ShRNA-Based Targeting of mAKAP? in Heart Failure

Pathological cardiac remodeling constitutes a common pathway to heart failure in diseaseDespite current pharmacologic therapy and other advances that attenuate remodelingmortality due to heart failure remains highNewmore 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 failureMuscle A kinase anchoring proteinmAKAPis the organizer of multimolecular signaling complexes critical for the induction and progression of pathological cardiac remodelingBy binding a diverse set of signaling moleculesmAKAPdynamically orchestrates multiple signaling modules that transduce cAMPmitogen activated protein kinaseMAPKCaphosphoinositideand hypoxic stress signalsAccordinglycardiomyocyte specific mAKAPknock out in mice inhibited remodeling and the development heart failure in multiple models of cardiovascular diseaseCRI is a company developing novelpatent protected therapeutics for the prevention and or treatment of heart failureIn this Fast Tract SBIRCRI will test a new gene therapy vector designed to inhibit mAKAPexpression selectively in the cardiac myocyte by RNA interferenceThe AAV sc shmAKAP biologic is a selfcomplementarycardiotropicserotypeadeno associated virusAAVthat expresses an mAKAP specific small hairpin RNAshRNAunder the control of a cardiac myocyte specific promoterIn this applicationCRI will test the new biologic in a clinically relevant large animal model for post myocardial infarctionMIheart failurePhase ISpecific AimWe will perform a dose response curve for the biologic in Yorkshire swine to determine the minimum dose required for consistent inhibition of mAKAPexpression in the heartPhase IISpecific AimEfficacy of mAKAP RNAi for heart failure in a large animal modelThe core of this project is to test whether mAKAPRNAi will mitigate pathological remodeling induced by MI in swinepreventing heart failureSwine will be subjected to ischemia reperfusion to induce MI or sham procedure and then treated with the AAV sc shmAKAP biologic by intracoronary infusion immediately after ormonth later at the dose determined in Phase IThe pigs will be followed by serial echocardiography and studied at endpointmonths post MI by catheterization for left ventricular pressure volume loop hemodynamicsThe goal for this Aim is the demonstration that mAKAP RNAi will preserve cardiac structure and function in a large animal model of MI diseaseSpecific AimAAV sc shmAKAP mediated inhibition of the molecular and cellular pathology associated with heart failureTaking advantage of tissue collected from the same animals used in Aimthe benefits of mAKAP RNAi in swine will be demonstrated by gravimetrichistologicaland molecular analyses for fibrosis and other markers of cardiac remodeling and heart failureIn additioninitial toxicology screens will be done to support the biologic s safetyThis project will show that mAKAPtargeting 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 aboutinAmericansDespite a range of existing therapiesthe mortality rate for patients with heart failure remains very high with aboutof patients dying withinyears of a diagnosisIn this applicationwe aim to develop a new therapy for heart failure based upon the selective targeting of the scaffold protein mAKAP