Antioxidant enzyme gene transfer for ischemic diseases

作者：Wu Jian^*; Hecker James G; Chiamvimonvat Nipavan

来源：Advanced Drug Delivery Reviews, 2009, 61(4): 351-363.

DOI：10.1016/j.addr.2009.01.005

• Ischemia/reperfusion
• Ischemic injury
• Oxidant stress
• Reactive oxygen species
• Antioxidant
• Gene transfer
• Gene therapy
• Liver
• Heart
• Lung
• Central nervous system
• Intestine
• Superoxide dismutase
• Catalase
• Glutathione peroxidase
• Heme oxygenase-1
• Xanthine oxidase
• NADPH oxidase

The balance of redox is pivotal for normal function and integrity of tissues. Ischemic insults occur as results of a variety of conditions, leading to an accumulation of reactive oxygen species (ROS) and an imbalanced redox status in the tissues. The oxidant stress may activate signaling mechanisms provoking more toxic events, and eventually cause tissue damage. Therefore, treatments with antioxidants, free radical scavengers and their mimetics, as well as gene transfer approaches to overexpress antioxidant genes represent potential therapeutic options to correct the redox imbalance. Among them, antioxidant gene transfer may enhance the production of antioxidant scavengers, and has been employed to experimentally prevent or treat ischemic injury in cardiovascular, pulmonary, hepatic. intestinal, central nervous or other systems in animal models. With improvements in vector systems and delivery approaches, innovative antioxidant gene therapy has conferred better outcomes for myocardial infarction, reduced restenosis after coronary angioplasty, improved the quality and function of liver grafts, as well as outcome of intestinal and cerebral ischemic attacks. However, it is crucial to be mindful that like other therapeutic armentarium, the efficacy of antioxidant gene transfer requires extensive preclinical investigation before it can be used in patients, and that it may have unanticipated short- or long-term adverse effects. Thus, it is critical to balance between the therapeutic benefits and potential risks, to develop disease-specific antioxidant gene transfer strategies, to deliver the therapy with an optimal time window and in a safe manner. This review attempts to provide the rationale, the most effective approaches and the potential hurdles of available antioxidant gene transfer approaches for ischemic injury in various organs, as well as the possible directions of future preclinical and clinical investigations of this highly promising therapeutic modality.

• 出版日期2009-4-28