Title
In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency
UMMS Affiliation
Department of Pediatrics, Division of Pediatric Pulmonology; RNA Therapeutics Institute; Horae Gene Therapy Center; Department of Microbiology and Physiological Systems; Program in Bioinformatics and Integrative Biology; Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology
Publication Date
2018-03-29
Document Type
Article
Disciplines
Bioinformatics | Biomedical Engineering and Bioengineering | Computational Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genomics | Therapeutics
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.
DOI of Published Version
10.1089/hum.2017.225
Source
Hum Gene Ther. 2018 Mar 29. doi: 10.1089/hum.2017.225. Link to article on publisher's site
Journal/Book/Conference Title
Human gene therapy
Related Resources
PubMed ID
29597895
Repository Citation
Song, Chun-Qing; Wang, Dan; Jiang, Tingting; O'Connor, Kevin; Tang, Qiushi; Cai, Lingling; Li, Xiangrui; Weng, Zhiping; Yin, Hao; Gao, Guangping; Mueller, Christian; Flotte, Terence R.; and Xue, Wen, "In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency" (2018). Pediatric Publications and Presentations. 207.
https://escholarship.umassmed.edu/peds_pp/207