Angiogenic Gene Therapy for Lower Extremity Ischemia: Experimental Advances and Clinical Experience

Peripheral arterial disease and critical limb-threatening ischemia remain major clinical challenges, particularly in patients who are not candidates for surgical or endovascular revascularization. These limitations have stimulated extensive investigation into therapeutic angiogenesis using gene therapy approaches. This review summarizes experimental and clinical studies employing non-viral and viral gene delivery systems for the transfer of angiogenic factors, including VEGF, FGF-2, HGF, HIF-1α, and SDF-1. Particular attention is given to vector platforms, study design, patient populations, clinical endpoints, and safety outcomes reported in preclinical investigations and clinical trials. Although several studies demonstrated biological activity and favorable safety profiles, randomized trials such as RAVE and TAMARIS failed to demonstrate consistent and significant clinical efficacy. These findings emphasize the translational challenges associated with therapeutic angiogenesis and highlight the persistent gap between promising preclinical data and clinical outcomes in humans. Future progress in the field will likely depend on improved vector engineering, tissue-specific and regulated gene expression systems, optimized delivery strategies, and the integration of gene therapy with emerging regenerative technologies.