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Pump the CRISPR Brakes

In a preprint article on bioRxiv, Memorial Sloan Kettering Cancer Center's Maria Jasin, Harvard's George Church, and their colleagues sound a note of scientific caution on a recent Nature study that reported using the gene-editing tool CRISPR/Cas9 to correct a heart disease mutation in viable human embryos for the very first time.

A team led by researchers at Oregon State Health and Science University used the CRISPR/Cas9 gene-editing system to correct mutations within MYBPC3 in embryos. They targeted an autosomal dominant mutation in MYBPC3 that leads to hypertrophic cardiomyopathy, which affects about one in every 500 people and is a common cause of sudden death in young people. The researchers said they were able to edit the embryos with high efficiency, while largely avoiding mosaicism and off-target cleavage, two key concerns with the use of the technology, particularly in the clinic.

In their article, Jasin and her colleagues write that the authors of the Nature paper "conclude that repair using the homologous chromosome was as or more frequent than mutagenic nonhomologous end-joining (NHEJ). Their conclusion is significant, if validated, because such a 'self-repair' mechanism would allow gene correction without the introduction of a repair template." But that study's analysis relied on the failure to detect mutant alleles, rather that finding direct evidence for interhomologue recombination. 

"Given the far-reaching implications, providing direct evidence for correction of the pathogenic allele, rather than the inability to detect the mutant allele, cannot be overemphasized," Jasin and her team write. "Clear evidence for a novel linkage of maternal and paternal alleles is an imperative for any embryo that would be considered for future implantation."

The team suggests approaches for providing direct evidence for interhomologue recombination in its preprint paper. More importantly, it notes that while the Nature paper was indeed a huge step forward for CRISPR technology, further investigation is needed.