Key result
CRISPR-Cas9 gene editing targeting ANGPTL3 reduces ANGPTL3 levels with few adverse events.
Why the study?
Does CTX310 (CRISPR-Cas9 targeting ANGPTL3) cause adverse events in adults with uncontrolled dyslipidemia?
Does CTX310 (CRISPR-Cas9 targeting ANGPTL3) cause adverse events in adults with uncontrolled dyslipidemia?
A single intravenous dose of CRISPR-Cas9 gene editing therapy targeting ANGPTL3 was generally safe and resulted in substantial reductions in ANGPTL3 levels in adults with uncontrolled dyslipidemia.
Answers are grounded in this paper and cite their sources.
Should not yet change practice in lipid management; leaves open long-term safety and cardiovascular benefit of ANGPTL3 gene editing.
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.).
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Laffin et al. (2025) studied uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia (n=15). CTX310 was evaluated on adverse events, including dose-limiting toxic effects. CTX310, a CRISPR-Cas9 therapy targeting ANGPTL3, caused no dose-limiting toxicities and reduced ANGPTL3 levels by up to 79.7% at 0.7 mg/kg in adults with uncontrolled dyslipidemia.
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