Pathological cardiac remodeling constitutes a common pathway to heart failure in disease. Despite current pharmacologic therapy and other advances that attenuate remodeling, mortality due to heart failure remains high. New, more effective therapeutic options are desperately needed in an increasing patient population to improve both the survival and quality of life for patients with or susceptible to heart failure. Muscle A-kinase anchoring protein ? (mAKAP?) is the organizer of multimolecular signaling complexes critical for the induction and progression of pathological cardiac remodeling. By binding a diverse set of signaling molecules, mAKAP? dynamically orchestrates multiple signaling modules that transduce cAMP, mitogen-activated protein kinase (MAPK), Ca2+, phosphoinositide, and hypoxic stress signals. Accordingly, cardiomyocyte-specific mAKAP? knock-out in mice inhibited remodeling and the development heart failure in multiple models of cardiovascular disease. CRI is a company developing novel, patent protected therapeutics for the prevention and/or treatment of heart failure. In this Fast-Tract SBIR, CRI will test a new gene therapy vector designed to inhibit mAKAP? expression selectively in the cardiac myocyte by RNA interference. The AAV9sc.shmAKAP biologic is a self- complementary, cardiotropic, serotype 9 adeno-associated virus (AAV9) that expresses an mAKAP-specific small hairpin RNA (shRNA) under the control of a cardiac myocyte-specific promoter. In this application, CRI will test the new biologic in a clinically relevant large animal model for post-myocardial infarction (MI) heart failure. Phase I - Specific Aim: We will perform a dose response curve for the biologic in Yorkshire swine to determine the minimum dose required for consistent inhibition of mAKAP? expression in the heart. Phase II - Specific Aim 1: Efficacy of mAKAP RNAi for heart failure in a large animal model. The core of this project is to test whether mAKAP? RNAi will mitigate pathological remodeling induced by MI in swine, preventing heart failure. Swine will be subjected to ischemia-reperfusion to induce MI or sham procedure and then treated with the AAV9sc.shmAKAP biologic by intracoronary infusion immediately after or 1 month later at the dose determined in Phase I. The pigs will be followed by serial echocardiography and studied at endpoint 3 months post-MI by catheterization for left ventricular pressure-volume loop hemodynamics. The goal for this Aim is the demonstration that mAKAP RNAi will preserve cardiac structure and function in a large animal model of MI disease.
Specific Aim 2 : AAV9sc.shmAKAP-mediated inhibition of the molecular and cellular pathology associated with heart failure. Taking advantage of tissue collected from the same animals used in Aim 1, the benefits of mAKAP RNAi in swine will be demonstrated by gravimetric, histological, and molecular analyses for fibrosis and other markers of cardiac remodeling and heart failure. In addition, initial toxicology screens will be done to support the biologic?s safety. This project will show that mAKAP? targeting is a viable therapeutic strategy for heart failure post-MI and justify a first-in-human clinical trial for heart failure.
Heart failure is a syndrome of major public heath significance that is the cause of death for about 1 in 8 Americans. Despite a range of existing therapies, the mortality rate for patients with heart failure remains very high with about 50% of patients dying within 5 years of a diagnosis. In this application, we aim to develop a new therapy for heart failure based upon the selective targeting of the scaffold protein mAKAP?.
