First-in-human trial of CRISPR gene-editing therapy safely lowered cholesterol, triglycerides

Research Highlights:

• In a Phase 1, first-in-human trial, 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 about 55%.
• Cholesterol and triglyceride levels began to drop within the two weeks after treatment, with effects sustained for at least 60 days of follow-up.
• The treatment edited genes in the liver to durably turn off ANGPTL3 gene expression, and if confirmed in larger and longer-term studies, may eliminate the need for daily or monthly cholesterol-lowering medications in the future for some people with lipid disorders.
• Three participants experienced minor infusion-related reactions, such as back pain and nausea that resolved with medication, and one participant with elevated liver enzymes at screening had a temporary further rise in liver enzymes that lasted a few days and returned to normal without need for any treatment.
• Note: This abstract/trial is simultaneously published today as a full, peer-reviewed manuscript in The New England Journal of Medicine.

Embargoed until 8:56 a.m. CT / 9:56 a.m. ET, Saturday, Nov. 8, 2025

NEW ORLEANS, Nov. 8, 2025 - In a 15-patient, Phase 1 one, 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 today at the American Heart Association's Scientific Sessions 2025. The meeting, 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.

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 and triglycerides, two blood fats linked to heart disease. It is known that people born with natural mutations that turn off ANGPTL3 have lifelong low cholesterol and triglyceride levels without 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:

• LDL cholesterol and triglycerides were reduced by up to 60% at the highest dose.
• Reductions appeared within the first two weeks of treatment and were sustained through at least 60 days, the latest follow-up data included in this analysis.
• Three participants experienced minor infusion-related reactions, such as back pain and nausea that resolved with medication, and one participant with elevated liver enzymes at screening had a temporary further rise in liver enzymes that lasted a few days and returned to normal without need for any treatment.
• No long-term or serious safety concerns have been observed in any participants to-date. Longer-term safety monitoring is ongoing.

"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:

• First-in-human trial of CTX310, administered as a one-time intravenous infusion at doses from 0.1 to 0.8 mg/kg during the single infusion, after pre-treatment with corticosteroids and antihistamines.
• In this ascending dose study, each participant received a single intravenous infusion of CTX310 at one of five dose levels.
• Study participants were 15 adults, ages 18-75 years , with a median age of 53 years; 13 male participants and 2 female participants.
• All participants had elevated lipid levels despite maximum tolerated therapies, including one with homozygous familial hypercholesterolemia (FH) (a rare, inherited form of very high cholesterol); five with heterozygous FH; one with mixed dyslipidemia (high cholesterol and triglycerides); and two participants with severe hypertriglyceridemia (very high blood triglycerides).
• The study was conducted between June 2024 and August 2025 at six sites in Australia, New Zealand and the United Kingdom.
• Participants were followed for safety of the treatment, how the gene therapy was processed in the body, and cholesterol and triglyceride levels. All patients had at least 60 days of safety follow-up for inclusion in this study's analysis cut-off in September 2025.
• Patients will be monitored for one year within this trial, with additional long-term safety follow-up for 15 years, as recommended by the FDA for all CRISPR-based therapies.

"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 for heart disease and stroke, the leading causes of death worldwide. According to the American Heart Association's 2025 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.

Co-authors, disclosures and funding sources are listed in the manuscript.

Statements and conclusions of studies that are presented at the American Heart Association's scientific meetings are solely those of the study authors and do not necessarily reflect the Association's policy or position. The Association makes no representation or guarantee as to their accuracy or reliability. Abstracts presented at the Association's scientific meetings are not peer-reviewed, rather, they are curated by independent review panels and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting. The findings are considered preliminary until published as a full manuscript in a peer-reviewed scientific journal.

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Additional Resources:

• Multimedia is available on the right column of the release link
• View the abstract in the American Heart Association Scientific Sessions 2025 Online Program Planner
• American Heart Association health information: HDL (Good), LDL (Bad) Cholesterol and Triglycerides
• American Heart Association initiative: Lower Your LDL Cholesterol Now™ Initiative
• About Scientific Sessions 2025
• For more news at AHA Scientific Sessions 2025, follow us on X @HeartNews,#AHA25

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