We demonstrate CRISPR-Cas9–mediated correction of a Fah mutation in hepatocytes in a mouse model of the human disease hereditary tyrosinemia. Delivery of components of the CRISPR-Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ∼1/250 liver cells. Expansion of Fah-positive hepatocytes rescued the body weight loss phenotype. Our study indicates that CRISPR-Cas9–mediated genome editing is possible in adult animals and has potential for correction of human genetic diseases.
We thank I. Zhuang and W. Cai for technical assistance, F. Zhang for sharing pX330 CRISPR vectors, and D. Crowley and K. Cormier for histology. This work was supported in part by grants 2-PO1-CA42063 to P.A.S. and T.J. and core grant P30-CA14051 from the National Cancer Institute. This work was supported in part by National Institutes of Health (NIH) Grant R01-CA133404 and the Marie-D. & Pierre Casimir-Lambert Fund to P.A.S. T.J. is a Howard Hughes Investigator, the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. H.Y. and S.C. are supported by 5-U54-CA151884-04 NIH Centers for Cancer Nanotechnology Excellence and the Harvard-MIT Center of Cancer Nanotechnology Excellence. W.X. is supported by grant 1K99CA169512. S.C. is a Damon Runyon Fellow (DRG-2117-12). The authors acknowledge the service of the late Sean Collier to the MIT community. We thank the Swanson Biotechnology Center for technical support.