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Sci Rep. 2017 Mar 16;7:44624. doi: 10.1038/srep44624.

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease.

Author information

1
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Bioengineering, Rice University, Houston, TX 77030, USA.
4
Houston Methodist Research Institute, Houston, TX 77030, USA.
5
Weill Cornell Medicine, Houston, TX 77030, USA.
6
Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
7
Texas Heart Institute, Houston, TX 77030, USA.

Abstract

Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis. Here we show that hepatic disruption of Ldlr with AAV-CRISPR results in severe hypercholesterolemia and atherosclerosis. We further demonstrate that co-disruption of Apob, whose germline loss is embryonically lethal, completely prevented disease through compensatory inhibition of hepatic LDL production. This new concept of metabolic disease modeling by somatic genome editing could be applied to many other systemic as well as liver-restricted disorders which are difficult to study by germline manipulation.

PMID:
28300165
PMCID:
PMC5353616
DOI:
10.1038/srep44624
[Indexed for MEDLINE]
Free PMC Article

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