A team of scientists from the Oregon Health & Science University have successfully used CRISPR/Cas9 to snip off a defective gene in human embryos that leads to the hereditary coronary disease hypertrophic cardiomyopathy.

The researchers also found a way to solve the gene editing problem in embryos called "mosaicism," which occurs when only a fraction of the cells gets repaired, and some defective genes still get carried over.

The new gene-editing method demonstrated by OHSU scientists could potentially prevent succeeding generations from inheriting the disease again, which is good news for families who are doomed to inherit the disease, and the 1 in 500 people it affects.

"Although it affects men and women of all ages, it's a common cause of sudden cardiac arrest in young people," study co-author Dr. Sanjiv Kaul explained.

In order to determine whether Cas9 can do the job properly, 54 embryos resulting from a healthy egg and sperm carrying the mutated MYBPC3 gene — the gene responsible for causing hypertrophic cardiomyopathy — were used in the study.

What the team did was to implant DNA into the egg to serve as a template to be copied while Cas9 worked on cutting the defective gene that the sperm carried.

Editing Out Diseases

The authors previously worked on editing genes in skin cells that were reprogrammed to mimic human embryos, and results from those tests suggested that the team will achieve a less than 30 percent success rate. They were surprised, however, when they moved on to human embryos, and Cas9 actually fixed 72 percent of the faulty genes.

"By using this technique, it's possible to reduce the burden of this heritable disease on the family and eventually the human population," OHSU Center for Embryonic Cell and Gene Therapy director and senior author Dr. Shoukhrat Mitalipov expressed.

Solutions And Surprises Along The Way

One of the main concerns in gene editing is that embryos could end up being a patchwork of corrected and faulty genes if not done properly and thoroughly, and this is what the researchers were trying to avoid.

Out of the 54 embryos the team worked on, 13 embryos developed mosaicism. However, the team noted that the 13 affected embryos were first allowed to fertilize and develop for a day before introducing the Cas9 enzyme.

In order to determine whether the delayed Cas9 introduction could have led to mosaicism, the team decided to introduce the Cas9 enzyme together with the sperm in the next batches, and this change in tactic actually worked to prevent mosaicism.

The embryo also gave the team a surprise by completely ignoring the DNA template they implanted on the egg cell. The embryo copied the healthy genes from the egg cell after Cas9 snipped off the faulty one instead, leading the team to believe that repairing mutations required the other parent to be free of the same mutation.

The discovery of this behavior could be a good response to ethicists who are concerned about CRISPR bringing the dawn of designer babies.

"If you can't introduce a template, then you can't do anything wild," Dr. Robin Lovell-Badge said. Dr. Lovell-Badge is a professor of genetics and embryology at the Francis Crick Institute in London and is not involved in the study.

The research was published on Aug. 2 in the journal Nature.

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