Advancements in Omics and Breakthrough Gene Therapies: A Glimpse into the Future of Peripheral Artery Disease.

Peripheral artery disease (PAD), a highly prevalent global disease, associates with significant morbidity and mortality in affected patients. Despite progress in endovascular and open revascularization techniques for advanced PAD, these interventions grapple with elevated rates of arterial restenosis and vein graft failure attributed to intimal hyperplasia (IH). Novel multi-omics technologies, coupled with sophisticated analyses tools recently powered by advances in artificial intelligence, have enabled the study of atherosclerosis and intimal hyperplasia with unprecedented single cell and spatial precision. Numerous studies have pinpointed gene hubs regulating pivotal atherogenic and atheroprotective signaling pathways as potential therapeutic candidates. Leveraging advancements in viral and non-viral gene therapy platforms, gene editing technologies, and cutting-edge biomaterial reservoirs for delivery uniquely positions us to develop safe, efficient, and targeted gene therapies for PAD-related diseases. Gene therapies appear particularly fitting for ex vivo genetic engineering of IH-resistant vein grafts. This manuscript highlights currently available state-of-the-art multi-omics approaches, explores promising gene therapy-based candidates, and details gene therapy delivery modalities employed by our laboratory and others to thwart mid-term vein graft failure caused by IH, as well as other PAD-related conditions. The potential clinical translation of these targeted gene therapies holds the promise to revolutionize PAD treatment, thereby enhancing patients' quality of life and life expectancy.