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

Nov 24, 2025

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Author/Summarized by Author:
Carlos A Vergara Sanchez, MD
Summary Reviewer:
Fred M. Kusumoto, MD, FACC; R. Scott Wright, MD, FACC
Original Posted Date:
11/24/2025
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Contribution To Literature:

A one-time infusion of an investigational CRISPR-Cas9 therapy targeting angiopoietin-like protein 3 (ANGPTL3) was safe and reduced LDL cholesterol by nearly 50% and reduced triglycerides by approximately 55%, based on findings from the CRISPR-Cas9 trial.

Study Design:

  • Total number of enrollees: 15 participants
  • Duration of follow-up: 60 days
  • Intervention: CTX310 at dose 0.1, 0.3, 0.6, 0.7 or 0.8 mg/kg infused over several hours
  • Median patient age (IQR): 53 (31-68) years
  • Demographics (i.e., gender and race etc.):
    • Gender: Male 13 (87%)
    • Race/ethnicity: White 14 (93%)
    • Clinical atherosclerotic cardiovascular disease: 6 (40%)
    • Familial hypercholesterolemia: 6 (40%)
    • Severe hypertriglyceridemia: 2 (13%)
    • Mixed dyslipidemia: 6 (40%)
    • Mean LDL cholesterol: 154.6 mg/dL
    • Median triglycerides: 192.2 mg/dL

Principal Findings:

Primary Outcome- Safety:

  • Incidence of Adverse Events
    • No dose-limiting toxic effects or serious adverse events related to CTX310.
    • Serious adverse events (n=2): 13%; 1 participant spinal disk herniation, 1 participant died suddenly 179 days after treatment (0.1 mg/kg dose), deemed unrelated to CTX310.
    • Infusion-related reactions (n=3): 20%.
      • Back pain and nausea; resolved with supportive care.
    • Elevation of aminotransferases (n=1): 7%.
      • 3-5x baseline, normalized by day 14.

Secondary Efficacy Outcomes:

Mean change from baseline/Dose 0.1 mg/kg* (n=3) 0.3 mg/kg* (n=3) 0.6 mg/kg* (n=3) 0.7 mg/kg** (n=2) 0.8 mg/kg** (n=4)
ANGPTL3 +9.6% +9.4% -32.7% -79.7% -73.2%
LDL cholesterol +4.2% +15.4% -39.2% -21% -48.9%
Triglycerides +46.7% +38.8% -62% -19.2% -55.2%
Apolipoprotein B +9.7% +14.3% -38% -23.7% -33.4%
Apolipoprotein C-III +31.7% -3.0% -52.5% -43.8% -61.7%
Non-HDL cholesterol +13.3% +15.7% -44.6% -22.9% -49.8%
Remnant cholesterol +55.9% -33.3% -58.3% -27.3% -42.2%

*Reported at 90 days following CTX310 doses.
**Reported at 60 days following CTX310 doses.

Interpretation:

This phase 1 trial of in vivo CRISPR-Cas9-mediated ANGPTL3 gene editing demonstrated no dose-limiting toxicities. One serious adverse event (sudden death) was deemed unrelated to the intervention, but the novelty of the therapy necessitates the need for longer follow-up and further studies to establish long-term safety. The trial showed dose-dependent reductions in lipid parameters, especially at higher doses (0.6–0.8 mg/kg), supporting a potential benefit that should be evaluated by further investigation in a phase 2 trial. These findings support a potential role for gene editing with regard to lipid management if subsequent studies establish safety and efficacy.

References

Laffin LJ, Nicholls SJ, Scott RS, et al. Phase 1 trial of CRISPR-CAS9 Gene Editing Targeting ANGPTL3. N Engl J Med. Published online Nov. 8, 2025. doi:10.1056/nejmoa2511778.

Presented by Stephen J. Nicholls, MBBS, PhD, FACC, at the American Heart Association Scientific Sessions (AHA 2025), New Orleans, LA, Nov. 8, 2025.

Resources

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia

Keywords: AHA Annual Scientific Sessions, AHA25, Dyslipidemias