US scientists correct heritable heart condition in human embryos

Scientists have corrected a mutation implicated in a heritable heart condition in preimplantation human embryos using the CRISPR–Cas9 genome editing technique, a Nature paper reports 

More than 10,000 heritable disorders controlled by a single gene have been identified, including hypertrophic cardiomyopathy (HCM), a disease of the heart muscle that affects about one person in 500 and can cause sudden cardiac death and heart failure. Inheriting a single copy of a mutation in the MYBPC3 gene can result in HCM. Current treatments for HCM relieve the symptoms without addressing the genetic cause.

The latest findings add to the understanding of the safety and efficacy of editing the DNA of the human germline (eggs, sperm or early embryos). However, many issues remain to be considered before clinical applications can be explored, including the reproducibility of these findings with other mutations.

One approach to prevent harmful mutations being transmitted to offspring is preimplantation genetic diagnosis (PGD), followed by the selection of embryos without the harmful mutation for transfer and use in an in vitro fertilisation cycle. Recent developments in precise genome-editing techniques, such as CRISPR–Cas9, suggest that these techniques could potentially be used to correct disease-causing mutations in human embryos, thus increasing the number of embryos available for transfer.

To evaluate the safety and efficacy of gene correction for heritable diseases in the human germline, Shoukhrat Mitalipov and colleagues focused on the MYBPC3 mutation implicated in HCM. They produced zygotes by fertilising oocytes from healthy donors with sperm from a heterozygous male carrier of the MYBPC3 mutation, who carries one mutated copy and one normal copy of the gene.

They used CRISPR–Cas9 to make a cut on the mutant gene sequence and monitored how human embryos repair these DNA breaks. In most cases, the breaks were repaired efficiently using the non-mutated copy of this gene from the unaffected donor as a mirror. As a result, about two-thirds of targeted embryos contained two mutation-free copies of the MYBPC3 gene. The authors also found a way to eliminate the mosaicism, in which embryos are composed of two or more genetically different types of cells.

The results indicate that the approach is effective and the CRISPR–Cas9 targeting very accurate, providing some assurance regarding safety concerns; moreover, there was no evidence of off-target mutations. These findings suggest that this approach might potentially have applications for the correction of heritable mutations in human embryos in conjunction with PGD.