A comprehensive atlas of AAV tropism in the mouse.

IF 12 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-25 DOI:10.1016/j.ymthe.2025.01.041

Christopher J Walkey, Kathy J Snow, Jote Bulcha, Aaron R Cox, Alexa E Martinez, M Cecilia Ljungberg, Denise G Lanza, Marco De Giorgi, Marcel A Chuecos, Michele Alves-Bezerra, Carlos Flores Suarez, Sean M Hartig, Susan G Hilsenbeck, Chih-Wei Hsu, Ethan Saville, Yaned Gaitan, Jeff Duryea, Seth Hannigan, Mary E Dickinson, Oleg Mirochnitchenko, Dan Wang, Cathleen M Lutz, Jason D Heaney, Guangping Gao, Stephen A Murray, William R Lagor

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Abstract

Gene therapy with adeno-associated virus (AAV) vectors requires knowledge of their tropism within the body. Here we analyze the tropism of 10 naturally occurring AAV serotypes (AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, and AAVrh74) following systemic delivery into male and female mice. A transgene-expressing ZsGreen and Cre recombinase was used to identify transduction in a cell-dependent manner based on fluorescence. Cre-driven activation of tdTomato fluorescence offered superior sensitivity for transduced cells. All serotypes except AAV3B and AAV4 had high liver tropism. Fluorescence activation revealed transduction of unexpected tissues, including adrenals, testes, and ovaries. Rare transduced cells within tissues were also readily visualized. Biodistribution of AAV genomes correlated with fluorescence, except in immune tissues. AAV4 was found to have a pan-endothelial tropism while also targeting pancreatic beta cells. This public resource enables selection of the best AAV serotypes for basic science and preclinical applications in mice.

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小鼠AAV趋向性的综合图谱。

用腺相关病毒（AAV）载体进行基因治疗需要了解其在体内的趋向性。本研究分析了10种天然存在的AAV血清型（AAV3B、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAVrh8、AAVrh10和AAVrh74）在雄性和雌性小鼠体内的致向性。使用表达ZsGreen和Cre重组酶的转基因，以细胞依赖的方式基于荧光鉴定转导。tdTomato荧光的cred驱动激活为转导细胞提供了优越的灵敏度。除AAV3B和AAV4外，其余血清型均有较高的肝嗜性。荧光激活揭示了意想不到的组织的转导，包括肾上腺、睾丸和卵巢。组织内罕见的转导细胞也很容易被观察到。除免疫组织外，AAV基因组的生物分布与荧光相关。发现AAV4具有泛内皮性，同时也靶向胰腺β细胞。这一公共资源能够为基础科学和小鼠临床前应用选择最佳的AAV血清型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.