CRISPR Gene Editing Therapy CTX310 Lowers LDL-C and Triglycerides in Lipid Disorders

CTX310, a one-time CRISPR-Cas9 gene-editing therapy, has safely reduced LDL cholesterol and triglycerides in adult patients with difficult-to-treat lipid disorders.1

Presented at the American Heart Association’s Scientific Sessions 2025 in New Orleans, Louisiana, by Stephen Nicholls, MD, director of the Victorian Heart Institute at Monash University, this phase 1 trial represents the first-in-human trial of gene editing targeting angiopoietin-like protein 3 (ANGPTL3).1

“This is really unprecedented. A single treatment that simultaneously lowered LDL cholesterol and triglycerides,” Luke Laffin, MD, lead study author and preventive cardiologist at the Cleveland Clinic, said in a statement. “If confirmed in larger trials, this one-and-done approach could transform care for people with lifelong lipid disorders and dramatically reduce cardiovascular risk.”1

ANGPTL3 regulates lipid metabolism via inhibition of endothelial and lipoprotein lipase. ANGPTL3 loss-of-function genetic variants have been associated with reduced LDL-C, lower serum triglycerides, and decreased risk of atherosclerotic cardiovascular disease (ASCVD), without any known adverse effects.2

CTX310, an investigational lipid nanoparticle therapy, targets the liver to deliver mRNA encoding a Cas9 nuclease and a guide RNA. It is designed to induce a loss-of-function mutation in the ANGPTL3 gene in hepatocytes. This first-in-human trial evaluated its safety, pharmacokinetics, pharmacodynamics, and lipid-lowering effects.2

The trial itself was a phase 1 single ascending dose clinical trial, investigating doses from 0.1 mg/kg to 0.8 mg/kg of estimated lean body weight. A total of 15 patients were enrolled between June 2024 and August 2025 in 6 sites across Australia and New Zealand. Patients were eligible for inclusion if they were 18-75 years of age, with or without ASCVD, and if they had medically refractory homozygous or heterozygous familial hypercholesterolemia, severe hypertriglyceridemia, or mixed dyslipidemia.2

Additionally, patients were required to have a serum triglyceride level of >150 mg/dL and/or serum LDL-C level of >100 mg/dL or >70 mg/dL for patients with ASCVD, and/or ApoB >100 mg/dL, and/or non-HDL-C >160 mg/dL at the time of enrollment.2

Each patient was given a single intravenous infusion of CTX310 at 1 of 5 dose levels. Ultimately, CTX310 reduced both LDL-C and triglycerides by ≥50% on average at the highest dose. Additionally, LDL-C and triglyceride levels dropped across all 5 doses within 2 weeks of treatment, remaining low for ≥60 days. CTX310 is the first therapy to achieve large reactions in both LDL-C and triglycerides at the same time. Although 3 participants experienced minor infusion-related reactions, including back pain, nausea, and a temporary increase in liver enzymes, no long-term safety concerns have been observed in any patients. Long-term safety monitoring is ongoing.1

Investigators did note several limitations of the study, including the small and primarily male participant group. Due to this, these results may not be applicable to women and patients in other age groups or countries. Additionally, participants had several different types of lipid disorders; as a result, phase 2 studies are necessary to evaluate the treatment and confirm these findings in a more diverse patient cohort.1

“Adherence to cholesterol-lowering therapy is one of the biggest challenges in preventing heart disease,” Steven Nissen, MD, co-author of the study and chief academic officer at the Cleveland Clinic Heart, Vascular and Thoracic Institute, said in a statement. “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.”1

References

1. Kirkwood M. First-in-human trial of CRISPR gene-editing therapy safely lowered cholesterol, triglycerides. Heart.org Newsroom. November 8, 2025. Accessed November 8, 2025. https://newsroom.heart.org/news/first-in-human-trial-of-crispr-gene-editing-therapy-safely-lowered-cholesterol-triglycerides

2. Nicholls S, Laffin L, Scott R, et al. First-in-Human Phase 1 Clinical Trial of a CRISPR-Cas9 Gene Editing Therapy Targeting ANGPTL3. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.