Key result
Single-infusion PCSK9 gene-editing therapies achieve sustained, dose-dependent LDL-C reductions with acceptable short-term safety.
Why the study?
Available lipid-lowering therapies for ASCVD require long-term administration and are limited by efficacy, adherence, cost, and access, motivating in vivo PCSK9 gene-editing strategies aimed at permanently reducing LDL-C through a single administration.
Does a single administration of in vivo PCSK9 gene editing achieve a sustained reduction in LDL-C for the prevention of atherosclerotic cardiovascular disease?
Does a single administration of in vivo PCSK9 gene editing achieve a sustained reduction in LDL-C for the prevention of atherosclerotic cardiovascular disease?
In vivo gene editing of PCSK9 offers a potential one-time therapeutic strategy to achieve permanent LDL-C reduction and overcome adherence and access limitations of current chronic lipid-lowering therapies.
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide, and low-density lipoprotein cholesterol (LDL-C) is the primary causal and modifiable risk factor.Available lipid-lowering therapies-statins, ezetimibe, anti-PCSK9 monoclonal antibodies, and RNA interference-have been shown to reduce cardiovascular events, but they require long-term administration and are limited by efficacy, adherence, cost, and access.Proprotein convertase subtilisin/kexin type 9 (PCSK9) is, to date, the most genetically validated target for the development of in vivo gene-editing strategies aimed at achieving a permanent reduction in LDL-C through a single therapeutic administration.This review describes the biology of PCSK9, the available gene-editing platforms-CRISPR-Cas9, base editing, and primer editing-and their delivery to hepatocytes via lipid nanoparticles.It summarizes preclinical data and ongoing clinical trials (VERVE-101, VERVE-102, and YOLT-101) showing sustained, dose-dependent reductions in LDL-C following a single infusion, with acceptable short-term safety profiles.Finally, the long-term safety, regulatory, economic, and ethical challenges that will determine the eventual translation of this technology into routine clinical practice are discussed.
No takes yet. Share an insight, caveat, or question.
Corral et al. (2026) conducted a review in Atherosclerotic cardiovascular disease (ASCVD). In vivo gene editing of PCSK9 (CRISPR-Cas9, base editing, and primer editing delivered via lipid nanoparticles, including VERVE-101, VERVE-102, and YOLT-101) was evaluated on Low-density lipoprotein cholesterol (LDL-C) reduction. In vivo PCSK9 gene-editing therapies (VERVE-101, VERVE-102, YOLT-101) demonstrate sustained, dose-dependent LDL-C reductions following a single infusion with acceptable short-term safety.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: