20180329 In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency-医学研究院
科学研究
20180329 In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency
发布时间:2018-03-29  来源:  阅读次数:


2018 Mar 29. doi: 10.1089/hum.2017.225. [Epub ahead of print]

In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency.

Song CQ 1, Wang D 2, Jiang T 3, O'Connor K 4, Tang Q 5, Cai L 6, Li X 7, Weng Z 8, Yin H 9, Gao G 10, 11, Mueller C 12, Flotte TR 13, Xue W 14.

Abstract

CRISPR genome editing holds promise in the treatment of genetic diseases that currently lack effective long-term therapies. Patients with Alpha-1 Antitrypsin (AAT) deficiency develop progressive lung disease due to the loss of AAT's antiprotease function and liver disease due to a toxic gain of function of the common mutant allele. However, it remains unknown whether CRISPR-mediated AAT correction in the liver, where AAT is primarily expressed, can correct either or both defects. Here we show that AAV delivery of CRISPR can effectively correct Z-AAT mutation in the liver of a transgenic mouse model. Specifically, we co-injected two AAV: one expressing Cas9 and another encoding an AAT guide RNA and homology-dependent repair template. In both neonate and adult mice, this treatment partially restored M-AAT in the serum. Furthermore, deep sequencing confirmed both indel mutations and precise gene correction in the liver, permitting careful analysis of gene editing events in vivo. This study demonstrates a proof-of-concept for the application of CRISPR-Cas9 technology to correct AAT mutations in vivo and validates continued exploration of this approach for the treatment of patients with AAT deficiency.

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