byAmerican Heart Association

In a 15-patient, Phase 1, first-in-human trial, a one-time CRISPR-Cas9 gene-editing therapy safely reduced LDL cholesterol and triglycerides in people with difficult-to-treat lipid disorders, according to a preliminary late-breaking science presentation Saturday at the American Heart Association'sScientific Sessions 2025. The meeting, held Nov. 7–10 in New Orleans, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science. The paper was simultaneouslypublishedin theNew England Journal of Medicine.

This trial tested CTX310, an experimental CRISPR-Cas9 gene-editing treatment delivered as a one-time infusion. CTX310 uses tiny fat-based particles to carry the CRISPR editing mechanism into the liver, where it switches off a gene called angiopoietin-like protein 3 (ANGPTL3). Turning off this gene lowers LDL ("bad") cholesterol andtriglycerides, two blood fats linked to heart disease. It is known that people born with natural mutations that turn off ANGPTL3 have lifelong low cholesterol andtriglyceride levelswithout apparent harmful effects, and a lower lifetime risk of atherosclerotic cardiovascular disease.

CRISPR-Cas9 is a type of gene-editing technology that can durably change DNA inside cells. For that reason, the U.S. Food and Drug Administration recommends long-term safety monitoring, typically up to 15 years, for all studies using CRISPR-based therapies.

In this trial, both LDL cholesterol and triglyceride levels dropped within two weeks after treatment and stayed low for at least 60 days. Researchers said the results were stronger than expected: a 30%–40% drop would have been a success; however, CTX310 reduced both LDL cholesterol and triglycerides by nearly 50% or more on average at the highest dose. Importantly, it is the first therapy to achieve large reductions in both LDL cholesterol and triglycerides at the same time, a major advance for patients with both high cholesterol and high triglycerides (known as mixed lipid disorders), who often have elevations in both.

"This is really unprecedented. A single treatment that simultaneously lowered LDL cholesterol and triglycerides," said Luke J. Laffin, M.D., lead study author and a preventive cardiologist at the Cleveland Clinic. "If confirmed in larger trials, this one-and-done approach could transform care for people with lifelong lipid disorders and dramatically reduce cardiovascular risk."

Key results:

"Adherence to cholesterol-lowering therapy is one of the biggest challenges in preventing heart disease," said Steven E. Nissen, M.D., FAHA, a co-author of the study and chief academic officer at the Cleveland Clinic Heart, Vascular and Thoracic Institute. "Many patients stop taking their cholesterol medications within the first year. The possibility of a one-time treatment with lasting effects could be a major clinical advance."

Study background and design:

"This has been a great opportunity to perform a pivotal first-in-human gene editing study of ANGPTL3 in patients in Australia and New Zealand," said Stephen J. Nicholls, lead study investigator and director of the Victorian Heart Institute at Monash University.

High cholesterol is a major risk factor forheart diseaseand stroke, the leading causes of death worldwide. According to the American Heart Association's2025 Heart Disease and Stroke Statistics, an estimated 86.4 million U.S. adults (about 35%) have total cholesterol levels of 200 mg/dL or higher.

The Association recently launched the Lower Your LDL Cholesterol Now Initiative, a three-year national effort to help heart attack and stroke survivors better understand their LDL cholesterol, improve testing, and support treatment adherence. A recent survey found that while 75% of survivors reported having high cholesterol, nearly half were unaware of their LDL number, yet 98% said they would get their cholesterol checked if recommended by a health care professional.

This study had several limitations, particularly as an early safety and efficacy trial with a small, primarily male group of adult participants in Australia, New Zealand and the UK. Therefore, the results may not be applicable to people in other countries, women or people in other age groups. Participants also had different types of lipid disorders, so larger Phase 2 studies that include more diverse participants will be needed to evaluate the treatment and to confirm these findings.

Future Phase 2 studies are planned to begin in late 2025 or early 2026, focusing on broader patient populations and long-term outcomes.

More information: Luke J. Laffin et al, Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3, New England Journal of Medicine (2025). DOI: 10.1056/nejmoa2511778 Journal information: New England Journal of Medicine

Provided by American Heart Association