The genetic clue that could change heart disease prevention forever

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Scientists discovered that some people are naturally protected from heart attack. Now researchers are trying to turn that insight into a one-time medicine.

Some people are born with a natural advantage against heart disease.

About two decades ago, scientists discovered that certain individuals carry naturally occurring variants in a gene called PCSK9 that keep their LDL cholesterol remarkably low for life – and dramatically reduce their risk of heart attack. The finding transformed how researchers thought about cardiovascular disease.

If nature could permanently protect people from heart attack, could medicine do the same?

Today, Sekar Kathiresan serves as SVP and Head of Obesity Research at Eli Lilly and Company and co-founder of Verve Therapeutics, a wholly owned subsidiary of Lilly. But for decades, the physician-scientist and human geneticist has focused on a single question: what can human genetics teach us about preventing heart disease?

“Human genetics is one of the most powerful tools we have for understanding disease,” Kathiresan said. “Nature is already running experiments for us.”

Cardiovascular disease remains the leading cause of death worldwide, driven in large part by elevated LDL cholesterol. For people with heterozygous familial hypercholesterolemia (HeFH), an inherited condition affecting roughly 1 in 250 people, dangerously high LDL cholesterol begins at birth and significantly increases the risk of early heart disease.

For many patients, cardiovascular risk accumulates silently over decades before a first heart attack occurs. Existing cholesterol-lowering medicines can be highly effective, but they depend on something difficult to sustain over decades: consistent adherence. Human genetics suggested another possibility – a treatment designed to work once and potentially be lasting.

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Learning from nature

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Between 2003 and 2006, a series of landmark discoveries established that PCSK9 works both ways. Too much activity in the gene can drive dangerously high cholesterol levels while naturally reduced activity appears to protect against heart disease for life.

The findings helped lead to the development of PCSK9 inhibitors, medicines now widely used to lower cholesterol. But for Kathiresan and others in the field, the discoveries also raised a more ambitious question: if lifelong reduction of PCSK9 appeared safe and protective in nature, could scientists replicate that biology through medicine?

“Over the last 25 years, we and others searched across the genome for genes that might protect people from heart attacks,” Kathiresan said. “We found nine such genes and all nine pointed to lifelong low cholesterol as the answer to avoiding heart attack.”

Today, researchers at Verve Therapeutics and Lilly are studying an investigational gene editing approach designed to inactivate the PCSK9 gene in the liver after a single administration. The goal is to make a precise change in the gene so the liver produces less PCSK9 protein, helping keep LDL cholesterol lower over time.

Rather than adding new DNA, the approach is designed to make a single precise spelling change in the PCSK9 gene in liver cells. Kathiresan compares it to using a pencil and eraser to change one letter in a genetic sentence – a small alteration intended to have a lasting effect.

“It’s essentially a one-time treatment designed to mimic what nature already showed us,” Kathiresan said.

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A different vision for cardiovascular care

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The investigational therapy is currently being evaluated in adults with HeFH and premature coronary artery disease in an ongoing clinical trial.

While the leading investigational program focuses on PCSK9 and LDL cholesterol, researchers believe the broader potential may extend beyond a single disease target. Verve’s other investigational programs aim to deliver lifelong cardiovascular risk reduction with a single dose by targeting genes strongly linked to cardiovascular disease, with additional investigational therapies currently under evaluation.

If successful, this type of approach could represent a fundamental shift in cardiovascular care – from managing high cholesterol over decades to potentially treating its underlying genetic driver once.

For Kathiresan, the ambition extends beyond lowering cholesterol. It’s about changing the trajectory of cardiovascular disease before a heart attack ever happens.

“I see a future free of heart attack,” he said. “Ideally, people early in life would receive a one-time treatment, keep cholesterol low for decades and avoid heart attack altogether. We could give heart disease protection to people who weren't born with it.”

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