Highly promising one-time treatment for hyperlipidaemia

An investigational single-infusion gene-editing therapy demonstrated multiple beneficial outcomes in patients with hyperlipidaemia. This approach may help overcome the adherence challenges associated with the current lipid-lowering treatments and represents a potential new frontier in cardiovascular therapeutics. 

“The problem with the current atherogenic lipid-lowering agents is that adherence diminishes over time and patients often experience side effects,” explained Prof. Stephen Nicholls (Monash University, Australia), outlining the treatment landscape of hypercholesterolaemia [1]. His team developed CTX310, a CRISPR-Cas9-based gene-editing therapy designed to target angiopoietin-like protein 3 (ANGPTL3), a key regulator of lipid metabolism.

“Hepatocytes take up the CTX310 lipid nanoparticle,” Prof. Nicholls elaborated on the mechanism-of-action. “Within the cytoplasm, the nanoparticle is broken down, releasing Cas9 mRNA and ANGPTL3-specific guide RNA. The subsequently translated Cas9-guide RNA-ribonucleoprotein complex then translocates into the nucleus, where it disrupts the target ANGPTL3 gene, preventing the formation of functional ANGPTL3 protein.”

To evaluate this therapy, 15 participants with familial hypercholesterolaemia, elevated triglycerides, or mixed dyslipidaemia, all on maximally tolerated medical treatment, were randomised to various single doses of CTX310, ranging from 0.1 mg/kg to 0.8 mg/kg.

The mean percentage reduction from baseline in ANGPTL3 levels reached 79.7% with the 0.7 mg/kg dose. In addition, LDL-cholesterol decreased by 48.9% (0.8 mg/kg dose), and triglycerides were reduced by 62.0% in the 0.6 mg/kg arm. “We also observed substantial reductions in apolipoprotein B, apolipoprotein CIII, remnant cholesterol, and non-HDL cholesterol,” noted Prof. Nicholls. These lipid improvements were evident within 2–3 weeks post-infusion and remained stable throughout the 90–day follow-up period.

“There were no serious adverse events deemed related to CTX310,” said Prof. Nicholls. One participant experienced a mild allergic reaction, 3 participants had infusion-related reactions, and 1 participant showed transient elevations in aspartate aminotransferase or alanine aminotransferase levels. “These levels returned to baseline by day 14 and were not associated with concurrent bilirubin elevation,” clarified Prof. Nicholls.

The current phase 1 study demonstrated that CTX310 can be safely administered to reduce ANGPTL3 levels in patients with hyperlipidaemia. While efficacy results were promising, the small sample size warrants cautious interpretation. “We will continue to investigate this therapy and assess its efficacy in specific populations in future trials,” concluded Dr Nicholls.

1. Nicholls SJ, et al. Phase 1 trial of CRISPR-Cas9 gene editing targeting ANGPTL3. Groundbreaking trials in cardiometabolic therapeutics. AHA scientific sessions 2025, 7-10 November, New Orleans, LA, USA.

Medical writing support was provided by Robert van den Heuvel.
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Posted on 11 November 20255 December 2025