A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing

被引：625

作者：

Finn, Jonathan D. ^{[1
]}

Smith, Amy Rhoden ^{[1
]}

Patel, Mihir C. ^{[1
]}

Shaw, Lucinda ^{[1
]}

Youniss, Madeleine R. ^{[1
]}

van Heteren, Jane ^{[1
]}

Dirstine, Tanner ^{[1
]}

Ciullo, Corey ^{[1
]}

Lescarbeau, Reynald ^{[1
]}

Seitzer, Jessica ^{[1
]}

Shah, Ruchi R. ^{[1
]}

Shah, Aalok ^{[1
]}

Ling, Dandan ^{[1
]}

Growe, Jacqueline ^{[1
]}

Pink, Melissa ^{[1
]}

Rohde, Ellen ^{[1
]}

Wood, Kristy M. ^{[1
]}

Salomon, William E. ^{[1
]}

Harrington, William F. ^{[1
]}

Dombrowski, Christian ^{[1
]}

Strapps, Walter R. ^{[1
]}

Chang, Yong ^{[1
]}

Morrissey, David V. ^{[1
]}

机构：

[1] Intellia Therapeut, Cambridge, MA 02139 USA

来源：

CELL REPORTS | 2018年 / 22卷 / 09期

关键词：

LIVER HOMEOSTASIS; SIRNA DELIVERY; MOUSE-LIVER; REGENERATION; HEPATOCYTES; CELLS; CAS9; SYSTEM; VITRO; RNA;

D O I：

10.1016/j.celrep.2018.02.014

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform.

引用

页码：2227 / 2235

页数：9

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