期刊
NATURE BIOTECHNOLOGY
卷 34, 期 3, 页码 328-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3471
关键词
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资金
- National Institutes of Health (NIH) [5R00CA169512]
- Worcester Foundation
- Skoltech Center
- NIH Centers for Cancer Nanotechnology Excellence [5-U54-CA151884-04]
- Harvard-MIT Center of Cancer Nanotechnology Excellence [5-U54-CA151884-04]
- National Institute of Biomedical Imaging and Bioengineering [1F32EB017625]
- Russian scientific fund [14-34-00017]
- NIH [P30-CA14051]
- [5P30EY012196-17]
The combination of Cas9, guide RNA and repair template DNA can induce precise gene editing and the correction of genetic diseases in adult mammals. However, clinical implementation of this technology requires safe and effective delivery of all of these components into the nuclei of the target tissue. Here, we combine lipid nanoparticle-mediated delivery of Cas9 mRNA with adeno-associated viruses encoding a sgRNA and a repair template to induce repair of a disease gene in adult animals. We applied our delivery strategy to a mouse model of human hereditary tyrosinemia and show that the treatment generated fumarylacetoacetate hydrolase (Fah)-positive hepatocytes by correcting the causative Fah-splicing mutation. Treatment rescued disease symptoms such as weight loss and liver damage. The efficiency of correction was >6% of hepatocytes after a single application, suggesting potential utility of Cas9-based therapeutic genome editing for a range of diseases.
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