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


Document Type



Bioinformatics | Biomedical Engineering and Bioengineering | Computational Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genomics | Therapeutics


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



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