Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3.

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.).