First-in-Human CRISPR Trial for Cholesterol and Triglycerides

Abstract

A Phase 1 clinical trial at Cleveland Clinic demonstrated that a single intravenous infusion of CTX310, a CRISPR-Cas9 gene-editing therapy targeting the ANGPTL3 gene in the liver, safely and substantially reduced both LDL cholesterol (~50%) and triglycerides (~55%) in patients with lipid disorders resistant to conventional medications. Effects appeared within two weeks and persisted for at least 60 days.

Key Contributions

• First-in-human trial of CRISPR therapy for cardiovascular lipid management
• Single infusion — not ongoing medication — addressing the major adherence problem (50% of patients stop cholesterol drugs within a year)
• Targeted ANGPTL3 gene knockout in liver cells via lipid nanoparticle delivery
• Dual effect: reduces both LDL cholesterol AND triglycerides simultaneously
• No serious adverse events related to treatment

Methodology

• Therapy: CTX310 (CRISPR-Cas9 editing therapy)
• Target: ANGPTL3 gene in liver cells
• Delivery: Single intravenous infusion via lipid nanoparticles
• Mechanism: Switches off ANGPTL3, which normally inhibits lipid-clearing enzymes
• Study design: Phase 1, 6 sites across Australia, New Zealand, United Kingdom
• Study period: June 2024 to August 2025

Results

• 15 adult patients (ages 31-68) with uncontrolled high triglycerides and LDL cholesterol
• LDL cholesterol reduced ~50% within 2 weeks
• Triglycerides reduced ~55% within 2 weeks
• Reductions sustained for at least 60 days of follow-up
• Safety: No serious adverse events related to treatment
• Minor side effects: back pain and nausea (resolved with medication)
• One participant: temporary elevated liver enzymes (normalized without intervention)

Clinical Significance

• Half of patients on cholesterol-lowering drugs stop within a year — a one-time gene editing treatment eliminates adherence entirely
• ANGPTL3 is a validated target: genetic studies show people born with ANGPTL3 loss-of-function mutations have very low cardiovascular risk
• This is the cardiovascular equivalent of Casgevy for Sickle Cell — potentially curative, one-time treatment
• Opens the door for CRISPR therapies targeting other cardiovascular risk genes

Limitations

• Small sample size (n=15) — Phase 1 safety study, not powered for efficacy endpoints
• 60-day follow-up — long-term durability and safety data needed
• Liver-targeted delivery only — ANGPTL3 happens to be expressed in the liver, which is the easiest organ to target with lipid nanoparticles
• Cost and manufacturing scalability of CRISPR therapies remains a barrier to widespread adoption
• Editing is permanent — if unexpected long-term effects emerge, they cannot be reversed

Source: Cleveland Clinic CRISPR Trial by Laffin, Nissen et al.