NEW ORLEANS — New data from a first-in-human trial of a CRISPR-based gene therapy for cholesterol disorders are giving lipids experts reason for optimism about the approach for treating cardiovascular diseases. But a death last month in a trial of an unrelated gene therapy for a specific cardiac condition has raised questions about the overall safety of the approach.

At the 2025 Scientific Sessions of the American Heart Association in New Orleans, researchers presented findings from a phase 1 study of CTX310, an experimental CRISPR-Cas9 therapy that targets loss of function of variants of the ANGPTL3 gene, which plays a key role in regulating LDL cholesterol (LDL-C) and triglycerides.

The one-time infusion appeared to safely reduce cholesterol, triglycerides, and other markers in people with difficult-to-treat lipid disorders, according to Stephen Nicholls, MBBS, PhD, director of the Victoria Heart Institute at Monash University in Melbourne, Australia, who helped conduct the study. The results were published simultaneously in The New England Journal of Medicine.

"Gene editing is now feasible for a CRISPR-based therapy for a variety of types of patients. This approach may provide highly effective treatments for a variety of cardiovascular diseases,” Nicholls told attendees. 

The study enrolled 15 patients who had been diagnosed with familial or nonfamilial hypercholesterolemia, moderate-to-severe hypertriglyceridemia, or mixed dyslipidemia that resisted maximum treatment. 

Among the adverse events Nicholls reported was one death, which drew particular scrutiny in the wake of a report earlier this month of a fatality in a phase 3 trial of nexiguran ziclumeran, a CRISPR-based therapy for transthyretin amyloidosis with cardiomyopathy (ATTR-CM). The patient who died was previously hospitalized for grade 4 liver transaminases. 

However, Nicholls told Medscape Medical News the patient in the CTX310 trial who died was a 51-year-old man with a “significant history” of heart disease (along with other cardiopulmonary risks) and had coronary artery bypass graft a few years before enrolling in the study. The death occurred 6 months after he received the infusion of CTX310.

“We had not had any liver patterns” like those reported in the ATTR-CM study, he said. “We were satisfied that this patient’s death was not related to the study drug.”

Patients in the CTX310 trial received four ascending doses of the treatment: 0.1-, 0.3-, 0.6-, 0.7-, and 0.8-mg/kg of body weight. Those in the 0.8-mg/kg group had the greatest reduction in LDL-C (49%), whereas those in the 0.6-mg/kg group had the most significant reduction in triglycerides (62%). 

Among other biomarkers in which significant reductions with treatment occurred were apolipoprotein B (38% for 0.6 mg/kg, 33.4% for 0.8 mg/kg); non-HDL cholesterol (44.6% for 0.6 mg/kg, 49.8% for 0.8 mg/kg); apolipoprotein C3 (52.5% for 0.6 mg/kg, 61.7% for 0.8 mg/kg); and remnant cholesterol (58.3% for 0.6 mg/kg, 42.2% for 0.8 mg/kg).

Patients in the higher-dose groups experienced benefits early on, Nicholls said. “The LDL-cholesterol reduction continued to develop over the first 30 days of the study and the triglyceride changes appeared early, within a week to 10 days,” he said. 

Patients in the two highest-dose groups demonstrated approximately a 70% reduction in ANGPTL3 protein in the first 30 days after infusion, while the 0.6- and 0.8-mg/kg groups had the most significant reductions in LDL-C at 60 and 90 days post-infusion, ranging from 40%-50%. 

Levels of triglycerides also dropped in the 0.6- and 0.8-mg/kg groups within 60 or 90 days, Nicholls said. 

A ‘Slam Dunk,’ but … 

Kiran Musunuru, MD, PhD, MPH, director of the Genetic and Epigenetic Origins of Disease program at the University of Pennsylvania in Philadelphia, called the results “a slam dunk” in terms of efficacy. “There’s no question that this therapy works well,” he said at a press conference.

“Now, the big question mark with this study, which would always be the case, is of course safety,” Musunuru said. Patients experienced a “modest, transient rise” in alanine aminotransferase (ALT), a liver enzyme that can be a surrogate for cardiovascular risk. “But that’s not uncommon for this type of therapy that uses lipid nanoparticles as the delivery vehicle,” he said. 

Musunuru said the Cas9 gene editor used in the ATTR-CM study in which the patient death had been reported is “very similar” to the ANGPTL3 therapy CTX310. But the two trials have “important differences,” namely different gene targets and different patient populations, he said.

“It is formally possible that a hazard scene with the therapy might show up in some shape or form in the future with this ANGPTL3 therapy,” he added. “That's why we do clinical trials.”

The study was funded by CRISPR Therapeutics. Nicholls reports relationships with Amarin Pharma, Amgen, Anthera, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Cerenis, CSL Seqirus, Cyclarity, Daiichi Sankyo, Eli Lilly and Company, Esperion, F. Hoffmann-La Roche, InfraReDx, Kiniksa Pharmaceuticals, LipoScience, New Amsterdam Pharma, Novartis, Novo Nordisk, Resverlogix, Sanofi-Regeneron, Scribe Therapeutics, The Medicines Company, and Vaxxinity. 

Musunuru reports financial relationships with Verve Therapeutics, Beam Therapeutics, Nava Therapeutics, Capstan Therapeutics, Lexeo Therapeutics, Variant Bio, and Verve Therapeutics. 

Richard Mark Kirkner is a medical journalist based in Philadelphia.