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

Dan Wang; Jia Li; Chun-Qing Song; Karen Tran; Haiwei Mou; Pei-Hsuan Wu; Phillip W L Tai; Craig A Mendonca; Lingzhi Ren; Blake Y Wang; Qin Su; Dominic J Gessler; Phillip D Zamore; Wen Xue; Guangping Gao

doi:10.1038/nbt.4219

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

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

Authors

Dan Wang^{1

2

3}, Jia Li^{1

2}, Chun-Qing Song⁴, Karen Tran^{1

2}, Haiwei Mou⁴, Pei-Hsuan Wu^{4

5}, Phillip W L Tai^{1

2

3}, Craig A Mendonca^{1

2}, Lingzhi Ren^{1

2}, Blake Y Wang^{1

2}, Qin Su⁶, Dominic J Gessler^{1

2

3}, Phillip D Zamore^{4

5}, Wen Xue^{4

7}, Guangping Gao^{1

2

3

8}

Affiliations

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.

Publication types

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

MeSH terms

Alleles*
Animals
CRISPR-Associated Protein 9*
Dependovirus / genetics
Gene Editing
Genes, Recessive*
Genetic Vectors
Heterozygote*
Mice
Mutation*

Substances

CRISPR-Associated Protein 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding