"Right now the problem is that a lot of people are getting their DNA sequenced and to their surprise it comes back as variants, after variants, after variants — essentially a whole bunch of variants of uncertain significance — and they don't know what that means," said Dr. Joseph Wu, professor and director of the Stanford Cardiovascular Institute at the Stanford School of Medicine, who was lead author of the study.
"Patients often ask us what do these variants of uncertain significance mean. But in reality, we don't know most of the time ourselves. So we end up having to follow the patients for the next five, 10, 20, or 30 years to see if the patient manifests the disease or not," Wu said.
"This is one of the very first proof of principles to show that concept," Wu said.
For the new study, researchers sequenced the DNA of 54 healthy people with no clinical history of cardiac disease and took a close look at the genes associated with hypertrophic cardiomyopathy, a heart condition characterized by thickening of the heart muscle.
Hypertrophic cardiomyopathy is thought to be the most common inherited or genetic heart disease. The condition is a common cause of sudden cardiac arrest in young people, including young athletes.
The researchers found 592 genetic variants across the 54 people. While 78% of the variants were categorized as benign, there were 17 people who each carried a variant categorized as "likely pathogenic." For four of those people, their variant was hypertrophic cardiomyopathy-related.
One study participant, carrying a hypertrophic cardiomyopathic-related variant in the gene called MYL3, also had several family members carrying the gene. The researchers noticed that these family members were asymptomatic in nature, meaning they had no irregular heartbeat and no enlarged heart muscle tissue.
So the researchers then took that knowledge and used CRISPR to turn the patient's stem cells with this MYL3 genetic variant from being heterozygous, meaning they have one normal and one recessive form of the variant, to being homozygous, so that they have two recessive forms of the variant.
Specifically, the researchers took the one study participant's blood cells, turned them into induced pluripotent stem cells, and then used CRISPR to edit those cells in a petri dish. The researchers then differentiated the edited stem cells so they would become heart muscle cells, and performed a comprehensive analysis to evaluate the variant, determining exactly how harmful the variant was or whether it was benign.
In this case, the study participant's variant was predicted to be benign.
"Much work remains to further develop stepping stones between editing cells in a dish and genome editing therapeutics that can treat patients, but studies such as this one help identify variants that are promising targets for therapeutic editing," said David Liu, core institute member of the Broad Institute and professor of chemistry and chemical biology at Harvard University, who was not involved in the study.
"While it's very elegant, the major limitation of this work is that it took years of expensive work by a team of very talented scientists to do this for just one patient," said Dr. Kiran Musunuru, an associate professor of cardiovascular medicine at the University of Pennsylvania's Perelman School of Medicine, who was not involved in the new study but has conducted separate research involving CRISPR.
"It's an important step towards precision medicine, but going forward we will need to scale this up and be able to do this for dozens, hundreds, or even thousands of patients at a time, in a matter of weeks and much more cheaply," he said.
"Cost-wise, it takes us probably about $10,000 and time-wise about six months," he said. Those six months would involve making the induced pluripotent stem cells, using CRISPR to edit the cells and then analyzing the differentiated heart cells.
"This addresses a major unmet need in patient care by helping determine whether your specific mutation is something to worry about," said Lagor, who was not involved in the study but has conducted separate research on CRISPR.
Then once a mutation has been identified as disease-causing, "this is an ideal platform for testing potential new drugs or gene therapy approaches in a patient-specific manner. This is truly personalized medicine," he said.
"The first therapeutic application of this technology would be to correct rare genetic diseases of the heart itself, where the potential benefit far outweighs the risk to the patient. Some of this technology already exists today, and it is now a matter of demonstrating that this can be done safely and effectively," he said.
A separate study published last year in the journal Nature showed how CRISPR could be used in human embryos to correct a pathogenic gene mutation called MYBPC3, which is associated with inherited heart conditions, including left ventricular noncompaction, familial dilated cardiomyopathy, and familial hypertrophic cardiomyopathy.
Whereas, "in this study CRISPR was used to make edits in cells outside of the body, so that the scientists could better analyze the cells, which is straightforward even if it takes a lot of effort," said Musunuru, who led a separate study in February that involved using CRISPR to lower cholesterol levels in mice, reducing their risk of heart disease.
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