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通过RNA驱动的生物淘选实现血脑屏障穿透性腺相关病毒衣壳的快速进化。

Rapid evolution of blood-brain-barrier-penetrating AAV capsids by RNA-driven biopanning.

作者信息

Nonnenmacher Mathieu, Wang Wei, Child Matthew A, Ren Xiao-Qin, Huang Carol, Ren Amy Zhen, Tocci Jenna, Chen Qingmin, Bittner Kelsey, Tyson Katherine, Pande Nilesh, Chung Charlotte Hiu-Yan, Paul Steven M, Hou Jay

机构信息

Voyager Therapeutics, Cambridge, MA 02139, USA.

出版信息

Mol Ther Methods Clin Dev. 2020 Dec 23;20:366-378. doi: 10.1016/j.omtm.2020.12.006. eCollection 2021 Mar 12.

DOI:10.1016/j.omtm.2020.12.006
PMID:33553485
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7841218/
Abstract

Therapeutic payload delivery to the central nervous system (CNS) remains a major challenge in gene therapy. Recent studies using function-driven evolution of adeno-associated virus (AAV) vectors have successfully identified engineered capsids with improved blood-brain barrier (BBB) penetration and CNS tropism in mouse. However, these strategies require transgenic animals and thus are limited to rodents. To address this issue, we developed a directed evolution approach based on recovery of capsid library RNA transcribed from CNS-restricted promoters. This RNA-driven screen platform, termed TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA), was tested in the mouse with AAV9 peptide display libraries and showed rapid emergence of dominant sequences. Ten individual variants were characterized and showed up to 400-fold higher brain transduction over AAV9 following systemic administration. Our results demonstrate that the TRACER platform allows rapid selection of AAV capsids with robust BBB penetration and CNS tropism in non-transgenic animals.

摘要

向中枢神经系统（CNS）递送治疗性有效载荷仍然是基因治疗中的一项重大挑战。最近利用腺相关病毒（AAV）载体的功能驱动进化进行的研究已成功鉴定出在小鼠中具有改善的血脑屏障（BBB）穿透能力和CNS嗜性的工程衣壳。然而，这些策略需要转基因动物，因此仅限于啮齿动物。为了解决这个问题，我们开发了一种基于从CNS限制性启动子转录的衣壳文库RNA回收的定向进化方法。这个称为TRACER（通过RNA的细胞类型特异性表达实现AAV嗜性重定向）的RNA驱动筛选平台在小鼠中用AAV9肽展示文库进行了测试，并显示出优势序列的快速出现。对十个单独的变体进行了表征，结果显示在全身给药后，它们在脑中的转导效率比AAV9高400倍。我们的结果表明，TRACER平台能够在非转基因动物中快速筛选出具有强大BBB穿透能力和CNS嗜性的AAV衣壳。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/9644bbed284d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/6c9b9f7ac97e/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/11ce11d3a26f/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/fa2d45e5833c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/d5fea0cd507c/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/e58a66180701/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/63b3d253fda4/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/9644bbed284d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/6c9b9f7ac97e/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/11ce11d3a26f/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/fa2d45e5833c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/d5fea0cd507c/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/e58a66180701/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/63b3d253fda4/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf4c/7841218/9644bbed284d/gr6.jpg

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