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

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    Authors
    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.
    Xue, Wen
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    UMass Chan Affiliations
    Department of Molecular, Cell and Cancer Biology
    Program in Molecular Medicine
    Program in Bioinformatics and Integrative Biology
    Department of Microbiology and Physiological Systems
    Horae Gene Therapy Center
    RNA Therapeutics Institute
    Department of Pediatrics, Division of Pediatric Pulmonology
    Document Type
    Journal Article
    Publication Date
    2018-03-29
    Keywords
    Bioinformatics
    Biomedical Engineering and Bioengineering
    Computational Biology
    Congenital, Hereditary, and Neonatal Diseases and Abnormalities
    Genomics
    Therapeutics
    
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    Link to Full Text
    https://doi.org/10.1089/hum.2017.225
    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.
    Source

    Hum Gene Ther. 2018 Mar 29. doi: 10.1089/hum.2017.225. Link to article on publisher's site

    DOI
    10.1089/hum.2017.225
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/43636
    PubMed ID
    29597895
    Related Resources

    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1089/hum.2017.225
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