CRISPR-Cas9 Gene Editing for Refractory Dyslipidemia Shows Safety and Preliminary Efficacy

A first-in-human treatment using CRISPR-Cas9 to edit the ANGPTL3 gene was well tolerated and substantially reduced both low-density lipoprotein (LDL) cholesterol and triglycerides in a phase 1 trial. The study was reported as a late-breaking science presentation at the 2025 American Heart Association Scientific Sessions and simultaneously published in the New England Journal of Medicine.

The trial assessed one-time infusion of a range of doses of CTX310, a lipid nanoparticle-encapsulated CRISPR-Cas9 therapy designed to induce permanent loss of function for the ANGPTL3 gene. These findings will allow further development of the therapy in larger trials evaluating safety and efficacy in broader populations.

“Gene editing is now feasible with CRISPR-based therapies for a variety of targets,” says Cleveland Clinic cardiologist Luke Laffin, MD, the study’s co-first author. “This study represents one of the first applications of gene editing in preventive cardiology, which is one of the largest potential patient populations for which gene editing has been assessed to date. While its findings are preliminary and further study is needed, this approach raises the prospect of treating lipid disorders over a lifetime with a one-time infusion instead of with chronic treatment with lifelong medication regimens.”

“The ability to safely edit an individual’s genome to permanently reduce atherogenic lipoproteins could overcome the significant challenge of waning adherence to current lipid-lowering therapies that require chronic administration,” adds senior author Steven Nissen, MD, Chief Academic Officer of Cleveland Clinic’s Heart, Vascular and Thoracic Institute. “Although it is early in the study of gene-editing therapies, the efficacy shown in this phase 1 trial is quite promising and represents a new frontier for drug development.”

Rationale for ANGPTL3-targeted gene editing

The development of CTX310 stemmed from recognition that angiopoietin-like 3 (ANGPTL3), a hepatically produced protein, is an important regulator of lipid metabolism via inhibition of lipoprotein and endothelin lipase. Even more notably, naturally occurring loss-of-function gene variants for ANGPTL3 are known to result in lifelong reductions in LDL cholesterol, triglycerides and risk of atherosclerotic cardiovascular disease (ASCVD) without evidence of adverse effects.

These observations prompted interest in using the in vivo gene-editing technology CRISPR-Cas9 to edit the ANGPTL3 gene to produce an enduring genetic modification and resulting permanent reductions in circulating atherogenic lipoproteins. This led to development of CTX310, a lipid nanoparticle-encapsulated CRISPR-Cas9 formulation with two components — an mRNA and a guide RNA — targeting ANGPTL3 to cause a loss-of-function mutation in hepatocytes.

“The lipid nanoparticle is taken up exclusively in the liver, where the Cas9 enzyme cuts the two strands of DNA associated with ANGPTL3,” Dr. Laffin explains. “This causes a nonfunctional mutation in the ANGPTL3 gene. We know from large genetic studies that individuals born with a nonfunctioning variant of ANGPTL3 have lower triglycerides, lower LDL cholesterol and lower risk of cardiovascular events without any known adverse consequences. But there’s always a concern about whether editing the genome might have any off-target effects or side effects at the time of treatment. That was a key focus of this trial.”

Study design: One-time infusion of a range of doses

The study was an open-label phase 1a investigation conducted at six sites in Australia, New Zealand and the United Kingdom among 15 adults with uncontrolled familial (n = 6) or nonfamilial (n = 1) hypercholesterolemia, moderate to severe hypertriglyceridemia (n = 2) or mixed dyslipidemia (n = 6). Six patients (40%) had clinical ASCVD. Median age was 53 years (range, 31 to 68), and 87% of the cohort was male.

Patients’ lipid conditions had to be refractory to maximally tolerated doses of lipid-lowering therapies, and study participants continued their baseline lipid-lowering therapies throughout the trial. At baseline, median LDL cholesterol was 155 mg/dL and median triglyceride level was 192 mg/dL.

Patients were enrolled to receive one of five doses of CTX310: 0.1, 0.3, 0.6, 0.7 or 0.8 mg/kg body weight. All doses of CTX310 were given as a one-time intravenous infusion over 1.5 to 4.5 hours. Patients were premedicated with a corticosteroid and an antihistamine to minimize infusion-related reactions.

The primary endpoint was safety and tolerability through one-year follow-up. Secondary endpoints were changes from baseline over time in ANGPTL3 concentrations and in LDL cholesterol, triglycerides and other lipid levels.

Although no U.S. patients were enrolled in this phase 1 trial, Cleveland Clinic investigators (including Drs. Laffin and Nissen) were involved in trial design, oversight and interpretation, including independent statistical review of results.

Key results

No serious adverse events or dose-limiting toxicities occurred that were deemed related to CTX310, although two patients (13%) had unrelated serious adverse events. Three patients (20%) experienced infusion-related reactions; all were successfully managed, and infusion was subsequently completed. One patient had transient elevation of aminotransferase levels.

Results for key secondary efficacy endpoints are detailed in the table below.

The effects on levels of apolipoprotein B and non-HDL cholesterol over time were very similar to those seen on levels of LDL cholesterol and triglycerides.

On to phase 2 trial assessment

The investigators conclude that CTX310-induced loss of function in the ANGPTL3 gene was safe and well tolerated in this small initial human study, with the highest doses of CTX3210 yielding substantial reductions in the target ANGPTL3 protein and in atherogenic lipoproteins. They note that these reductions — approximately 50% for LDL cholesterol and 55% for triglycerides with the highest CTX310 dose — are similar to those with evinacumab, an ANGPTL3-targeting monoclonal antibody approved for treatment of homozygous familial hypercholesterolemia and administered as a once-monthly infusion.

The researchers acknowledge the limitations of the study’s small size and heterogeneous patient population with varying types of dyslipidemia. They note that assessment of efficacy in specific populations will be feasible in phase 2 trials, in which Cleveland Clinic plans to be involved. They also underscore the imperative for long-term follow-up in much larger samples to evaluate for any late-emerging or low-incidence safety issues.

“Despite the caveats that go with any phase 1 investigation, this demonstration of reductions in ANGPTL3 and lipid biomarkers with the highest doses of CTX310 suggests that gene editing in the hepatocytes was effectively achieved,” Dr. Laffin observes. “If that ultimately translates to permanent reduction in cardiovascular risk, it will amount to a remarkable innovation with significant implications for the dyslipidemia treatment landscape, especially for patients with rare high-risk disorders or other forms of severe hypercholesterolemia.”

The study was funded by CRISPR Therapeutics AG, which is developing CTX310.

Drs. Laffin and Nissen do not accept any personal compensation from CRISPR Therapeutics. Both work with the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), which receives funding from CRISPR Therapeutics for clinical trial-related responsibilities, including academic oversight and independent statistical analysis.