Gene therapy for cardiovascular disease - A case for cautious optimism

There is currently intense interest in the development of gene therapy for cardiovascular disease. The stimulation of therapeutic angiogenesis for isc hemic heart disease has been one of the areas of greatest promise. Encourag ing results have been obtained with the angiogenic cytokines vascular endot helial growth factor (VEGF) and basic fibroblast growth factor in animal mo dels, leading to clinical trials in ischemic heart disease. VEGF also has t herapeutic potential in a second area of cardiovascular gene therapy, the e nhancement of arterioprotective endothelial functions to prevent postangiop lasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of VEGF promote endothelial regeneration, whereas V EGF-induced endothelial production of NO and prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal hyperplasia may also be achieved by gene transfer of endothelial NO synthase (eNOS), PGI s ynthase, or cell cycle regulators (retinoblastoma, cyclin or cyclin-depende nt kinase inhibitors, p53, growth arrest homeobox gene, fas ligand) or anti sense oligonucleotides to c-myb, c-myc, proliferating cell nuclear antigen, and transcription factors such as nuclear factor KB and E2F. An improved u nderstanding of etiologically complex pathologies involving the interplay o f genes and the environment, such as atherosclerosis and systemic hypertens ion, has led to the identification of new targets for gene therapy, with th e potential to alleviate inherited genetic defects such as familial hyperch olesterolemia. The use of vasodilator gene overexpression and antisense kno ckdown of vasoconstrictors to reduce blood pressure in animal models of sys temic and pulmonary hypertension offers the prospect of gene therapy for hu man hypertensive disease. The renin-angiotensin system has been the target of choice for antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and th e identification of additional target genes will be required before its ful l therapeutic potential can be realized.