Scientists have, for the first time, corrected a disease-causing mutation in early stage human embryos using gene editing.
The technique, which uses the CRISPR-Cas9 system, corrected the mutation for a heart condition at the earliest stage of embryonic development so that the defect would not be passed on to future generations.
The work, a collaboration between the Salk Institute, Oregon Health and Science University and Korea’s Institute for Basic Science, could pave the way for improved in vitro fertilization (IVF) techniques as well as eventual cures for some of the diseases caused by mutations in single genes.
Gene editing remains in its early stages of development but holds much promise, according to Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and a corresponding author on the paper outlining the development.
He said: “Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people.
“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.”
The work focused on hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in otherwise healthy young athletes, which affects approximately one in 500 people overall.
It is caused by a dominant mutation in the MYBPC3 gene, but often goes undetected until it is too late. Since people with a mutant copy of the MYBPC3 gene have a 50% chance of passing it on to their own children, being able to correct the mutation in embryos would prevent the disease not only in affected children, but also in their descendants, say the researchers.
The researchers generated induced pluripotent stem cells from a skin biopsy donated by a male with HCM and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair.
Using IVF techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs newly fertilised with the donor’s sperm.
Not only were a high percentage of embryonic cells repaired, but also gene correction didn’t induce any detectable off-target mutations and genome instability—major concerns for gene editing.
Jun Wu, a Salk staff scientist and one of the paper’s authors, said: “Even though the success rate in patient cells cultured in a dish was low, we saw that the gene correction seems to be very robust in embryos of which one copy of the MYBPC3 gene is mutated.
“Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos.”
The team emphasises that, although promising, these are preliminary results and more research will need to be done to ensure no unintended effects occur.
Juan Carlos Izpisua Belmonte said: “Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits.”
Future work will continue to assess the safety and effectiveness of the procedure and efficacy of the technique with other mutations.
The work was funded by Oregon Health and Science University, the Institute for Basic Science, the G. Harold and Leila Y. Mathers Charitable Foundation, the Moxie Foundation, the Leona M. and Harry B. Helmsley Charitable Trust and Shenzhen Municipal Government of China.
