Although one may conclude from this description of clinical trials that therapeutic angiogenesis has been pretty much a dismal failure, it can and should be argued that such a conclusion is premature. Indeed, a number of factors likely have influenced these outcomes and the lessons learned should facilitate future studies.
Perhaps one of the biggest reasons for failure is that none of these trials has explicitly addressed the arteriogenesis versus angiogenesis issues in trial design, drug delivery, or evaluation. Indeed, VEGFs are not primarily arteriogenic and, given the typically short duration of tissue residence following protein injection or expression after adenoviral or plasmid-based transfer in the myocardium, the negative results are not surprising. Similarly, although FGFs are arteriogenic, the short duration of tissue exposure following protein or adenoviral-based transfer likely limited their efficacy. No trial to date has evaluated the efficacy of what currently appears to be the most potent arteriogenic growth factor, PDGF-BB, whether given in combination with FGF2 or not.
Indeed, it could be argued that augmentation of mono-cyte accumulation at the site of desired arteriogenesis could be the most effective therapeutic strategy. In that regard it should be noted that a small clinical trial that evaluated GM-CSF infusions in patients with CAD reported positive results. Yet another approach may involve administration of MCP-1, a potent monocyte chemoattractant. The side effects of such strategies, however, have not been evaluated.
Another very important issue is the length of exposure of tissues to the therapeutic agent, such as a growth factor. This has been brought into a stark focus by the study of Dor et al. showing that 32-day duration of expression of VEGF165 in mouse myocardium is needed for induction of stable vessel growth, whereas a shorter time course (12 days) had no lasting effect. These numbers likely translate into much longer time intervals in patients. In light of these considerations it is interesting that the trial demonstrating the most benefit involved prolonged sustained-release delivery of FGF2.
An issue closely related to the length of tissue exposure is the means of delivery and the formulation used for the growth factor administration. Preclinical studies have clearly demonstrated minimal tissue deposition and the fast washout of growth factors given by an intracoronary route. The efficiency of adenoviral transfer by this method appears to be equally dismal. In contrast, intramyocardial injections result in much higher local concentrations and increased duration of tissue exposure to the agent. However, it is unlikely that intramyocardial protein therapy in the absence of sustained-release polymer formulations will be effective. Furthermore, it is unclear if the adenoviral or the plasmid-based gene transfer produces a length of expression long enough for the therapeutic effect to take place.
Finally, patient selection also presents an important challenge. It has become abundantly clear that populations under study demonstrate a very significant placebo effect as well as spontaneous improvement even in such "hard" end points as myocardial blood flow and function. In addition, the choice of "no-option" patients in clinical trails to date may have inadvertently selected a particularly resistant population with a failure of the native angiogenic response due to any number of defects in the angiogenic cascade. This premise is illustrated by the differences in response to hypoxia of monocytes selected from patients with CAD that correlated with the prevalence of coronary collaterals.
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