Correction of a pathogenic gene mutation in human embryos

Abstract

Over recent years, the Yearbook has followed the rapid advances in CRISPR-Cas9 gene editing technology, initially as a widely adopted research tool, but also as an emerging form of gene therapy. Here, Ma et al. report the first use of CRISPR–Cas9 to efficiently and safely correct a pathogenic heterozygous mutation in human embryos. These embryos carried a dominantly inherited 4 base-pair deletion in the gene MYBPC3. Mutations in this gene account for 40% of all known genetic causes of hypertrophic cardiomyopathy, which is the most common cause of sudden death in otherwise healthy young athletes. CRISPR–Cas9 induces DNA double-strand breaks at specific genomic sequences, which are then repaired by endogenous mechanisms, including homology-directed repair, during which the normal, non-mutated sequence can be restored if a normal template is provided. Here, unaffected oocytes provided the healthy non-mutated alleles. Furthermore, by targeting oocytes arrested in meiosis, before the first zygotic division, they achieved high efficiency (72.4% of injected embryos were fully corrected) with very low level of mosaicism. CRISPR-Cas9 has a potential drawback of creating off-target mutations at other sites in the genome. While the current study showed very high specificity, as have most other experimental studies, more concerning evidence of off-target effects, occurring beyond the immediate vicinity of the target site, has been very recently identified using newer long-range DNA sequencing techniques (1). Hence, CRISPR–Cas9 is moving cautiously towards clinical use.