Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype

Hao Yin; Wen Xue; Sidi Chen; Roman L Bogorad; Eric Benedetti; Markus Grompe; Victor Koteliansky; Phillip A Sharp; Tyler Jacks; Daniel G Anderson

doi:10.1038/nbt.2884

Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype

Nat Biotechnol. 2014 Jun;32(6):551-3. doi: 10.1038/nbt.2884. Epub 2014 Mar 30.

Authors

Affiliations

¹ 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2].
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
³ Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA.
⁴ Skolkovo Institute of Science and Technology, Skolkovo, Russian Federation.
⁵ 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁶ 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [3] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁷ 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [3] Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts, USA. [4] Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CRISPR-Associated Proteins / genetics*
CRISPR-Cas Systems*
Gene Editing / methods*
Genetic Therapy / methods*
Genome / genetics
Hydrolases / genetics*
Mice
Mice, Transgenic
Mutation / genetics
Phenotype
Treatment Outcome
Tyrosinemias / therapy*

Substances

CRISPR-Associated Proteins
Hydrolases
fumarylacetoacetase

Abstract

Publication types

MeSH terms

Substances

Grants and funding