A one-time infusion of an investigational CRISPR-Cas9 therapy targeting angiopoietin-like protein 3 (ANGPTL3) was safe and reduced LDL cholesterol by nearly 50% and reduced triglycerides by approximately 55%, based on findings from the CRISPR-Cas9 trial presented at AHA 2025 and simultaneously published in NEJM.

The phase 1, first-in-human trial, included 15 participants with uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia and who were receiving maximally tolerated lipid-lowering therapy. Each participant received a single intravenous dose of CTX310 (0.1, 0.3, 0.6, 0.7, or 0.8 mg per kilogram of body weight) and the average follow-up was at least 60 days.

In presenting the results, researchers said the primary end point of serious adverse events occurred in two participants (13%), while no dose-limiting toxic effects related to CTX310 occurred. Reductions in LDL cholesterol and triglycerides occurred across all dosing levels (~60% at the highest dose), with initial reductions appearing within the first two weeks of treatment and remaining sustained through at least 60 days.

"Adherence to cholesterol-lowering therapy is one of the biggest challenges in preventing heart disease," said Steven E. Nissen, MD, MACC, a co-author of the study. "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."

In presenting the findings, Stephen J. Nicholls, MBBS, PhD, FACC; Luke J. Laffin, MD, FACC, et al., called the findings unprecedented. "If confirmed in larger trials, this one-and-done approach could transform care for people with lifelong lipid disorders and dramatically reduce cardiovascular risk," they explain.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia

Keywords: AHA Annual Scientific Sessions, AHA25, Dyslipidemias