EDITING OUT CARDIOVASCULAR RISK: A NARRATIVE REVIEW OF GENE-EDITING APPROACHES TO PCSK9

Abstract

Background: PCSK9 is a circulating protease that regulates plasma low-density lipoprotein (LDL) cholesterol levels. It binds to the LDL receptor on the surface of hepatocytes and directs the receptor toward intracellular degradation, so that greater PCSK9 activity leaves fewer LDL receptors available to clear LDL-C from the bloodstream. PCSK9 was established as a drug target largely through human genetics: naturally occurring loss-of-function variants are associated with lifelong low LDL-C and a markedly reduced risk of atherosclerotic cardiovascular disease with no apparent adverse consequences, whereas gain-of-function variants cause a severe, early onset form of familial hypercholesterolemia. Pharmacological PCSK9 inhibitors, monoclonal antibodies, and small interfering RNA (siRNAs) are currently in clinical use; however, all require repeated, lifelong administration. Aim: This review argues that PCSK9 gene editing has progressed from a theoretical concept to an emerging therapeutic class, with three distinct technical strategies currently under active development. We compared CRISPR-Cas9 nuclease knockout, base editing, and epigenetic silencing with established antibody and siRNA classes, focusing on efficacy, durability, and safety. Materials and Methods: A search of relevant research databases and a hand search of selected journals were conducted to identify eligible papers. Results:  Several programs based in the United States and China have demonstrated that a single dose of a gene-editing agent can lower PCSK9 and LDL-C levels in humans and animal models. Nuclease-mediated knockout and base editing produced the largest reductions, whereas epigenetic silencing produced a smaller but reversible effect. The principal safety signal identified to date was attributed to the lipid-nanoparticle delivery vehicle, rather than the editing mechanism itself. Conclusions: Early clinical and preclinical evidence supports the feasibility of PCSK9 gene editing. The remaining gaps are long-term safety data, direct evidence of reduced cardiovascular events rather than biomarker changes alone, and a strategy for equitable access and pricing.