An evolved AAV variant enables efficient genetic engineering of murine T cells

被引：26

作者：

Nyberg, William A. ^{[1
,2
]}

Ark, Jonathan ^{[3
]}

To, Angela ^{[1
,2
]}

Clouden, Sylvanie ^{[4
]}

Reeder, Gabriella ^{[1
,2
,5
]}

Muldoon, Joseph J. ^{[1
,2
]}

Chung, Jing-Yi ^{[1
,2
]}

Xie, William H. ^{[1
,5
]}

Allain, Vincent ^{[1
,2
,6
]}

Steinhart, Zachary ^{[1
,2
]}

Chang, Christopher ^{[1
,2
,5
,7
]}

Talbot, Alexis ^{[1
,2
,6
]}

Kim, Sandy ^{[8
]}

Rosales, Alan ^{[9
]}

Havlik, L. Patrick ^{[9
]}

Pimentel, Harold ^{[8
,10
,11
]}

Asokan, Aravind ^{[3
,9
]}

Eyquem, Justin ^{[1
,2
,12
,13
]}

机构：

[1] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[2] Gladstone UCSF Inst Genom Immunol, San Francisco, CA 94158 USA

[3] Duke Univ, Sch Med, Dept Mol Genet & Microbiol, Durham, NC 27710 USA

[4] Duke Univ, Sch Med, Dept Surg, Durham, NC 27710 USA

[5] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94131 USA

[6] Univ Paris Cite, Hop St Louis, INSERM UMR976, Paris, France

[7] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94131 USA

[8] Univ Calif Los Angeles, Bioinformat Interdept Program, Los Angeles, CA 90095 USA

[9] Duke Univ, Dept Biomed Engn, Durham, NC 27710 USA

[10] Univ Calif Los Angeles, Sloan Fdn, Howard Hughes Med Inst, Dept Computat Med, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, Sloan Fdn, Howard Hughes Med Inst, Dept Human Genet, Los Angeles, CA 90095 USA

[12] Parker Inst Canc Immunotherapy, San Francisco, CA 94143 USA

[13] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

来源：

CELL | 2023年 / 186卷 / 02期

关键词：

ADENOASSOCIATED VIRUS VECTORS; HIGHLY EFFICIENT; RECEPTOR; QA-2; EXPRESSION; ANTIGEN; CAR; BINDING; TITER;

D O I：

10.1016/j.cell.2022.12.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Precise targeting of large transgenes to T cells using homology-directed repair has been transformative for adoptive cell therapies and T cell biology. Delivery of DNA templates via adeno-associated virus (AAV) has greatly improved knockin efficiencies, but the tropism of current AAV serotypes restricts their use to human T cells employed in immunodeficient mouse models. To enable targeted knockins in murine T cells, we evolved Ark313, a synthetic AAV that exhibits high transduction efficiency in murine T cells. We performed a genome-wide knockout screen and identified QA2 as an essential factor for Ark313 infection. We demon-strate that Ark313 can be used for nucleofection-free DNA delivery, CRISPR-Cas9-mediated knockouts, and targeted integration of large transgenes. Ark313 enables preclinical modeling of Trac-targeted CAR-T and transgenic TCR-T cells in immunocompetent models. Efficient gene targeting in murine T cells holds great potential for improved cell therapies and opens avenues in experimental T cell immunology.

引用

页码：446 / +

页数：35

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