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

3-29-2018

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

Link to Article in PubMed

PubMed ID

29597895

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