Adenoviruses In Clinical Trials A Look Into The Future

Due to their several advantages AdVs are the most common vectors for clinical gene therapy trials ( Excluding a transient elevation in serum CRP values, transient fever and production of anti-AdV antibodies, low and intermediate doses of AdVs have been well tolerated and safe in cardiovascular gene therapy trials [21, 23, 31-34]. Unfortunatelly, very little positive results have been obtained in these trials. Increased myocardial perfusion was detected in patients with coronary artery disease (CAD) six months after intra-coronary AdVEGF gene transfer [21]. In contrast, patients that received either Ringer's lactate or VEGF in a plasmid vector did not show increased myocardial perfusion. Recently, AdVEGF was found to improve exercise tolerance above the maximal medical treatment in CAD patients 26 weeks after the gene transfer but surprisingly no difference was found at 12 weeks [35]. Furthermore, a significant placebo effect may hamper the interpretation of this study due to the lack of proper controls. Increased vascularity was found in PAD patients that received AdVEGF [22]. However, especially the hard clinical endpoints, such as improved exercise tolerance, have been difficult to achieve in randomized controlled PAD trials [36]. The lack of truly positive results in these trials is most likely explained by the lack of basic knowledge about the optimal vector doses and subsequent transgene expression.

Basic knowledge has been widely acquired from the preclinical trials, but results obtained in small animal model such as in the mouse skeletal muscle or myocardium are difficult to translate into large animals or humans [2]. For example, in mice a single injection to the tibialis anterior muscle might be enough to spread the vector throughout the whole muscle because of the very small size of the muscle. In rabbit skeletal muscle or pig myocardium gene transfer injections have to be done about 5mm apart from each other to yield abundant transgene expression in the target area [2, 17]. Thus, clinical trials with a single or very few injections of the vector to the entire human lower limb cannot be expected to reach similar efficacies. Also, gene transfer efficacy with many vectors is still largely unknown in the context of human in vivo conditions. In preclinical large animal models very little efficacy has been achieved with naked plasmid transfection or injections of recombinant proteins [17]. Still, many clinical trials are based on these methods. The binding and internalisation of AdVs in human skeletal muscle and myocardium should also be investigated in more detail. In the preclinical studies it has also been established that intramuscular or intra-adventitial gene transfer is often more efficient than intravascular approaches with viral vectors due to the neutralising action of the blood components against the viral particles [37]. Thus, in the future it would be preferable to concentrate on the optimization of the transduction efficiency with the best gene therapy vectors that have been found effective in preclinical large animal studies instead of performing small trials with several different vectors, routes and growth factors or their combinations.

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