Manganese-based Contrast Agent for Cardiovascular MRI

项目总结。缺血性心脏病是美国发病率和死亡率的主要原因

Project Summary. Ischemic heart disease is the leading cause of morbidity and death in the United States representing 1 in 3 American deaths and globally (17 million deaths annually). Contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI) play a key role in managing heart disease by enabling non-invasive assessment of myocardial perfusion, infarction, and viability. Contrast enhanced scans are increasingly relied upon for ischemic heart disease diagnosis and treatment planning, and for assessing treatment efficacy. Thus, cardiac imaging is the fastest growing segment of the MRI market in Europe and increasing in the United States with the recent randomized controlled MR-INFORM trial demonstrating equivalency between invasive catherization and contrast enhanced MRI. Unfortunately, both iodinated CT radiocontrast and gadolinium-based MRI contrast agents are contraindicated in patients suffering moderate to severe renal impairment. Iodinated contrast media can cause acute and irreversible kidney injury in renally impaired patients and gadolinium-based MRI contrast agents (GBCAs) are directly linked to nephrogenic systemic fibrosis (NSF) in renally impaired patients. Chronic kidney disease (CKD) afflicts 16% of US adults and is increasing due to the diabetes and obesity epidemics and the aging population. Cardiac and renal output are inextricably linked - renal dysfunction is present in 33% of patients with heart failure complicating their diagnostic workup and management despite the clear benefit of non-invasive cardiac MRI over invasive percutaneous catherization. As a result, when imaging heart disease patients with CKD, clinicians are either faced with limited radiologic information or placing the patient at higher risk for complications by using GBCA. There is a major unmet clinical need for contrast-enhanced cardiovascular imaging using safer alternatives to gadolinium-based contrast agents. Reveal Pharmaceuticals is developing a gadolinium-free contrast agent based on technology developed at Massachusetts General Hospital. Our lead compound RVP-001 is an stable manganese chelate with relaxivity and pharmacokinetics similar to GBCAs resulting in equivalent imaging properties. RVP-001 is rationally designed for partial hepatobiliary elimination, which provides a compensatory elimination mechanism for renally impaired patients. Our ultimate goal is to develop RVP-001 as a contrast agent for use in renally impaired subjects as well as the general patient population. In this SBIR application we will demonstrate the efficacy of RVP-001 for cardiac imaging in a porcine model of myocardial infarction to demonstrate and validate RVP-001 equivalency to a commercially available GBCA. We will first identify a formulation of RVP-001 best suited for bolus delivery, and then demonstrate that RVP-001 is equivalent or better than the commercial GBCA Gd-DOTA for assessing myocardial perfusion and viability. The proposed imaging will support the commercialization of RVP-001 as a cardiovascular contrast agent for use in the large and growing population of renally impaired patients.