In a world first, scientists have used gene editing to successfully repair a disease-causing mutation in human embryos, which is an achievement that marks a major step forward for the prevention of inherited diseases.

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Scientists have used CRISPR-Cas9 to repair a mutation in human embryos.

In a study recently published in the journal Nature, an international team of researchers reveal how they used CRISPR-Cas9 gene editing on newly fertilized eggs to repair a mutated MYBPC3 gene known to cause hypertrophic cardiomyopathy (HCM).

HCM is a condition characterized by the thickening of the heart muscle. According to the American Heart Association (AHA), HCM is estimated to affect up to half a million people in the United States, and it is a common cause of sudden cardiac death, particularly among young athletes.

An inherited mutation of the MYBPC3 gene accounts for up to 30 percent of familial HCM cases; individuals with one copy of this gene mutation have a 50 percent chance of passing it to their offspring.

In recent years, scientists have looked to gene editing as a way of eliminating disease-causing mutations. One type of gene editing technique that has gained momentum is CRISPR-Cas9, which involves adding, removing, or modifying sequences of DNA to influence the function of a gene.

While CRISPR-Cas9 has demonstrated success in animal models, there have been ethical concerns about its use in humans. In particular, critics have cautioned that the technique may be exploited for non-therapeutic purposes, such as creating "designer babies."

What is more, there is a worry that in using CRISPR-Cas9 to repair one disease-causing mutation in human embryos, other potentially harmful mutations may be unintentionally introduced.

However, scientists from China, South Korea, and the U.S. have become the first to successfully repair the MYBPC3 gene mutation in human embryos using CRISPR-Cas9, without any unintended consequences.

Mutations repaired in 72 percent of embryos

Using in vitro fertilization, the researchers injected sperm retrieved from men with an MYBPC3 gene mutation into eggs retrieved from healthy women.

Unlike in previous studies, the researchers applied CRISPR-Cas9 to the healthy eggs at the same time as they injected the sperm. According to the team, this process helps to reduce "mosaicism," whereby some of the mutated cells in an embryo are repaired and some are not.

The researchers found that the CRISPR-Cas9 technique edited the DNA at the correct position for 100 percent of the embryos, and MYBPC3 gene mutations were fully repaired in 42 out of 58 embryos tested, representing a success rate of 72.4 percent.

"Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos," says co-first study author Jun Wu, of the Salk Institute for Biological Studies in La Jolla, CA.

Specifically, the researchers found that the gene editing technique used DNA from the healthy eggs as a "template," which helped to identify the location of DNA mutations in sperm that needed repairing.

Next, the team used whole-genome sequencing on the edited embryos to determine whether or not CRISPR-Cas9 had induced any unwanted changes to the genome. The researchers found no such changes.

In essence, the study provides the first evidence that CRISPR-Cas9 could be used to repair MYBPC3 gene mutations and prevent the development of familial HCM.

"Every generation on would carry this repair because we've removed the disease-causing gene variant from that family's lineage," says senior study author Shoukhrat Mitalipov, Ph.D., of Oregon Health & Science University (OHSU) in Portland. "By using this technique, it's possible to reduce the burden of this heritable disease on the family and eventually the human population."

Ethical concerns remain

This groundbreaking study does not only offer the hope of a cure for HCM, however. Researchers believe that it represents a major advancement in the use of gene editing for a wealth of hereditary diseases.

"This research significantly advances scientific understanding of the procedures that would be necessary to ensure the safety and efficacy of germline gene correction."

Daniel Dorsa, Ph.D., senior vice president for research at OHSU

That said, Wu and colleagues caution that further research is needed before clinical trials can be conducted, and many ethical concerns remain.

"Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations," says study co-author Juan Carlos Izpisua Belmonte, also of the Salk Institute for Biological Studies.

"The ethical considerations of moving this technology to clinical trials are complex and deserve significant public engagement before we can answer the broader question of whether it's in humanity's interest to alter human genes for future generations," adds Dorsa.