A Phase 1, first-in-human trial of an investigational CRISPR-Cas9 gene-editing therapy, CTX310, demonstrated safety and efficacy in lowering LDL cholesterol and triglycerides in patients with difficult-to-treat lipid disorders, according to a late-breaking presentation at the American Heart Association's Scientific Sessions 2025.
The study, involving 15 adults with elevated lipid levels despite maximum tolerated therapies, showed that a one-time intravenous infusion of CTX310 reduced LDL cholesterol and triglycerides by up to 60% at the highest dose. These reductions occurred within two weeks and were sustained for at least 60 days of follow-up, the latest data included in the analysis. The treatment targets the ANGPTL3 gene in the liver, turning it off durably to lower blood fats linked to heart disease.
“This is really unprecedented. A single treatment that simultaneously lowered LDL cholesterol and triglycerides,” said Luke J. Laffin, M.D., lead study author and 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.”
The therapy uses tiny fat-based particles to deliver CRISPR-Cas9 machinery to liver cells, where it edits the ANGPTL3 gene. People born with natural mutations that turn off this gene have lifelong low cholesterol and triglycerides without apparent harm, supporting the therapy's rationale. The U.S. Food and Drug Administration recommends long-term safety monitoring for up to 15 years for CRISPR-based therapies, as per the FDA guidelines.
Adverse events were minor: three participants experienced infusion-related reactions like back pain and nausea that resolved with medication, and one participant with pre-existing elevated liver enzymes had a temporary further rise that returned to normal without treatment. No serious safety concerns were observed.
“Adherence to cholesterol-lowering therapy is one of the biggest challenges in preventing heart disease,” said Steven E. Nissen, M.D., FAHA, co-author 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.”
The study enrolled participants aged 18-75 (median 53 years), predominantly male, from six sites in Australia, New Zealand, and the United Kingdom. Lipid disorders included homozygous and heterozygous familial hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. All patients had at least 60 days of safety follow-up as of September 2025.
The findings are limited by the small, primarily male sample and short follow-up. Larger Phase 2 studies are planned to begin in late 2025 or early 2026, focusing on broader populations and long-term outcomes. According to the American Heart Association, about 86.4 million U.S. adults have high cholesterol, a major risk factor for heart disease and stroke.
