Authors: Luke J. Laffin, M.D., Stephen J. Nicholls, M.B., B.S., Ph.D., Russell S. Scott, M.B., Ch.B., Ph.D., Peter M. Clifton, M.B., B.S., Ph.D., John Baker, M.D., Ashish Sarraju, M.D. https://orcid.org/0000-0003-1649-2110, Shweta Singh, Ph.D., +6 , Qiuqing Wang, M.S., Kathy Wolski, M.P.H., Huansheng Xu, Ph.D., Jen Nielsen, M.S., Naimish Patel, M.D., Jason M. Duran, M.D., Ph.D., and Steven E. Nissen, M.D. https://orcid.org/0000-0002-7231-6464
Published November 8, 2025
N Engl J Med 2025;393:2119-2130
DOI: 10.1056/NEJMoa2511778
Abstract
Background
Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases. ANGPTL3 loss-of-function genetic variants are associated with decreased levels of low-density lipoprotein cholesterol and triglycerides and a decreased lifetime risk of atherosclerotic cardiovascular disease.
Methods
We conducted an ascending-dose phase 1 trial to assess the safety and efficacy of CTX310, a lipid-nanoparticle–encapsulated clustered regularly interspaced short palindromic repeats–Cas9 endonuclease (CRISPR-Cas9) messenger RNA (mRNA) and guide RNA targeting hepatic ANGPTL3 to induce a loss-of-function mutation. Adults who had uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia and were receiving maximally tolerated lipid-lowering therapy received a single intravenous dose of CTX310 (0.1, 0.3, 0.6, 0.7, or 0.8 mg per kilogram of body weight). The primary end point was adverse events, including dose-limiting toxic effects.
Results
A total of 15 participants received CTX310 and had at least 60 days of follow-up. No dose-limiting toxic effects related to CTX310 occurred. Serious adverse events occurred in two participants (13%): one participant had a spinal disk herniation, and the other died suddenly 179 days after treatment with the 0.1-mg-per-kilogram dose. Infusion-related reactions were reported in three participants (20%), and one participant (7%) who had elevated levels of aminotransferases at baseline had a transient elevation in aminotransferases to between three times and five times as high as those at baseline, peaking on day 4 and returning to baseline by day 14. The mean percent change in ANGPTL3 level was 9.6% (range, −21.8 to 71.2) with the dose of 0.1 mg per kilogram, 9.4% (range, −25.0 to 63.9) with 0.3 mg per kilogram, −32.7% (range, −51.4 to −19.4) with 0.6 mg per kilogram, −79.7% (range, −86.8 to −72.5) with 0.7 mg per kilogram, and −73.2% (range, −89.0 to −66.9) with 0.8 mg per kilogram.
Conclusions
Editing of ANGPTL3 was associated with few adverse events and resulted in reductions from baseline in ANGPTL3 levels. (Funded by CRISPR Therapeutics; Australia New Zealand Clinical Trials Registry number, ACTRN12623000809639.)
Notes
This article was published on November 8, 2025, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by CRISPR Therapeutics.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.