Cleveland Clinic doctors say gene-editing therapy could revolutionize cholesterol treatment

Pioneering CRISPR trial shows single infusion permanently lowers bad cholesterol by 50% in patients who don’t respond to medication.

CLEVELAND — Gene editing is the revolution in medical history and a groundbreaking Cleveland Clinic trial is demonstrating how this technology could transform the way millions of Americans manage high cholesterol.

A Phase 1 clinical trial at Cleveland Clinic has shown that a single infusion of gene-editing therapy can significantly and permanently reduce cholesterol and triglyceride levels in patients whose conditions don’t respond to standard medications.

The trial results, presented Saturday at the American Heart Association’s Scientific Sessions 2025 and published simultaneously in the New England Journal of Medicine, showed the experimental CRISPR-Cas9 treatment reduced LDL cholesterol by approximately 50% and triglycerides by about 55% in study participants.

“This treatment is still very early in development but if future trials continue to demonstrate safety and efficacy, the therapy has the potential to change the way we treat lipid disorders,” said Cleveland Clinic cardiologist Dr. Luke Laffin, first author of the study and a preventive cardiologist and cardiovascular clinical trialist. “Rather than a once-daily pill or monthly injection, this therapy would potentially offer a one-time infusion that is safe and durable for patients with high cholesterol.”

The 15-patient trial, conducted between June 2024 and August 2025 at six sites in Australia, New Zealand and the United Kingdom, included adults ages 31 to 68 with uncontrolled high triglycerides and elevated LDL cholesterol levels. Researchers observed substantial reductions in both measures within two weeks of treatment, with levels remaining low for at least 60 days. Follow-up continues.

Dr. Steven Nissen, Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic and senior author of the study, emphasized the revolutionary nature of the therapy. “Once the gene is edited, this is a one and done treatment, and, you know, this is really quite revolutionary because the alternative is to take medication every day or inject it every week or two for the rest of your life for these high levels of cholesterol or triglycerides,” Nissen said.

The treatment, called CTX310, uses CRISPR-Cas9 gene-editing technology to modify specific regions of DNA. Dr. Laffin described the mechanism as “molecular scissors” that permanently switches off a gene called ANGPTL3 in the liver. Turning off this gene can lower LDL cholesterol and triglycerides, both linked to heart disease.

“Large-scale studies looking at genetic data from patients show that individuals that are born with a loss of function mutation, meaning that gene, ANGPTL3 doesn’t work, they have lifelong low levels of LDL cholesterol, lifelong low levels of triglycerides, and most importantly, a lifetime lower risk of cardiovascular disease without any apparent harmful effects,” Dr. Laffin explained.

Too much LDL cholesterol, often called “bad” cholesterol, can lead to atherosclerotic disease—plaque buildup in artery walls—increasing the risk of heart attack or stroke. Recent estimates indicate that as of 2018, 26.4% of U.S. adults have elevated LDL cholesterol. High triglycerides also raise the risk of heart and vascular disease. About 25% of people in the United States have high triglycerides.

The trial used a single ascending dose approach, starting with very low doses and gradually increasing to evaluate safety and effectiveness. During the trial, participants received CTX310 as a one-time intravenous infusion over 1.5 to 4 hours at doses ranging from 0.1 to 0.8 mg/kg, after pre-treatment with corticosteroids and antihistamines. At the highest dose of 0.8 mg per kilogram, the therapy reduced both LDL cholesterol and triglycerides by approximately 50% on average.

“The primary objective in most first in human studies is to assess safety. And the most important take-home point was, is that there were no serious adverse events related to the drug itself,” Dr. Laffin said.

The trial reported no serious adverse events related to the treatment during short-term follow-up. Three participants experienced minor infusion-related reactions including back pain and nausea that resolved with anti-nausea medication. One participant with elevated liver enzymes before treatment experienced a temporary additional rise in liver enzymes that lasted a few days and returned to normal without requiring treatment. All participants completed the treatment.

The therapy addresses a critical gap in cardiovascular treatment. According to Dr. Nissen, adherence to cholesterol medications remains a major challenge. “We know that up to 50% of people by a year after their statin prescription stop taking it, which is really a shocking statistic,” Dr. Laffin noted.

Dr. Nissen explained why this happens. “Having a high cholesterol or high triglycerides doesn’t hurt. You know, if you have arthritis and you get a medicine that makes you feel better, you’re gonna keep taking it. But if you have something that doesn’t cause any symptoms, you know, high blood level of cholesterol, you know, people get tired of it and they stop.”

The gene-editing approach offers a solution to this compliance problem while also addressing treatment limitations. “We can lower in most people LDL cholesterol, but not in every patient. Some people, you give everything we have and you just can’t get their levels down, and those are good candidates for this,” Dr. Nissen said. “But we really don’t have good therapies for high triglycerides, which many people have. And it’s really pretty, quite extraordinary to have a single therapy that can affect both high cholesterol and high triglycerides. And to affect those levels permanently.”

The trial specifically targeted patients who were refractory to current medical therapy. “The majority of patients were on multiple other cholesterol lowering medicines, statins, a drug called ezetimibe, and then other injectable medicines as well,” Dr. Laffin said.

For many of these patients, genetics play a dominant role in their cholesterol levels. “The majority of cholesterol, particularly LDL cholesterol and triglycerides, you know, about 70, 75% of that is determined by genetics,” Dr. Laffin explained. “So, people can eat like rabbits and, you know, exercise daily, and it’s going to improve their cholesterol. There’s no question. But these are individuals who still can’t get to the targets we need them to be to reduce their cardiovascular risk.”

Dr. Nissen reflected on the historical significance of the breakthrough. “I have to tell you, having been practicing for a long time, if you’d asked me 15 years ago, I used to tell people, we can change everything about you, we can give you drugs, we can change your cholesterol, the only thing we can’t change is your parents, cause we can’t change your genes. Well, that was wrong, because now for the first time in history, we can change people’s genes.”

The targeted nature of the therapy offers potential advantages over traditional medications. “If you look at the current therapies we have, we give a drug, and it has the effects we want, but it has some effects that we don’t want. And, you know, those side effects can be very troublesome for people,” Dr. Nissen said. “This is a very targeted therapy. It targets one gene, one way. And it doesn’t do anything else.”

Based on the positive results, the research team is moving forward with Phase 2 studies. “We concluded based on this study that the safety and efficacy were outstanding. And that it was suitable to then pivot to doing a phase two study, which is the next phase in drug development,” Dr. Nissen said. “And it is the intention to bring that to the United States.”

The doctors expressed optimism about the timeline for bringing the therapy to patients. “Assuming safety continues to show what we saw in this first smaller phase one study, as well as efficacy, we don’t anticipate necessarily the need for large, you know, 10,000 patient outcome trials as we’ve seen with other therapies because this is a one and done,” Dr. Laffin said. “My hope would be sometime, you know, within the next few years, we get in 2 to 3 years, we get into phase 3 studies.”

Phase 2 will refine the approach for specific patient populations. “In phase two, we’ll have separate tranches of patients to look at specifically high triglycerides, specifically high LDL cholesterol,” Dr. Laffin explained. The current trial enrolled patients with high LDL cholesterol, high triglycerides, or the combination of both, which is called mixed hyperlipidemia.

The researchers are moving quickly to expand access. “We told the maker of this drug company in Boston, smaller company, that we want to go fast. We think that there’s good enough evidence for both safety and effectiveness to move as quickly as possible,” Dr. Nissen said. “And now we’ll need clearance from the FDA to begin enrolling in the United States. We think we can get that with the safety data that we have now.”

Dr. Nissen, who serves as a special government employee advising the FDA, expressed confidence in the approval process despite recent government changes. “There are a lot of good people at the FDA, and they understand that their mission is to help us help patients,” he said. “And so I am confident that Dr. Laffin and I when we go with the sponsor of the study to meet with the FDA that we can make a compelling case for why they ought to let us go forward.”

Dr. Laffin added, “This is a high unmet need. We know that this is the next frontier in terms of treatment, and we know that cardiovascular disease is still rampant within the United States.”

The importance of this research cannot be overstated. “This disease is the leading cause of death in both men and women in the United States and most other developed countries,” Dr. Nissen said. “And so, you know, when you can affect this disease, you can help a lot of people.”

Study participants will be monitored for one year following the trial, with additional long-term safety follow-up extending for 15 years, as recommended by the FDA for all gene-editing therapies. Future Phase 2 studies are planned to begin in 2026, focusing on broader patient populations and longer-term outcomes.

The study was funded by CRISPR Therapeutics AG of Zug, Switzerland.

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