A novel, single-dose CRISPR-Cas9 gene editing therapy has shown dose-dependent reductions in angiopoietin-like protein 3 (ANGPTL3) levels in a first-in-human, phase 1 trial (ACTRN12623000809639).¹ The findings suggest a potential new approach for managing dyslipidaemia in patients on maximally tolerated lipid-lowering therapy.
CTX310 is an investigational therapy consisting of a lipid nanoparticle that delivers messenger RNA for the Cas9 endonuclease and a guide RNA targeting the hepatic ANGPTL3 gene. The therapy is designed to induce a loss-of-function mutation, mimicking naturally occurring genetic variants associated with lower levels of low-density lipoprotein cholesterol, triglycerides, and a reduced lifetime risk of atherosclerotic cardiovascular disease.
This ascending-dose, phase 1 trial enrolled 15 adults with uncontrolled hypercholesterolaemia, hypertriglyceridaemia, or mixed dyslipidaemia who were already receiving maximally tolerated lipid-lowering therapy. Participants received a single intravenous infusion of CTX310 at one of five doses: 0.1, 0.3, 0.6, 0.7, or 0.8 mg per kilogram of body weight. The primary endpoint was the incidence of adverse events, including any dose-limiting toxic effects.
The therapy was associated with dose-dependent reductions in ANGPTL3 levels. The mean percent change from baseline was -32.7% with the 0.6 mg/kg dose, -79.7% with the 0.7 mg/kg dose, and -73.2% with the 0.8 mg/kg dose. The two lowest doses (0.1 and 0.3 mg/kg) did not result in a mean reduction.
No dose-limiting toxic effects related to CTX310 were observed. Serious adverse events occurred in two participants (13%): one experienced a spinal disk herniation, and another died suddenly 179 days after receiving the lowest dose (0.1 mg/kg). Infusion-related reactions were reported in three participants (20%). One participant (7%) with elevated baseline aminotransferases had a transient elevation that peaked on day 4 and returned to baseline by day 14.
These early data demonstrate the feasibility of using a single dose of a CRISPR-Cas9-based therapy to edit the ANGPTL3 gene and lower its protein levels. The study authors concluded that “Editing of ANGPTL3 was associated with few adverse events and resulted in reductions from baseline in ANGPTL3 levels.”¹ Further investigation in larger clinical trials will be necessary to establish the long-term safety and efficacy of this approach for cardiovascular risk reduction.
This study was funded by CRISPR Therapeutics.
References
1. Laffin LJ, Nicholls SJ, Scott RS, et al. Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3. N Engl J Med 2025;393:2119-2130. https://doi.org/10.1056/NEJMoa2511778.
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