In Vivo Base Editing of PCSK9

Summary

In a phase 1, open‑label, single‑ascending‑dose trial of 35 adults, a single IV infusion of the in vivo base‑editing therapy VERVE‑102 produced dose‑dependent reductions in circulating PCSK9 (up to 88%) and LDL‑C (up to 62%; 78 mg/dL absolute) with effects durable for at least 1 year in a subset. Safety was acceptable with no dose‑limiting toxicities, though transient liver enzyme elevations and infusion reactions occurred.

Key Findings

• Single IV dose VERVE‑102 produced dose‑dependent PCSK9 reductions from 51% (0.3 mg/kg) to 88% (1.0 mg/kg).
• Corresponding LDL‑C reductions ranged from 9% to 62%, with an absolute 78 mg/dL decrease at the highest dose.
• No dose‑limiting toxic effects; transient ALT elevations and infusion reactions were the main adverse events.
• Lipid‑lowering effects appeared durable through follow‑up, with ≥1‑year data in 15 participants.

Clinical Implications

If confirmed in larger controlled trials, a one‑time gene‑editing therapy could obviate chronic lipid‑lowering regimens for high‑risk patients, but long‑term safety, off‑target editing, and cardiovascular outcome benefits must be established.

Limitations

• Open‑label phase 1 design without a control group and small sample size
• Limited duration of follow‑up for most participants; off‑target editing not detailed in abstract

Future Directions

Randomized controlled trials with larger cohorts to assess long‑term safety, off‑target/on‑target specificity, and cardiovascular outcomes; exploration of applicability across diverse genetic backgrounds and comorbidities.