Gene Editing Therapies Targeting Lipid Metabolism for Cardiovascular Disease: Tools, Delivery Strategies, and Clinical Progress

Abstract

Highlights: What are the main findings? Gene editing therapies targeting liver-specific genes that are involved in lipid metabolism for treating cardiovascular diseases (LivGETx-CVD) have progressed from conceptual frameworks to early-phase clinical trials, with the potential to redefine prevention and long-term management of dyslipidemia and atherosclerotic cardiovascular diseases. Human genetics and preclinical studies suggest several promising genes, such as PCSK9, ANGPTL3, IDOL, ASGR1, APOC3, and LPA, for targeting in LivGETx-CVD to achieve durable LDL-C and triglyceride lowering after a single administration. What is the implication of the main findings? LivGETx-CVD is a potential “vaccine-like” intervention for cardiovascular disease, offering long-term protection without the adherence challenges and access barriers of chronic lipid-lowering medications. To translate LivGETx-CVD beyond rare, severe dyslipidemias toward broader preventive use, the field must address outstanding challenges in delivery safety, off-target effects, cost-effectiveness, as well as ethical and regulatory oversight, requiring larger and longer clinical trials and societal-level discussion. Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools—including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors—and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as PCSK9, ANGPTL3, CETP, APOC3, ASGR1, LPA, and IDOL, supported by findings from human genetics, preclinical models, and recent first-in-human trials. Emerging delivery vehicles (AAVs, LNPs, lentivirus, virus-like particles) and their translational implications are discussed. The review highlights ongoing clinical trials employing liver-targeted in vivo editing modalities (LivGETx-CVD) and provides insights into challenges in delivery, off-target effects, genotoxicity, and immunogenicity. Collectively, this review captures the rapid progress of LivGETx-CVD from conceptual innovation to clinical application, and positions gene editing as a transformative, single-dose strategy with the potential to redefine prevention and long-term management of dyslipidemia and atherosclerotic cardiovascular disease.