Christos Soteriou was 29 when he needed a quadruple bypass surgery. Four arteries in his heart had become so clogged with plaque that blood could no longer flow through them.
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It’s a surprisingly young age to need such a surgery, but extremely high levels of cholesterol run in Soteriou’s family — a genetic condition called familial hypercholesterolemia. His father died of heart disease at 46; his son was diagnosed with elevated cholesterol at 14; and Soteriou himself, now 51, has had two heart attacks since his operation.
He’s tried statins and a newer drug, Repatha, to lower his cholesterol, but nothing worked.
So, when the opportunity came to join an early-stage clinical trial investigating a cutting-edge way to lower dangerously high cholesterol with a one-time treatment, he jumped at the chance.
“I wasn’t too worried, because I’ll try anything at this point,” said Soteriou, from South Australia.
The experimental treatment would use CRISPR, a gene-editing tool likened to biological scissors, to make precise cuts in the DNA to turn off a liver gene that prevents lipids — fatty substances including LDL cholesterol and triglycerides — from being cleared from the blood. By turning off the gene, called ANGPTL3, blood lipid levels should fall.
Gene editing has emerged as a game-changing therapy for rare genetic diseases including sickle cell disease and beta thalassemia, but it remains relatively unproven in more common health conditions.
When the trial’s results were published in The New England Journal of Medicine last November, they created a stir. Patients who received the highest dose saw their LDL cholesterol levels fall by 49% and their triglyceride levels fall by 55%.
“It was quite remarkable, the influx of messages we received,” said Dr. Luke Laffin, the trial’s lead investigator and a preventative cardiologist at the Cleveland Clinic. “I still get a message once every couple weeks from physicians saying, ‘My patients saw this on TV and they want to do this.’”
Soteriou was among the trial participants who benefited from a significant cholesterol reduction. “My doctors and cardiologist, they’ve been quite shocked,” he said. “They said, ‘Jeez, it’s better than it’s ever been.’”
This study, funded by CRISPR Therapeutics, was carried out in just 15 people in 2024, but experts say it may represent a paradigm shift in the management of heart disease. Larger trials are already underway, including some exploring new ways of lowering lipid levels through inhibiting or switching off different genes. While there is still much to be learned about the long-term safety of this approach, and how well it works across different patient groups, some cardiologists believe it will ultimately be transformative.
In the late 2000s, the cardiologist Dr. Kiran Musunuru, a professor of medicine at the University of Pennsylvania, began investigating a long-standing medical mystery: why some families reported having extraordinarily low levels of cholesterol.
Using a new technology which enabled scientists to sequence all 20,000 genes in a person’s DNA at once, Musunuru and others began to uncover their secrets. Key liver genes — including ANGPTL3 and another called PCSK9 — were either dialed down or turned off entirely. When Musunuru later experimented with using CRISPR to switch off PCSK9 in mice and primates, their cholesterol levels fell and remained low.
“These people won the genetic lottery,” Musunuru said. “They are protected against heart disease, and they have no adverse health consequences whatsoever.”
Over the following decade, Musunuru co-founded a company, Verve Therapeutics, with the aim of using this discovery to permanently lower cholesterol in humans. The company has two trials in progress: one using gene-editing to inactivate PCSK9 in people with familial hypercholesterolemia or coronary artery disease, and another using the same approach to inactivate ANGPTL3 in people deemed at high risk of a heart attack or stroke. While the results are yet to be published, preliminary data from the PCSK9 trial indicates significant reductions in LDL cholesterol.
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Musurunu said he is optimistic that these treatments could become available by the early 2030s to a subset of patients, for example people recuperating from a heart attack.
“Before they leave [the hospital], they get this one-time therapy that permanently reduces their cholesterol levels,” he said. “They’re protected from that next heart attack.”
If safety could be guaranteed, he believes that the use cases could be expanded to high-risk groups for heart disease, such as people with Type 2 diabetes. Perhaps eventually, he said, it could be administered more broadly to certain people in early adulthood as a way of conferring lifelong protection against cardiovascular diseases.
“If enough people in the population took this at like, 20 years of age, it would improve life expectancy,” he said. “People won’t be having heart attacks. That is the potential impact of this.”
That vision is still a ways off, with larger and longer trials needed. But other cardiologists with no commercial stake in the technology are also captivated by the concept of using gene editing to deliver a one-time therapy to prevent people from accruing damaging levels of blood lipids.
“I love the idea of one and done,” said Dr. Priscilla Hsue, chief of the cardiology division at UCLA Health. “Durably lowering cholesterol for the rest of your life, could be transformational for some patients.”
The reason for this excitement is simple: Though current cholesterol-lowering medications are effective, they often require patients to take them for the rest of their lives. Many find that impossible.
Marco Carabott, 54, knows he should have paid more attention to taking his medications. After 15 years managing various fast-food restaurants, and, by his own admission, eating breakfast, lunch and dinner at them, he was diagnosed with high LDL cholesterol and prescribed a cocktail of statins.
“But I’ve been notoriously poor at taking medication,” Carabott, of Adelaide, South Australia, said. “Forgetful, lazy. I kind of assumed I was going to die a bit younger than perhaps the average, and I just took that in my stride a little bit.”
Eventually he had a heart attack, and, like Soteriou, needed a quadruple bypass to open his blocked arteries. It’s a story that reflects one of the ongoing challenges faced in heart disease prevention.
On the one hand, cardiologists have never had so many cholesterol-lowering drugs at their disposal. They include statins and ezetimibe, newer drugs such as bempedoic acid, and a class of injectable medications called PCSK9 inhibitors that block the protein produced by the PCSK9 gene, allowing the liver to remove more cholesterol from the blood.
But relatively few patients take them for a sustained period of time. Reasons range from patients forgetting to take multiple drugs, to costs, to symptoms of statin intolerance such as muscle and joint pains. Research has suggested that anywhere between 25-50% of statin users stop taking the drugs within one year, while another study found that more than 50% of heart attack survivors quit their statins within two years, despite being medically advised to take them for the rest of their life.
“If you look at how many patients are taking these therapies at two years, at five years, the numbers are really staggeringly low, even in patients that have known cardiovascular disease,” Hsue said.
Laffin, of the Cleveland Clinic, said one of the challenges is that high cholesterol is completely symptomless, and patients often feel perfectly well, up to the point where they have a heart attack. “People are walking around, they don’t feel any better taking a statin, for example,” he said. “So there’s less impetus to take these medicines.”
Like Soteriou, Carabott also joined the CRISPR trial. Twelve months after he received the treatment, a blood test revealed that his triglyceride levels had fallen by more than half. He said he hopes that in the coming years, he’ll be able to take lower doses of his statins, or one day even quit them entirely.
Many questions still remain about using gene editing to lower cholesterol. Chief among them: Are there any unusual or unexpected side effects that might emerge years down the line as a result?
The Food and Drug Administration has recommended that researchers monitor the trial participants over the next 15 years.
“We need a better understanding of, are there downsides, or is something going to turn up five years from now that we never expected?” said Dr. Steven Nissen, chief academic officer at the Cleveland Clinic’s Heart, Vascular & Thoracic Institute and the CRISPR study’s senior investigator.
In the short term, the side effects reported in the trial were minor back pain, nausea and elevated liver enzymes, all of which went away on their own.
Musurunu said that some degree of temporary liver stress is expected, as the gene-editing machinery is being delivered to virtually all of the liver cells. “It’s typically not an issue,” he said. “You wait a few days or a few weeks, and then things come back to normal.”
But there’s a more worrisome concern in the minds of scientists. Namely, what happens if something goes awry and a tool like CRISPR mistakenly edits a different spot, somewhere else in the genome? The potential consequences of these so-called off-target effects are unknown. While this has never been observed in either humans or animals, cardiologists say it is of vital importance to rule it out.
“I think we’re still in the discovery phase,” Hsue said. “Could there be unintended damage to DNA that we just don’t know about? Will someone’s body react [to the treatment] in an unusual way that will lead to inflammation? We don’t really know.”
According to Dr. Robert Rosenson, a professor of cardiovascular medicine at the Icahn School of Medicine at Mount Sinai in New York, other trials are attempting to reduce the risk of off-target effects by using a different means of turning off key liver genes, known as base editing. Rosenson plans to be involved in one of those trials with Verve Therapeutics.
Rosenson said that if CRISPR is a scissor that cuts both strands of DNA, base editing is an eraser that substitutes one chemical letter, or base, in a single strand of DNA. Other researchers have previously suggested that base editing may be safer, although more human studies are needed.
“It’s a more specific approach, and I think this is critical as we offer this approach to larger numbers of individuals,” Rosenson said. “Safety becomes pre-eminent.”
Soteriou, now 16 months out from the clinical trial, said he hopes that the treatment will manage to preserve their health for a little longer. His son Jade is set to receive the same full dose of the therapy as part of the next stage of the trial, and Soteriou is optimistic that it could prevent him from experiencing a similar fate.
“For me, I know it’s not unclogging my arteries, but I just think it’s given me a little bit more hope for a few more years,” Soteriou said. “You’ve got to face reality sometimes, and before I was worried about not having long to live. I just hope my son won’t have to go through what I’ve had to go through.”
