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-07-11)
- 국외 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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