Therapeutic Genome Editing by Combined Viral and Non-viral Delivery of CRISPR System Components in Vivo

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2016 Feb 2

PMID 26829318

Citations 414

Authors

Hao Yin

Chun-Qing Song

Joseph R Dorkin

Lihua J Zhu

Yingxiang Li

Qiongqiong Wu

Angela Park

Junghoon Yang

Sneha Suresh

Aizhan Bizhanova

Ankit Gupta

Mehmet F Bolukbasi

Stephen Walsh

Roman L Bogorad

Guangping Gao

Zhiping Weng

Yizhou Dong

Victor Koteliansky

Scot A Wolfe

Robert Langer

Wen Xue

Daniel G Anderson

Affiliations

Soon will be listed here.

Abstract

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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