Gene Therapy of Chronic Limb-Threatening Ischemia: Vascular Medical Perspectives

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.

Keywords: angiogenesis; arteriogenesis; chronic limb-threatening ischemia (CLTI); gene therapy; peripheral arterial disease (PAD); transduction; transfection; vasculogenesis.

Figure 1

Gene therapy techniques. (A) Transduction uses a vector to deliver genetic material into the cell. (B) Lipofection: Liposomes become incorporated by the cell and releases genetic material after destruction of the endosome membrane (C) Sonoporation: Genetic information gets channeled either directly by ultrasound or via bursting microbubbles (D) Electroporation brings genetic material via electrically conductive pores into the cell.