CRISPR Gene Editing of ANGPTL3 Achieves Up to 80% Lipid Target Reduction in Phase 1 Cardiovascular Trial
A phase 1 dose-escalation trial of CTX310, a CRISPR-Cas9 therapy targeting hepatic ANGPTL3 to induce permanent loss-of-function mutations, showed dose-dependent ANGPTL3 reductions of up to 80% in 15 participants with uncontrolled dyslipidemia on maximally tolerated lipid-lowering therapy. No dose-limiting toxicities were observed, though one sudden death occurred 179 days after the lowest dose. This first-in-class approach could provide a one-time treatment for familial hypercholesterolemia and severe dyslipidemia, with implications for laboratory lipid panel monitoring protocols.
The original study
Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3.
- Authors
- Laffin LJ, Nicholls SJ, Scott RS, Clifton PM, Baker J, Sarraju A, et al.
- Journal
- The New England journal of medicine
- Type
- Clinical Trial, Phase I, Journal Article, Multicenter Study
- PMID
- 41211945
Original 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.).