A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice

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A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice

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Title: A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice
Author: Yang, Yang; Wang, Lili; Bell, Peter; McMenamin, Deirdre; He, Zhenning; White, John; Yu, Hongwei; Xu, Chenyu; Morizono, Hiroki; Musunuru, Kiran; Batshaw, Mark L.; Wilson, James M.

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Citation: Yang, Y., L. Wang, P. Bell, D. McMenamin, Z. He, J. White, H. Yu, et al. 2016. “A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice.” Nature biotechnology 34 (3): 334-338. doi:10.1038/nbt.3469. http://dx.doi.org/10.1038/nbt.3469.
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Abstract: Many genetic liver diseases present in newborns with repeated, often lethal, metabolic crises. Gene therapy using non-integrating viruses such as AAV is not optimal in this setting because the non-integrating genome is lost as developing hepatocytes proliferate1,2. We reasoned that newborn liver may be an ideal setting for AAV-mediated gene correction using CRISPR/Cas9. Here we intravenously infuse two AAVs, one expressing Cas9 and the other expressing a guide RNA and the donor DNA, into newborn mice with a partial deficiency in the urea cycle disorder enzyme, ornithine transcarbamylase (OTC). This resulted in reversion of the mutation in 10% (6.7% – 20.1%) of hepatocytes and increased survival in mice challenged with a high-protein diet, which exacerbates disease. Gene correction in adult OTC-deficient mice was lower and accompanied by larger deletions that ablated residual expression from the endogenous OTC gene, leading to diminished protein tolerance and lethal hyperammonemia on a chow diet.
Published Version: doi:10.1038/nbt.3469
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786489/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002437
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