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
Presented by Stephen J. Nicholls, MBBS, PhD, FACC, at the American Heart Association Scientific Sessions (AHA 2025), New Orleans, LA, Nov. 8, 2025.
Clinical Topics:
Diabetes and Cardiometabolic Disease, Dyslipidemia
Keywords:
AHA Annual Scientific Sessions, AHA25, Dyslipidemias