Journal of Genetic Syndromes & Gene Therapy
Open Access

Abstract

Systemic Delivery of Thiol-Specific Antioxidant hPRDX6 Gene by AAV2/8 Inhibits Atherogenesis in LDLR KO Mice on HCD

Zhu HQ, Cao M, Straub KD and Hermonat PL

Atherosclerosis is an inflammatory disorder of arteries and reactive oxygen species (ROS) have been implicated as a major etiology. Various anti-ROS genes, such as superoxide dismutates and catalase, have been studied by gene transfer for their abilities to limit a variety of ROS-related cardiovascular injuries such as balloon-induced and ischemia-reperfusion injury. However the thiol-ROS compartment has never been explored by gene therapy/ gene delivery for potential therapeutic intervention. Human peroxiredoxin 6 (hPRDX6, AOL2) is fully unique in that in addition to its thiol-specific anti-oxidant ability it has a coupled phospholipase A2 catalytic domain. Here we delivered hPRDX6, expressed by the cytomegalovirus immediate early promoter (CMV), by systemic pseudotyped adeno-associated virus 2/8 (AAV2/8) gene transfer into low density lipoprotein receptor knockout mice on high cholesterol diet (LDLR KO HCD). It was found that AAV2/8/hPRDX6 gene delivery and expression inhibited systolic blood velocity, aortic cross sectional area, and aortic wall thickness compared to Neo-HCD control, consistent with reduced atherosclerosis. Markers of macrophages/foam cells, CD68, ITGAM, EMR, verified lower atherosclerosis, as all were lower in the AAV8/hPRDX6-HCD-treated animals compared to Neo-HCD controls, analyzed by either quantitative reverse transcriptase polymerase chain reaction amplification or by immuno-histochemistry, or both. Analysis of the immune state of the aortas (Th1 or Th2 cytokine expression) revealed nothing significant, with only IL-10 expression being lower in PRDX6-treated animals. This study, for the first time, demonstrated that hPRDX6 gene delivery, augmenting endogenous mouse (m)PRDX6 expression, giving therapeutic benefit against HCDdriven atherosclerosis and suggests further studies of PRDX6, and related anti-thiol-ROS approaches, is warranted.