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Nat Biotechnol. 2018 Oct;36(9):839-842. doi: 10.1038/nbt.4219. Epub 2018 Aug 13.

Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice.

Wang D1,2,3, Li J1,2, Song CQ4, Tran K1,2, Mou H4, Wu PH4,5, Tai PWL1,2,3, Mendonca CA1,2, Ren L1,2, Wang BY1,2, Su Q6, Gessler DJ1,2,3, Zamore PD4,5, Xue W4,7, Gao G1,2,3,8.

Author information

1
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
2
Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
3
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
4
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
5
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
6
Viral Vector Core, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
7
Program in Molecular Medicine and Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
8
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Abstract

We report a genome-editing strategy to correct compound heterozygous mutations, a common genotype in patients with recessive genetic disorders. Adeno-associated viral vector delivery of Cas9 and guide RNA induces allelic exchange and rescues the disease phenotype in mouse models of hereditary tyrosinemia type I and mucopolysaccharidosis type I. This approach recombines non-mutated genetic information present in two heterozygous alleles into one functional allele without using donor DNA templates.

PMID:
30102296
PMCID:
PMC6126964
[Available on 2019-02-13]
DOI:
10.1038/nbt.4219

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