Supramolecular nanosubstrate-mediated delivery system enables CRISPR-Cas9 knockin of hemoglobin beta gene for hemoglobinopathies

文献类型： 外文期刊

第一作者： Yang, Peng

作者： Yang, Peng;Ban, Qian;Yang, Peng;Sun, Na;Zhang, Ryan Y.;Zhu, Yazhen;Smalley, Matthew;Zhang, Xinyue;Chen, Jiayuan;Tseng, Hsian-Rong;Chou, Shih-Jie;Tsai, Ming-Long;Lai, Henkie, I;Chou, Shih-Jie;Tsai, Ming-Long;Lai, Henkie, I;Chiou, Shih-Hwa;Li, Jindian;Chen, Kai;Hui, Wenqiao;Liu, Wenfei;Weiss, Paul S.;Liu, Wenfei;Weiss, Paul S.;Romero, Zulema;Kohn, Donald B.;Liu, Dahai;Ke, Zunfu;Zou, Chang;Lee, Chin-Fa;Jonas, Steven J.;Chiou, Shih-Hwa;Chiou, Shih-Hwa

作者机构：

期刊名称：SCIENCE ADVANCES （ 影响因子：14.136； 五年影响因子：16.446 ）

ISSN： 2375-2548

年卷期： 2020 年 6 卷 43 期

页码：

收录情况： SCI

摘要： Leveraging the endogenous homology-directed repair (HDR) pathway, the CRISPR-Cas9 gene-editing system can be applied to knock in a therapeutic gene at a designated site in the genome, offering a general therapeutic solution for treating genetic diseases such as hemoglobinopathies. Here, a combined supramolecular nanoparticle (SMNP)/supramolecular nanosubstrate-mediated delivery (SNSMD) strategy is used to facilitate CRISPR-Cas9 knockin of the hemoglobin beta (HBB) gene into the adeno-associated virus integration site 1 (AAVS1) safe-harbor site of an engineered K562 3.21 cell line harboring the sickle cell disease mutation. Through stepwise treatments of the two SMNP vectors encapsulating a Cas9 center dot single-guide RNA (sgRNA) complex and an HBB/green fluorescent protein (GFP)-encoding plasmid, CRISPR-Cas9 knockin was successfully achieved via HDR. Last, the HBB/GFP-knockin K562 3.21 cells were introduced into mice via intraperitoneal injection to show their in vivo proliferative potential. This proof-of-concept demonstration paves the way for general gene therapeutic solutions for treating hemoglobinopathies.

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