Gene therapy targeting inflammation in atherosclerosis.
The extensive cross-talk between the immune system and vasculature leading to the infiltration of immune cells into the vascular wall is a major step in atherogenesis. In this process, reactive oxygen species play a crucial role, by inducing the oxidation of LDL and the formation of foam cells, and by activating a number of redox-sensitive transcriptional factors such as nuclear factor kappa B (NFkappa B) or activating protein 1 (AP1), that regulate the expression of multiple pro/anti inflammatory genes involved in atherogenesis. Delivery of genes encoding antioxidant defense enzymes (e.g. superoxide dismutase, catalase, glutathione peroxidase or heme oxygenase- 1) or endothelial nitric oxide synthase (eNOS), suppress atherogenesis in animal models. Similarly, delivery of genes encoding regulators of redox sensitive transcriptional factors (e.g. NF-kappa B, AP-1, Nrf2 etc) or reactive oxygen species scavengers have been successfully used in experimental studies. Despite the promising results from basic science, the clinical applicability of these strategies has proven to be particularly challenging. Issues regarding the vectors used to deliver the genes (and the development of immune responses or other side effects) and the inability of sufficient and sustained local expression of these genes at the target-tissue are some of the main reasons preventing optimism regarding the use of these strategies at a clinical level. Therefore, although premature to discuss about effective "gene therapy" in atherosclerosis at a clinical level, gene delivery techniques opened new horizons in cardiovascular research, and the development of new vectors may allow their extensive use in clinical trials in the future.
Laboratory of Microbiology, Parasitology and Hygiene, Department of Pharmacology, University of Antwerp, Belgium.
Tim
T
Van-Assche
Veronique
V
Huygelen
Mark J
MJ
Crabtree
Charalambos
C
Antoniades
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology
D016207:Cytokines; D017382:Reactive Oxygen Species; D009569:Nitric Oxide