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 XuDavid 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, Shoukhrat Mitalipov

Research output: Contribution to journalArticle

398 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)413-419
Number of pages7
JournalNature
Volume548
Issue number7668
DOIs
StatePublished - Aug 24 2017

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Correction of a pathogenic gene mutation in human embryos'. Together they form a unique fingerprint.

  • Cite this

    Ma, H., Marti-Gutierrez, N., Park, S. W., Wu, J., Lee, Y., Suzuki, K., Koski, A., Ji, D., Hayama, T., Ahmed, R., Darby, H., Van Dyken, C., Li, Y., Kang, E., Park, A. R., Kim, D., Kim, S. T., Gong, J., Gu, Y., ... Mitalipov, S. (2017). Correction of a pathogenic gene mutation in human embryos. Nature, 548(7668), 413-419. https://doi.org/10.1038/nature23305