Gene therapy for therapeutic angiogenesis in critically ischaemic lower limb - on the way to the clinic

Currently, no effective pharmacological treatment is available for vascular isation defects in lower limbs. Many patients presenting with persistent pa in and ischaemic ulcers are not suitable candidates for surgical or endovas cular approaches. Further refinement of the available methods will undoubte dly lead to a more active approach towards treatment of peripheral arterial occlusive disease (PAOD). Recently, therapeutic angiogenesis, in the form of recombinant growth factor administration or gene therapy, has emerged as a novel tool to treat these patients. However, improved gene transfer meth ods and better understanding of blood vessel formation are required to brin g therapeutic angiogenesis to clinical practice. Here we review the clinica l problem (PAOD), mechanisms of blood vessel formation (angiogenesis, vascu logenesis and arteriogenesis), experimental evidence and clinical trials fo r therapeutic angiogenesis in critically ischaemic lower limbs. Also, angio genic growth factors, including vascular endothelial growth factors (VEGFs) and fibroblast growth factors (FGFs), delivery methods, and vectors for ge ne transfer in skeletal muscle, are discussed. In addition to vascular grow th, gene transfer of growth factors may enhance regeneration, survival, and innervation of ischaemic skeletal muscle. Nitric oxide (NO) appears to be a key mediator in vascular homeostasis and growth, and a reduction in its p roduction by age, hypercholesterolemia or diabetes leads to the impairment of ischaemic disorders.