We propose here the """"""""re-purposing"""""""" of atorvastatin to reduce pro-inflammatory host responses and improve cardiovascular outcome in children with acute Kawasaki disease (KD), a self-limited vasculitis that is the most common cause of acquired heart disease in children. Although high-dose intravenous immunoglobulin (IVIG) plus aspirin reduces the risk of coronary artery damage, 5-10% of children with KD will go on to develop coronary artery aneurysms that may result in myocardial ischemia, infarction, or death. Once aneurysms have formed, the damage to the arterial wall is irreversible and although myointimal proliferation can restore the lumen to a more normal caliber, these arteries are never normal and over time stenoses and calcification lead to ischemic complications. Thus, the goal of treatment should be prevention or attenuation of coronary artery damage. Based on preliminary data from our laboratory, arterial damage in KD results from immune activation and vessel wall infiltration by myofibroblasts, neutrophils, and T-cells with secretion of pro-inflammatory cytokines, elastases, and matrix metalloproteinases (MMPs). Resolution of inflammation and recovery from the acute illness occurs through T-cell regulation. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, have extensive anti-inflammatory effects that target all of these pathways and are independent of their cholesterol-lowering effect. Statins have been shown to inhibit cytokine-inducible expression of the co-stimulatory molecules necessary for T-cell activation, to increase the number and suppressive function of regulatory T-cells, to reduce epithelial/endothelial to mesenchymal transition, to inhibit the secretion of MMPs by myofibroblasts, and to increase the number of circulating endothelial progenitor cells. In a mouse model of KD, atorvastatin was recently shown to reduce secretion of MMP-9, a potent collagenase that contributes to aneurysm formation. Given these anti-inflammatory effects, statins would be a reasonable therapy to block CAA progression in KD. The proposed Phase I study will assess the safety of atorvastatin in a standard dose-escalation study design (Specific Aim 1) and pharmacokinetics with intensive sampling around the first oral dose (Specific Aim 2). A concomitant Phase IIa study will evaluate drug activity including changes in measures of oxidative stress and inflammation, enumeration and characterization of regulatory T-cells, and echocardiographic changes in the internal diameter of the coronary arteries over the first 6 weeks after fever onset (Specific Aim 3). These studies will determine if the non-lipid lowering effects of atorvastatin show promise in reducing arterial wall inflammation in children with acute KD.
The proposed research is relevant to public health because coronary artery aneurysms caused by acute Kawasaki disease are a burden to the patient, his/her family, and society. This clinical trial will test a novel therapy designed to attenuate or prevent aneurysm formation in children with Kawasaki disease and early signs of damage to the coronary arteries. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help to enhance health and reduce the burden of human illness and disability.
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|He, Ming; Chen, Zhen; Martin, Marcy et al. (2017) miR-483 Targeting of CTGF Suppresses Endothelial-to-Mesenchymal Transition: Therapeutic Implications in Kawasaki Disease. Circ Res 120:354-365|
|Tremoulet, Adriana H; Jain, Sonia; Burns, Jane C (2015) Evaluating a novel treatment for coronary artery inflammation in acute Kawasaki disease: A Phase I/IIa trial of atorvastatin. Expert Opin Orphan Drugs 3:967-970|