Journal
HUMAN GENE THERAPY
Volume 29, Issue 8, Pages 853-860Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2017.225
Keywords
alpha1-antitrypsin deficiency; AAT; CRISPR; genome editing; AAV; mouse model
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Funding
- National Institutes of Health [DP2HL137167, P01HL131471, R01 DK098252, R24OD018259]
- Lung Cancer Research Foundation
- American Cancer Society [129056-RSG-16-093]
- Hyundai Hope on Wheels
- ALS Association
- National Institute of General Medicine, National Institutes of Health [T32 GM107000]
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CRISPR (clustered regularly interspaced short palindromic repeats) 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 AAVs: one expressing Cas9 and another encoding an AAT guide RNA and homology-directed repair template. In both neonatal 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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