One-time gene editing cuts LDL cholesterol in early hypercholesterolemia trial

Study: In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia. Image Credit: crystal light / Shutterstock

In a recent study published in The New England Journal of Medicine, researchers presented the interim clinical outcomes of the ongoing Heart-2 clinical trial. Heart-2 is a trial meant to test the safety and efficacy of VERVE-102, an innovative in vivo base-editing therapeutic engineered to durably inactivate the proprotein convertase subtilisin-kexin type 9 (PCSK9) gene within hepatic tissue.

The study administered a single intravenous infusion of the novel base-editing therapy to 35 adults diagnosed with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease. Interim study findings revealed that the intervention was associated with substantial, dose-dependent, and apparently durable reductions in both patients’ circulating PCSK9 protein and low-density lipoprotein (LDL) cholesterol levels, with no dose-limiting toxic effects observed in this interim analysis.

These outcomes provide early clinical evidence that a targeted, single-dose genetic modification can successfully mimic highly protective, naturally occurring human variants, thereby supporting further evaluation of a potential novel therapeutic paradigm for sustained cardiovascular risk mitigation.

Background

Decades of human genetic association studies have revealed that carrying natural loss-of-function variants in the PCSK9 gene is associated with exceptionally low levels of blood PCSK9 protein and lifetime reductions in LDL cholesterol, physiologically manifesting as a significantly lower incidence of atherosclerotic cardiovascular disease events.

Traditional pharmacological management strategies have been shown to reduce the risk of major vascular events in this cohort by ~22% over 5 years. However, more recent evidence indicates that individuals with lifelong genetic protection exhibit up to an 88% reduction in lifetime coronary artery disease risk, indicating that the magnitude of cardiovascular risk reduction likely depends on the cumulative duration of an individual’s exposure to lower systemic LDL levels.

Unfortunately, because the standard treatment model relies on daily oral adherence or regular subcutaneous injections, structural barriers are frequently reported to compromise patient compliance, with 30%-50% of high-risk patients discontinuing their prescribed lipid-lowering therapies, including standard PCSK9 inhibitors, within the first 12 months of initiation.

Consequently, engineering an in vivo base-editing architecture capable of durably mimicking cardioprotective variants with a single therapeutic encounter addresses a vital, unmet clinical need.

About the study

This study presents the interim findings of the Heart-2 clinical trial, an active phase 1, open-label, single-ascending-dose study designed to assess the safety, tolerability, and initial pharmacodynamic profile of VERVE-102. The sample cohort comprised 35 participants (18 to 70 years), with clinically diagnosed heterozygous familial hypercholesterolemia or premature coronary artery disease.

Study candidates were screened to ensure a fasting baseline LDL cholesterol level of at least 70 mg/dL while receiving maximally tolerated oral lipid-lowering therapy. Participants were evaluated across six weight-based escalating-dose cohorts (0.3-1.0 mg of total RNA per kilogram of body weight) and longitudinally monitored for up to 18 months following the intervention.

VERVE-102 utilizes a multi-component delivery architecture primarily comprising a messenger RNA (mRNA) transcript encoding an engineered adenine base editor (ABE) protein, paired with a specific guide RNA (gRNA) targeting the PCSK9 locus.

These nucleic acid components are encapsulated within a lipid nanoparticle (LNP) delivery matrix, which includes an N-acetylgalactosamine (GalNAc) targeting ligand that mediates hepatocyte uptake via the asialoglycoprotein receptor, thereby supplementing native apolipoprotein E-mediated internalization pathways.

Study findings

Interim data analysis indicated that a single intravenous infusion of VERVE-102 triggered dose-dependent reductions in both participants’ circulating PCSK9 and LDL cholesterol levels. The analyses established a strong, inverse relationship between total administered RNA mass and the resulting LDL cholesterol reductions (Pearson’s correlation coefficient = -0.68).

At the lowest evaluated dose of 0.3 mg/kg, treated participants exhibited a mean reduction in PCSK9 protein of 51% by day 28, corresponding to a modest mean LDL cholesterol reduction of 9%. Escalation to the highest dose cohort (1.0 mg/kg) resulted in observable biomolecular changes, with a mean reduction in plasma PCSK9 levels of 88%.

The analyses further revealed a concurrent mean reduction in time-averaged LDL cholesterol levels of 62%, translating into a substantial mean absolute reduction of 78 mg per deciliter from the cohort’s baseline.

Longitudinal observation of the 15 participants who reached or exceeded 12 months of clinical follow-up revealed that the biomarker reductions established at day 28 appeared to remain broadly durable throughout the evaluation window, suggesting persistent gene inactivation across natural hepatocyte turnover cycles. This sustained pharmacodynamic response occurred despite rapid clearance of lipid nanoparticle components from circulation.

Notably, the intervention’s overall safety profile was encouraging for an interim phase 1 analysis, with no dose-limiting toxicities, trial withdrawals, or treatment-related deaths linked to the underlying VERVE-102 infusion. However, mild-to-moderate infusion-related reactions and transient alanine aminotransferase elevations were observed, and one serious adverse event of aspiration pneumonitis was judged unrelated to treatment.

Conclusions

The Heart-2 interim data suggest that a single administration of VERVE-102 can substantially and durably reduce circulating PCSK9 protein levels in humans, offering a potentially long-lasting therapeutic mechanism at the DNA level.

While the study was limited by its small sample size, geographical constraints, open-label design, nonprespecified interim analysis, and relatively short follow-up, these findings suggest that this single-intervention genetic strategy could transform preventive cardiology, provided that larger, longer studies confirm safety, durability, and cardiovascular outcome benefits.