ANGPTL3 Gene Silencing — Gene Therapy & Genetic Interventions
Genetic inactivation of ANGPTL3 to permanently lower triglycerides, LDL cholesterol, and cardiovascular risk.
Overview
ANGPTL3 (angiopoietin-like protein 3) is a hepatocyte-secreted protein that inhibits lipoprotein lipase and endothelial lipase. Natural loss-of-function mutations in ANGPTL3 result in familial combined hypolipidemia with markedly reduced triglycerides, LDL-C, and HDL-C, associated with 41% reduced coronary artery disease risk. Multiple approaches target ANGPTL3: evinacumab (monoclonal antibody, FDA-approved), vupanorsen/ARO-ANG3 (antisense/siRNA), and CRISPR/base editing for permanent gene inactivation. Verve Therapeutics and others are developing one-time gene editing approaches.
Indications
- Severe hypertriglyceridemia
- Familial hypercholesterolemia (refractory to standard therapy)
- Atherosclerotic cardiovascular disease
- Mixed dyslipidemia
- Elevated Lp(a) (partial effect)
Mechanism of Action
Gene editing introduces loss-of-function mutation in ANGPTL3 gene in hepatocytes, eliminating protein production
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Evinacumab (Evkeeza) | 15 mg/kg | Monthly IV infusion | FDA-approved for homozygous FH |
| ANGPTL3 base editing (investigational) | Study-specific | Single infusion | LNP-delivered; one-time treatment goal |
Safety & Contraindications
- Evinacumab is FDA-approved and has established safety profile
- Gene editing approaches are preclinical for this target
- Very low LDL-C levels (< 25 mg/dL) appear safe based on natural ANGPTL3 null individuals
- Hepatic steatosis may occur with ANGPTL3 loss of function
- Gene editing off-target effects require characterization
- Impact on fat-soluble vitamin absorption at very low lipid levels requires monitoring