Paul L. Hermonat
Central Arkansas Veterans Healthcare System, USA
Paul L. Hermonat completed his Ph.D. at the University of Florida in 1984, and postdoctoral studies at the National Institutes of Health. He is a professor of Internal Medicine and OB/GYN at the University of Arkansas for Medical Sciences and a Research Career Scientist at the Central Arkansas Veterans Healthcare System. He was the first to generate recombinant adeno-assocociated virus (AAV/NeoR) and to transfer genes into cells via this method. He has over 140 manuscripts published, mostly on the topic of AAV molecular biology and gene transfer.
Atherosclerosis is an inflammatory disorder of arteries and reactive oxygen species (ROS) have been implicated as a major etiologic cause. 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 ischemia-reperfusion and atherosclerosis. However the thiol-ROS compartment has never been explored by gene therapy for therapeutic intervention. Here, we delivered the thiol-specific anti-oxidant human peroxiredoxin 6 (hPRDX6, AOL2) gene by systemic adeno-associated virus type 8 (AAV8) gene transfer into low density lipoprotein receptor knockout mice on high cholesterol diet (LDLR KO HCD). It was found that AAV8/PRDX6 gene delivery 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, were also lower in the AAV8/PRDX6-HCD-treated animals compared to Neo-HCD controls by either quantitative reverse transcriptase polymerase chain reaction amplification or by immuno-histochemistry, or both, again, consistent with reduced atherosclerosis. Analysis of alterations of the immune state of the aortas (Th1 or Th2, etc.) were unclear, with only IL-10 expression being lower in PRDX6-treated animals. This study, for the first time, demonstrates that PRDX6 gene delivery gives therapeutic benefit against atherosclerosis and suggests further studies of PRDX6, and related anti-thiol-ROS approaches, is warranted.