Gene Therapy for Lipid Management: Dawn of a New Era

Abstract

Dyslipidemia is a major driver of atherosclerotic cardiovascular disease, with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides playing key roles in disease progression. Although conventional lipid-lowering therapies such as statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors are effective, their impact is often limited by lifelong treatment requirements, suboptimal adherence, and inadequate achievement of lipid targets, particularly in patients with inherited disorders such as familial hypercholesterolemia. Recent advances in gene-based therapies have introduced a paradigm shift by targeting lipid metabolism at its genetic and molecular basis. Techniques including CRISPR-Cas9 gene editing, small interfering RNA, and antisense oligonucleotides enable precise modulation of key genes such as PCSK9, ANGPTL3, APOC3, and LPA, leading to sustained reductions in atherogenic lipids. These therapies act upstream at the level of gene expression or mRNA, offering improved specificity, longer duration of action, and the potential for infrequent or single-dose administration. Clinical and translational studies demonstrate significant lipid-lowering efficacy across multiple pathways, including LDL-C, triglycerides, and lipoprotein(a), addressing previously unmet therapeutic needs. Despite their promise, important challenges remain, including long-term safety concerns, off-target effects, cost, ethical considerations, and regulatory complexities. Emerging strategies such as combination gene targeting and personalized genomic therapy further expand therapeutic potential while supporting a transition toward preventive cardiology. Overall, gene-based therapies represent a transformative approach in lipid management, with the potential to overcome the limitations of conventional treatments and enable durable, precision-based cardiovascular risk reduction.