In a 15-patient Phase 1 first-in-human trial, a one-time infusion of an investigational CRISPR-Cas9 gene-editing therapy safely reduced LDL cholesterol and triglycerides in people with difficult-to-treat lipid disorders, according to a late-breaking presentation at the American Heart Association’s Scientific Sessions 2025. The therapy, CTX310, uses tiny fat-based particles to deliver the CRISPR editing mechanism into the liver, where it switches off the angiopoietin-like protein 3 (ANGPTL3) gene. Turning off this gene lowers LDL cholesterol and triglycerides, two blood fats linked to heart disease.
Researchers reported that cholesterol and triglyceride levels began to drop within two weeks after treatment and were sustained for at least 60 days of follow-up. At the highest dose, LDL cholesterol and triglycerides were reduced by up to 60%. The results exceeded expectations—a 30–40% drop would have been considered a success. Importantly, CTX310 is the first therapy to achieve large reductions in both LDL cholesterol and triglycerides simultaneously, a major advance for patients with mixed lipid disorders.
“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.”
Adherence to cholesterol-lowering therapy is a major challenge in preventing heart disease. “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,” 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.
The trial included 15 adults (median age 53 years; 13 male, 2 female) with elevated lipid levels despite maximum tolerated therapies. Participants had homozygous familial hypercholesterolemia, heterozygous FH, mixed dyslipidemia, or severe hypertriglyceridemia. The study was conducted between June 2024 and August 2025 at six sites in Australia, New Zealand, and the United Kingdom.
Three participants experienced minor infusion-related reactions (back pain, nausea) that resolved with medication, and one participant with elevated liver enzymes at screening had a temporary further rise that returned to normal without treatment. No long-term or serious safety concerns have been observed. The U.S. Food and Drug Administration recommends long-term safety monitoring for up to 15 years for all CRISPR-based therapies, and participants will be followed accordingly.
“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.
According to the American Heart Association’s 2025 Heart Disease and Stroke Statistics, an estimated 86.4 million U.S. adults have total cholesterol levels of 200 mg/dL or higher. The Association recently launched the Lower Your LDL Cholesterol Now™ Initiative to help heart attack and stroke survivors improve cholesterol management.
The study had limitations, including a small, primarily male participant group in Australia, New Zealand, and the UK, so results may not be generalizable. Larger Phase 2 studies with more diverse participants are planned to begin in late 2025 or early 2026.
