Curative and Preventive Treatment for Cardiovascular Disease (CVD) Targeting Multiple Etiology

Abstract

Gene deficient or knockout (KO) mice and rabbits are models of atherosclerosis focusing on cholesterol plaques, which do not reflect the complex etiology of cardiovascular disease (CVD). Inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase or the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce cholesterol levels but not the rate of CVD. Moreover, the one-drug-one-gene paradigm particularly targeting any one of the G protein-coupled receptors (GPCRs), which represent the largest protein family encoded by the human genome, has at best produced palliative treatment. Vascular diseases including CVD are caused by extraneous (xeno) factors, which are of multifactorial etiology consisting of upstream and downstream phases. The upstream phase is the physical breach of the cells protective glycocalyx (GCX) shield by chemical and biological pollutants, resulting in a sequela of cell damages (plexic) that is manifested downstream in the form of diseases, herein called xenoplexic diseases. Xenoplexic disease is an etiologic description while chronic disease is symptom-centric. This study treated a natural mouse with extraneous agents, which produced plaques and plaque reduction was the end point to evaluate the curative and/or preventive treatment effect of the 3-component compound therapy. Histopathology monitored the presence of plaque, and a 4-panel biomarker, based on GCX disruption, was subsequently developed as a surrogate to monitor plaque formation. Of the several 3-NCE combos tested 4 combos were found to be preventive and curative of plaques indicating the effectiveness of a combo platform therapy. One combo is chosen as the lead candidate and hereby designated as Embotricin TM.