Reducing cholesterol levels has long been seen as a key in reducing the risk of myocardial infarction (MI). Genomic research has advanced that approach by identifying people with exceptionally low cholesterol levels due to naturally occurring gene mutations, suggesting the potential for the development of new medicines that mimic these mutations.

"Now, we have this unique ability to rewrite the genome of an adult. Imagine if I was able to give you a single shot, a single treatment that would lower your cholesterol for the rest of your life," says Sekar Kathiresan, MD, a physician and geneticist who is chief executive officer of Verve Therapeutics. He is currently on leave from his position as professor of medicine at Harvard Medical School.

Kathiresan discusses his research, which has uncovered genetic mutations that lower cholesterol levels, during the Eugene Braunwald keynote. He also discusses the CRISPR-Cas9 technology used to develop Verve's potential treatment, which has proven successful in lowering cholesterol levels in mice.

Kathiresan has studied the inherited basis for MI. He has identified genetic factors that raise risk, as well as several mutations that lower cholesterol levels, offering protection from MI.

"Most people understand the increased risk of MI that comes from genetics, but there is not as much appreciation that there are people who are naturally protected from MIs by mutations that lead to lower levels of cholesterol in the blood lifelong," Kathiresan says.

Kathiresan's research has led to a greater understanding of risk and resistance to MI, including how to measure it.

"We have this framework for interpreting the genome for risk that involves looking at specific mutations in genes and the combination of mutations that is called the polygenic score, which we have developed," he says. "I go into detail to help people understand why patients may be at genetic risk for an MI."

This understanding of risk and resistance has grown over the last decade and led Kathiresan to leave his academic research last year to focus on developing a new gene editing therapy that mimics the protective mutations that have been discovered. It was a long road from growing up in Viramathi, India, to founding a biotech company in the U.S.

"With a single injection, we have shown that we can lower the cholesterol for the life of a mouse. Now, we are moving to extend that to monkeys, which is where we are right now," Kathiresan says. "The goal of the company is to develop a one-time shot therapy for cholesterol by editing the adult liver and knocking out a given gene that normally raises cholesterol. As a result of that intervention, the cholesterol in that individual would be lowered for their adult life. We hope to be able to treat patients with this experimental therapy in about three years."

Watch the 2020 Eugene Braunwald Keynote at Virtual.ACC.org.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: ACC Publications, ACC Scientific Session Newspaper, ACC Scientific Session Newspaper 2020, ACC Annual Scientific Session, acc20, Cholesterol, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, Haplorhini, Liver, Mutation, Therapies, Investigational

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