| Autor: |
Mathieu Nonnenmacher, Wei Wang, Matthew A. Child, Xiao-Qin Ren, Carol Huang, Amy Zhen Ren, Jenna Tocci, Qingmin Chen, Kelsey Bittner, Katherine Tyson, Nilesh Pande, Charlotte Hiu-Yan Chung, Steven M. Paul, Jay Hou |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Methods & Clinical Development, Vol 20, Iss , Pp 366-378 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2329-0501 |
| DOI: |
10.1016/j.omtm.2020.12.006 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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