In Vivo Gene Editing of PCSK9 in the Prevention of Atherosclerotic Cardiovascular Disease: From Genetic Validation to Clinical Application

pp. 406-412

Abstract

Atherosclerotic cardiovascular disease (ACVD) 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.