Safety Concerns Regarding Cardivascular Gene Therapy

Given that the inhibition of angiogenesis may be of value in the treatment of neoplasms, concern has been raised that the administration of angiogenic growth factors could lead to development of tumors. There are neither in vitro nor in vivo data to suggest that either VEGF or FGF increases the risk of neoplastic growth and/or shmetastases, although longer-term follow-up will be required to address this issue in clinical trials. In our own experience with 88 subjects who have undergone VEGF gene transfer for CLI, the cumulative 7-year incidence of cancer has been limited to 2 patients with bladder cancer and 1 with liver and brain metastases from unknown primary (106). It was interesting to note that in the VIVA trial that there was a greater incidence of tumors in the placebo group compared with the VEGF group. This highlights the fact that the age group receiving such therapy will develop some unrelated tumors. Due to the theoretical risk of neoplastic growth, one must be vigilant about the possibility of cancer in patients treated with these angiogenic growth factors. In addition, concerns regarding the development of angiomata were raised in studies involving mice or rats treated with transduced myoblasts or supraphysiologic doses of plasmid DNA, respectively. Importantly, no other preclinical or clinical reports, including those using adenoviral vectors, have described this complication (107,108).

It is theoretically possible that VEGF may exacerbate pro-liferative and/or hemorrhagic retinopathy in patients with diabetes in view of the high VEGF levels demonstrated in the ocular fluid of patients with active proliferative retinopathy leading to loss of vision (109). To date, this adverse effect of therapeutic angiogenesis has not been observed. The local delivery of naked plasmid DNA encoding for VEGF-1 or VEGF-2 to more than 100 patients (one-third with diabetes and/remote retinopathy) treated at our institution with up to 4-year follow-up did not effect the visual acuity or fundoscopic findings as evidenced by serial funduscopic examinations pre-and post gene transfer by an independent group of retinal specialists.

Experiments in transgenic mice engineered to overexpress VEGF ± angiopoietin have demonstrated lethal permeability-enhancing effects of VEGF (110). However, even though VEGF has been reported to cause local edema, which manifests as pedal edema in patients treated with VEGF for CLI, it responds well to treatment with diuretics (44). As previously described, hypotension has been observed in therapies with recombinant proteins, particularly when used systemically and in higher doses (111,112). This is believed to be due to the fact that VEGF up-regulates NO synthesis. This complication, however, has never been described following gene transfer in either animals or humans (113,114).

Moulton et al. observed that when hypercholesterolemia apolipoprotein E- deficient mouse models were treated with inhibitors of angiogenesis (endostatin or TNP-470), there were significant regression of plaque areas and inhibition of intimal neovascularization (115). This study with several other studies raised concern regarding the potential for VEGF and other proangiogenic therapies to promote atherosclerosis (92, 116,117). However, data available from 4 separate animal studies and 2 clinical studies of human subjects fail to support the notion that accelerated atherosclerosis is a likely consequence of administering angiogenic cytokines (48-51, 118,119). The outcome is quite the opposite, in that adminis tration of VEGF led to a statistically significant reduction in intimal thickening due to accelerated reendothelialization, thereby refuting the notion that acceleration of atherosclerosis will be a consequence of VEGF-induced stimulation of angio-genesis.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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