Abstract
A decade ago, gene therapy seemed to be a promising approach for the treatment of chronic limb-threatening ischemia, providing new perspectives for patients without conventional, open or endovascular therapeutic options by potentially enabling neo-angiogenesis. Yet, until now, the results have been far from a safe and routine clinical application. In general, there are two approaches for inserting exogenous genes in a host genome: transduction and transfection. In case of transduction, viral vectors are used to introduce genes into cells, and depending on the selected strain of the virus, a transient or stable duration of protein production can be achieved. In contrast, the transfection of DNA is transmitted by chemical or physical processes such as lipofection, electro- or sonoporation. Relevant risks of gene therapy may be an increasing neo-vascularization in undesired tissue. The risks of malignant transformation and inflammation are the potential drawbacks. Additionally, atherosclerotic plaques can be destabilized by the increased angiogenesis, leading to arterial thrombosis. Clinical trials from pilot studies to Phase II and III studies on angiogenic gene therapy show mainly a mixed picture of positive and negative final results; thus, the role of gene therapy in vascular occlusive disease remains unclear.
Highlights
Peripheral artery disease (PAD) is one of the three most common manifestations of atherosclerosis and is mainly characterized by intermittent claudication and fatigue, affecting approximately 230 million people worldwide [1]
Despite advances in revascularization methods, many critical limb ischemia (CLI) patients are still considered unsuitable for these operations, among other things due to previous operations or general inoperability, and are treated with conservative limb therapies, e.g., best medical treatment of risk factors combined with pain medication and wound treatment [2]
It should be noted that no distinction has been made between neo-vascularization in vascular disease or other disciplines and as a potential component in tumor biology to cover all aspects of vascular biology
Summary
Peripheral artery disease (PAD) is one of the three most common manifestations of atherosclerosis and is mainly characterized by intermittent claudication and fatigue, affecting approximately 230 million people worldwide [1]. Gene therapy for the treatment of chronic limb-threatening ischemia (CLTI), one of the biological re-vascularization options, could provide new perspectives for those patients without conventional, open or endovascular therapeutic options. One problem with biological revascularization is the multifactorial nature of vascular disease, as the following paragraph will show Both circulating and local mediators of angiogenesis, with signal cascades from the endothelium up to the extracellular matrix, result in such a complex, redundant interaction that it is probably not possible to achieve an effective therapeutic success by using single target therapy. A number of other studies show the significant relationship between NO production and angio- and arteriogenesis [19–24] Another example of interfering factors are free radicals formed in ischemic tissues. A therapeutic success depends at the end on both the right agent, as well as the condition and reactivity of the target tissue itself [13,14,22,32,33]
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