衣壳
生物
基因传递
血脑屏障
体内
腺相关病毒
细胞生物学
计算生物学
转导(生物物理学)
病毒学
病毒
中枢神经系统
基因
遗传增强
载体(分子生物学)
重组DNA
遗传学
神经科学
生物物理学
作者
Qin Huang,Albert T. Chen,Ken Y. Chan,Hikari Sorensen,Andrew J. Barry,Bahar Azari,Qingxia Zheng,Thomas Beddow,Binhui Zhao,Isabelle G. Tobey,Cynthia Moncada-Reid,Fatma-Elzahraa Eid,Christopher J. Walkey,M. Cecilia Ljungberg,William R. Lagor,Jason D. Heaney,Yujia A. Chan,Benjamin E. Deverman
出处
期刊:PLOS Biology
[Public Library of Science]
日期:2023-07-19
卷期号:21 (7): e3002112-e3002112
被引量:26
标识
DOI:10.1371/journal.pbio.3002112
摘要
Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood-brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo thereby reducing the use of animals in comparison to conventional multi-round in vivo selections. The reproducible and quantitative data derived via this method enabled both saturation mutagenesis and machine learning (ML)-guided exploration of the capsid sequence space. Notably, during our validation process, we determined that nearly all published AAV capsids that were selected for their ability to cross the BBB in mice leverage either the LY6A or LY6C1 protein, which are not present in primates. This work demonstrates that AAV capsids can be directly targeted to specific proteins to generate potent gene delivery vectors with known mechanisms of action and predictable tropisms.
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