RSK3 Anchoring Disruptor Therapy for Heart Failure

DESCRIPTION provided by applicant Pathological cardiac remodeling including myocyte hypertrophy and apoptosis and myocardial interstitial fibrosis 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 We recently discovered that the protein kinase p ribosomal S kinase type RSK plays a critical role in the regulation of pathological cardiac remodeling In Anchored RSK Inhibitors LLC was founded by Dr Michael Kapiloff to develop novel therapeutics based upon RSK inhibition that will prevent and or treat heart failure RSK was required for pathological remodeling even though RSK is less abundant in the cardiac myocyte than other members of the RSK protein kinase family We found that in myocytes RSK andapos s unique N terminal domain conferred high affinity regulated binding to the scaffold protein muscle A kinase anchoring protein mAKAP This novel protein protein interaction explained the selective binding of that kinase isoform to the scaffold New preliminary data show that expression both in vitro and in vivo of an anchoring disruptor peptide that blocks mAKAP RSK binding will attenuate pathological remodeling preventing the development of heart failure in response to pressure overload The goal of this STTR application is to support the development of a new adeno associated virus AAV gene therapy vector that expresses the RSK anchoring disruptor peptide The proposed research will provide proof of concept for a new therapeutic approach for the treatment and or prevention of heart failure based upon RSK displacement within the myocyte SPECIFIC AIM Treatment of Pressure Overload induced Heart Failure by Anchoring Disruptor Therapy Cardiac myocyte selective expression of a mAKAP RSK binding peptide RBD using AAV prevents transverse aortic constriction induced heart failure in vivo In this Aim we will test whether RSK anchoring disruptor therapy can induce reverse remodeling and treat heart failure in mice with established pathology due to pressure overload SPECIFIC AIM Prevention of Myocardial Infarction induced Heart Failure by Anchoring Disruptor Therapy In this Aim we will test whether AAV RBD can block remodeling following myocardial infarction without having deleterious effects on infarct size or scar formation Results obtained through this phase I STTR grant will provide insight into how broadly AAV RBD therapy may be applied in cardiovascular disease and inform the choice of subsequent large animal studies necessary to progress to a FDA Investigational New Drug Application PUBLIC HEALTH RELEVANCE Heart failure is a syndrome of major public heath significance that is the cause of death for about in Americans accountable for nearly deaths each year Despite a range of existing therapies the mortality rate for patients with heart failur remains very high with about of patients dying within years of a diagnosis In this application we aim to develop a new therapy for heart failure based upon the selective targeting of RSK