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Nature. 2017 Aug 24;548(7668):413-419. doi: 10.1038/nature23305. Epub 2017 Aug 2.

Correction of a pathogenic gene mutation in human embryos.

Author information

1
Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 Southwest, Bond Avenue, Portland, Oregon 97239, USA.
2
Center for Genome Engineering, Institute for Basic Science, 70, Yuseong-daero 1689-gil, Yuseong-gu, Daejeon, 34047, Republic of Korea.
3
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
4
Department of Chemistry, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, Republic of Korea.
5
BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China.
6
China National GeneBank, BGI-Shenzhen, Jinsha Road, Dapeng District, Shenzhen, 518210, China.
7
BGI-Qingdao, 2877 Tuanjie Road, Sino-German Ecopark, Qingdao, 266000, China.
8
Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics, BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China.
9
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Oregon Health &Science University, 3303 Southwest, Bond Avenue, Portland, Oregon 97239, USA.
10
Knight Cardiovascular Institute, Oregon Health &Science University, 3181 Southwest, Sam Jackson Park Road, Portland, Oregon 97239, USA.

Abstract

Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR-Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.

PMID:
28783728
DOI:
10.1038/nature23305
[Indexed for MEDLINE]

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