Gene therapy angiogenesis

Rosengart TK, Lee LY Patel SR. Angiogenesis gene therapy phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF 121 cDNAto individuals with clinically significant severe coronary artery disease, Circulation 1999 100 468-474. 

Nanoparticles formulated with PLGA have been shown to be rapidly uptaken by the endothelial cells, the uptake was shown to depend on the nanoparticle concentration and the particles where mainly shown to localize in the cytoplasm (207). These nanoparticles were also shown to be biocompatible with the cells with no effect on cell viability (207). This is important due to the fact that endothelium is an important target for gene therapy in a number of disorders including angiogenesis, atherosclerosis, tumor growth, myocardial infarction, limb and cardiac ischemia, restenosis (207). 

Losordo, D.W., Vale, P.R., Symes, J.F., Dunnington, C.H., Esakof, D.D., Maysky, M. et al. (1998) Gene therapy for myocardial angiogenesis initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation, 98, 2800-2804. 

The transfection data summarized in Fig. 13 were obtained with primary human umbilical artery endothelial cells (HUAEC). Vascular endothelial cells, acting as an interface between circulating blood and tissues, are known to be involved in inflammatory processes, in atherosclerosis and angiogenesis, and represent a remarkable challenge as a gene therapy target. Their therapy with nonviral vectors... 

The efficacy of gene transfer approaches to therapeutic angiogenesis is now being tested in clinical trials. Controlled phase II trials are providing positive but not definitive results. Gene therapy appears to be safe based on these data. Hard clinical endpoints, such as mortality, myocardial infarction, and the need for revascularization are lacking, as is long-term follow-up. 

The lack of gene expression is another potential barrier. Some systems for inducible gene expressions have proved to be effective and safe in animal models (31), but they have not yet been tested in humans. Recent advances in stem cell research provide the possibility of combining gene therapy with ex vivo gene transfer into stem cells for angiogenesis therapy, as will be discussed later, If successful, this approach may overcome most of the obstacles presented by gene therapy. 

Two approaches have generally been used to achieve therapeutic angiogenesis protein therapy and gene transfer which are briefly discussed next. 

In contrast to that of myoblasts and mesenchymal cells, BM mononuclear or EPC delivery is primarily intracoronary (9), Presumably owing to the much smaller size of these angiogenic cells, their delivery has not been associated with significant adverse ischemic events, However, BM cell delivery has been associated with the theoretical potential for angiogenesis at unwanted sites, such as in occult tumors or retina, This unanticipated and potentially serious consequence illustrates our need to learn from our previous gene therapy colleagues and to expect the unexpected in this field,... 

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