Correction of a pathogenic gene mutation in human embryos

Hong Ma, Nuria Marti-Gutierrez, Sang-Wook Park, Jun Wu, Yeonmi Lee, Keiichiro Suzuki, Amy Koski, Dongmei Ji, Tomonari Hayama, Riffat Ahmed, Hayley Darby, Crystal Van Dyken, Ying Li, Eunju Kang, A.-Reum Park, Daesik Kim, Sang-Tae Kim, Jianhui Gong, Ying Gu, Xun Xu, David Battaglia, Sacha A. Krieg, David M. Lee, Diana H. Wu, Don P. Wolf, Stephen B. Heitner, Juan Carlos Izpisua Belmonte (), Paula Amato (), Jin-Soo Kim (), Sanjiv Kaul () and Shoukhrat Mitalipov ()
Additional contact information
Hong Ma: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Nuria Marti-Gutierrez: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Sang-Wook Park: Center for Genome Engineering, Institute for Basic Science, 70, Yuseong-daero 1689-gil
Jun Wu: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road
Yeonmi Lee: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Keiichiro Suzuki: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road
Amy Koski: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Dongmei Ji: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Tomonari Hayama: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Riffat Ahmed: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Hayley Darby: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Crystal Van Dyken: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Ying Li: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Eunju Kang: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
A.-Reum Park: Center for Genome Engineering, Institute for Basic Science, 70, Yuseong-daero 1689-gil
Daesik Kim: Seoul National University, 599 Gwanak-ro
Sang-Tae Kim: Center for Genome Engineering, Institute for Basic Science, 70, Yuseong-daero 1689-gil
Jianhui Gong: BGI-Shenzhen, Build 11, Beishan Industrial Zone
Ying Gu: BGI-Shenzhen, Build 11, Beishan Industrial Zone
Xun Xu: BGI-Shenzhen, Build 11, Beishan Industrial Zone
David Battaglia: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Sacha A. Krieg: Oregon Health & Science University, 3303 Southwest, Bond Avenue
David M. Lee: Oregon Health & Science University, 3303 Southwest, Bond Avenue
Diana H. Wu: Oregon Health & Science University, 3303 Southwest, Bond Avenue
Don P. Wolf: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Stephen B. Heitner: Knight Cardiovascular Institute, Oregon Health & Science University, 3181 Southwest
Juan Carlos Izpisua Belmonte: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road
Paula Amato: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue
Jin-Soo Kim: Center for Genome Engineering, Institute for Basic Science, 70, Yuseong-daero 1689-gil
Sanjiv Kaul: Knight Cardiovascular Institute, Oregon Health & Science University, 3181 Southwest
Shoukhrat Mitalipov: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest, Bond Avenue

Nature, 2017, vol. 548, issue 7668, 413-419

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature23305

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