Safety of gene therapy
An important end point in all VEGF trials has been safety. Stimulation of angiogenesis raises theoretical concerns, especially in relation to tumour growth, retinal neovascularization, haemorrhage from fragile new vessels, enhanced atherogenesis, hypotension, oedema and inflammatory responses. So far, no evidence of increased tumorigenesis, neovascularization in nontarget organs, vascular malformations, increased atherogenesis, or plaque destabilization has been observed in clinical trials using VEGF-A protein or gene transfer. High doses of adenovirus expressing VEGFs have been shown to cause tissue oedema and pericardial fluid accumulation in animal experiments. Consistently, peripheral oedema was also found to be associated to the adenoviral VEGF121 therapy in the RAVE trial. Recently, pericardial effusions were reported to occur in 1.37% of patients after percutaneous intramyocardial VEGF-C plasmid gene transfer in the GENASIS trial, most likely related to Stiletto catheter-mediated injections. Mild transient fever and development of anti-adenovirus antibodies have been reported after the intra-arterial administration of adenoviral vectors, however, an 8-10-year follow-up of AdVEGF patients in our clinic has not shown any safety concerns. In summary, according to current experience from clinical studies, treatment with VEGFs has been well tolerated, and no VEGF-related serious adverse effects have been reported.