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Nature, 548, 413-419 (24 August 2017) | doi:10.1038/nature23305 Correction of a pathogenic gene mutation in human embryos

Hong Ma^1*, Nuria Marti-Gutierrez^1*, Sang-Wook Park^2*, Jun Wu^3*, Yeonmi Lee¹, Keiichiro Suzuki³, Amy Koski¹, Dongmei Ji¹, Tomonari Hayama¹, Riffat Ahmed¹, Hayley Darby¹, Crystal Van Dyken¹, Ying Li¹, Eunju Kang¹, A.-Reum Park², Daesik Kim⁴, Sang-Tae Kim², Jianhui Gong^5,6,7,8, Ying Gu^5,6,7, Xun Xu^5,6,7, David Battaglia^1,9, Sacha A. Krieg⁹, David M. Lee⁹, Diana H. Wu⁹, Don P. Wolf¹, Stephen B. Heitner¹⁰, Juan Carlos Izpisua Belmonte^3,§, Paula Amato^1,9,§, Jin-Soo Kim^2,4,§, Sanjiv Kaul^10,§ & Shoukhrat Mitalipov^1,10,§¹Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue, Portland, Oregon 97239, USA. ²Center for Genome Engineering, Institute for Basic Science, 70, Yuseong-daero 1689-gil, Yuseong-gu, Daejeon, 34047, Republic of Korea. ³Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. ⁴Department of Chemistry, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, Republic of Korea. ⁵BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China. ⁶China National GeneBank, BGI-Shenzhen, Jinsha Road, Dapeng District, Shenzhen, 518210, China. ⁷BGI-Qingdao, 2877 Tuanjie Road, SinoGerman Ecopark, Qingdao, 266000, China. ⁸Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics, BGI-Shenzhen, Build 11, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China. ⁹Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3303 Southwest, Bond Avenue, Portland, Oregon 97239, USA. ¹⁰Knight Cardiovascular Institute, Oregon Health & Science University, 3181 Southwest, Sam Jackson Park Road, Portland, Oregon 97239, USA.
^*These authors contributed equally to this work.
^§These authors jointly supervised this work

Correspondence to: Shoukhrat Mitalipov or Sanjiv Kaul or Jin-Soo Kim or Paula Amato or Juan Carlos Izpisua Belmonte

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.

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TOP52017년 선정

형식Research article
게재일2017년 08월 (BRIC 등록일 2017-08-07)
연구진국내(교신)+국외 연구진
분야 생명과학 > 생화학

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