Early gene-editing holds promise for preventing inherited diseases

“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."

The secret to healing what ails you lies within your own DNA (photo credit: DREAMSTIME)
The secret to healing what ails you lies within your own DNA
(photo credit: DREAMSTIME)
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.
It could pave the way for improved in vitro fertilization outcomes as well as eventual cures for some thousands of diseases caused by mutations in single genes.
The breakthrough and accomplishment by American and Korean scientists, was recently explained in the journal Nature. It’s a collaboration between the Salk Institute, Oregon Health and Science University and South Korea’s Institute for Basic Science.
“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,” said Prof. Juan Carlos Izpisua Belmonte of Salk’s gene expression lab and a corresponding author of the paper. “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.”
Though gene-editing tools have the power to potentially cure a number of diseases, scientists have proceeded cautiously – partly to avoid introducing unintended mutations into the germ line (cells that become eggs or sperm).
Izpisua Belmonte is uniquely qualified to speak on the ethics of genome editing because, as a member of the Committee on Human Gene Editing at the US National Academies of Sciences, Engineering and Medicine, he helped author the 2016 roadmap Human Genome Editing: Science, Ethics and Governance.
Hypertrophic cardiomyopathy is the most common cause of sudden death in otherwise healthy young athletes, and affects approximately one in 500 people. 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.
The researchers generated induced pluripotent stem cells from a skin biopsy donated by a male with Hypertrophic cardiomyopathy and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair. The targeted mutated MYBPC3 gene was cut by the Cas9 enzyme, allowing the donor’s cells’ own DNA -repair mechanisms to fix the mutation during the next round of cell division by using either a synthetic DNA sequence or the non-mutated copy of MYBPC3 gene as a template.
Using IVF techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs that are newly fertilized with donor’s sperm. All the cells in the early embryos are then analyzed at single-cell resolution to see how effectively the mutation was repaired.
They were surprised by the safety and efficiency of the method. Not only were a high percentage of embryonic cells get fixed, but also gene correction didn’t induce any detectable off-target mutations and genome instability – major concerns for gene editing.
The researchers also developed an effective strategy to ensure the repair occurred consistently in all the cells of the embryo, as incomplete repairs can lead to some cells continuing to carry the mutation.
“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,” said Jun Wu, a Salk staff scientist and one of the authors.
This was in part because, after CRISPR- Cas9 mediated enzymatic cutting of the mutated gene copy, the embryo initiated its own repairs. Instead of using the provided synthetic DNA template, the team surprisingly found that the embryo preferentially used the available healthy copy of the gene to repair the mutated part.
“Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos,” said Wu.
The authors emphasized that although promising, these are very preliminary results and more research will need to be done to ensure no unintended effects occur.
“Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits,” they added.