Editors' ChoiceGenetics

Rewriting the genome in human embryos

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Science Translational Medicine  30 Aug 2017:
Vol. 9, Issue 405, eaao4215
DOI: 10.1126/scitranslmed.aao4215

Abstract

Researchers have edited the genome of human embryos to correct dominant myocardial disease.

The rapid rise of CRISPR/Cas9 as a tool for genome editing has raised the tantalizing possibility of directly repairing mutations underlying many forms of disease. An explosion of publications in recent years have used Cas9 in vitro or in vivo in a wide variety of models, demonstrating the potential of the approach despite raising questions about efficiency and off-target effects. In a groundbreaking publication, Ma et al. directly injected Cas9 protein into human embryos to correct a dominant mutation in MYBPC3, which causes severe heart defects, and evaluated the rates of both gene correction and off-target editing.

CRISPR-Cas9 works by creating double-strand breaks at specifically targeted sequences of DNA. Targeted repair of the DNA break requires a template DNA, from which the mutated sequence can be rewritten through homology-directed repair. Commonly, a piece of DNA is codelivered along with the Cas9 to provide this repair template. Interestingly, the authors showed that in heterozygous embryos, formed from a normal oocyte fertilized by sperm carrying a MYBPC3 mutation, Cas9-mediated editing is not only efficient but preferentially uses the normal maternal gene rather than the coinjected DNA for template-directed repair. Further, the authors noted that mosaicism, in which not all cells in the embryos were equally edited, occurred when Cas9 protein was delivered after multiple copies of the genome had been formed. However, early coinjection of Cas9 along with sperm, when only one copy of mutated DNA is present in the fertilized oocyte, eliminated mosaic embryos. Edited embryos were maintained until blastocyst stage, and the authors noted no abnormal development or change in the rates of survival. No off-target genome editing was identified in a panel of potential off-target regions that contained similar sequences to the targeted site.

Together, these results highlight the potential power of CRISPR-Cas9-based editing for human disease, while at the same time underscoring obstacles that must be overcome. The authors’ demonstration that the maternal allele is the preferred template for repair suggests that homozygous mutations may prove more challenging to treat. Also, the occurrence of mosaicism in edited embryos would currently be impossible to detect. In addition, the success of this work and the rapid rate of development of CRISPR-Cas9–based tools should stimulate urgent and thoughtful debate about the use of this technology in humans.

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