CTX310 Gene Editing Sustains ANGPTL3, LDL Reductions at 1 Year

A single infusion of CTX310, an investigational in vivo CRISPR-Cas9 gene editing therapy targeting ANGPTL3, produced durable reductions in ANGPTL3, LDL cholesterol, and triglycerides through 1 year of follow-up in a phase 1a trial in patients with lipid disorders, according to data presented at the European Society of Cardiology (ESC) Congress 2026 and published simultaneously in the New England Journal of Medicine.¹

Loss-of-function variants in ANGPTL3 (angiopoietin-like protein 3) are associated with reduced atherosclerotic cardiovascular disease risk, and CTX310 uses a lipid nanoparticle-encapsulated CRISPR-Cas9 messenger RNA and guide RNA to replicate this effect through a one-time hepatic gene edit. The current data extend findings previously reported in 2025, providing the first 1-year durability readout across all 15 phase 1a participants and addressing whether the initial reductions in atherogenic lipoproteins persist over time.

“What is compelling about this update is that the reductions in ANGPTL3, triglycerides, and LDL from a single infusion have persisted out to one-year, suggesting a sustained biological effect,” said Steven E. Nissen, MD, senior investigator, chief academic officer, Cleveland Clinic Heart, Vascular and Thoracic Institute, in a statement from CRISPR Therapeutics.²

CTX310 phase 1a trial design and 1-year efficacy data

The phase 1a portion of the trial was an open-label, dose-escalation study conducted in Australia and New Zealand (ACTRN12623000809639), enrolling 15 adults with uncontrolled hypercholesterolemia, moderate to severe hypertriglyceridemia, or mixed dyslipidemia between May 2024 and August 2025.

Participants received a single intravenous dose of CTX310 at 1 of 5 levels (0.1, 0.3, 0.6, 0.7, or 0.8 mg/kg lean body weight) across homozygous familial hypercholesterolemia, severe hypertriglyceridemia, heterozygous familial hypercholesterolemia, or mixed dyslipidemia cohorts. Investigators noted the majority of participants were on background statins and/or ezetimibe, and 40% were taking PCSK9 inhibitors.²

Among the 4 participants who received the highest dose (0.8 mg/kg), the mean percent change from baseline at 1 year was -78.6% (range, -89.0 to -63.1) in ANGPTL3, -52.5% (range, -84.2 to -24.4) in LDL cholesterol, and -47.8% (range, -77.6 to -14.7) in triglycerides.²

Across the full highest-dose cohort, ANGPTL3 reductions reached up to 89%, with a mean reduction of 79% sustained at 1 year following infusion. Non-HDL cholesterol and apolipoprotein B also declined by a mean of -52.0% and -37.2%, respectively, changes the investigators noted may be relevant to cardiovascular benefit given ANGPTL3's role in triglyceride-rich lipoprotein metabolism.²

CTX310 safety profile and next steps in phase 1b

The primary endpoint of the trial was adverse events, including dose-limiting toxic effects, and no dose-limiting toxicity was reported through 1 year. Two previously reported serious adverse events were assessed by investigators as unrelated to CTX310, with one subsequently determined to be a preexisting condition, and no new serious adverse events or adverse events of special interest occurred during extended follow-up.¹

Beyond a transient aminotransferase elevation in 1 participant shortly after treatment, no additional liver-function abnormalities occurred throughout the remainder of the trial, and infusion-related reactions in 3 participants were all grade 2 and resolved.

“For patients at high cardiovascular risk, the biggest challenge is often not starting therapy but staying on it, since daily medications require lifelong adherence that many patients are unable to maintain,” said Luke Laffin, MD, principal investigator and medical director, Cleveland Clinic Coordinating Center for Clinical Research.² “A single infusion producing durable reductions at one-year is an encouraging signal that a one-time approach could help close that adherence gap.”

CRISPR Therapeutics is now evaluating a fixed 0.8 mg/kg dose of CTX310 in a phase 1b trial (NCT07491172) in patients with refractory dyslipidemias, with an update from the severe hypertriglyceridemia cohort expected in the second half of 2026. The company's broader in vivo cardiovascular gene editing portfolio also includes CTX340, targeting angiotensinogen for refractory hypertension, and CTX321, targeting LPA for elevated lipoprotein(a).

References

1. Laffin LJ, Nicholls SJ, Scott RS, et al. Durability of CRISPR-Cas9 gene editing targeting ANGPTL3 with CTX310. N Engl J Med. Published August 28, 2026. doi:10.1056/NEJMc2609825

2. CRISPR Therapeutics. CRISPR Therapeutics presents phase 1a data for CTX310 demonstrating deep and durable ANGPTL3 editing, triglyceride and LDL lowering at ESC Congress 2026. Published August 28, 2026. Accessed August 29, 2026.