Novel Mitochondrial DNA Repair Enzyme for Heart Failure

ABSTRACT Previous studies have demonstrated that heart failure triggers and sustains increases in oxidative stress inducing mitochondrial DNA mtDNA damage that then propagates myocardial injury resulting in cardiac dysfunction and myocardial cell death Fortunately mtDNA injury is reparable via endogenous base excision repair BER mechanisms The rate limiting step within BER is the amount of glycosylase present Here we offer the novel therapeutic Exscien III to catalyze and enhance mtDNA repair by trafficking to the mitochondria the glycosylase necessary to overcome this first and rate determining stage and thereby disrupt the propagation of myocardial disease Exscien III is an innovatively engineered and patented three part fusion protein construct consisting of a TAT sequence to facilitate cell uptake a mitochondrial import sequence to direct the therapeutic into the mitochondria and a functional glycosylase to help effect mtDNA repair Exscien s research variation of the protein also contains an HA tag for experimental immunological localization Preliminary in vivo studies at LSU s Cardiovascular Center of Excellence have demonstrated significant cardioprotective action using Exscien III in murine models of acute myocardial infarction AMI and heart failure HF The protein significantly attenuated myocardial infarct size and improved left ventricular function following myocardial ischemia and reperfusion in mice Administration of Exscien III following the onset of severe HF attenuated myocardial fibrosis and left ventricular dilatation while improving left ventricular function in a murine pressure overload HF model To further advance this fusion protein as an ameliorative therapeutic for HF we seek to conduct a phased developmental program Phase I perform large animal efficacy dosing and disposition testing of Exscien III Phase II utilize the results of Phase I to demonstrate efficacy of Exscien III first as a therapy to prevent progression to HF following AMI and secondly as a therapy to treat progressive HF in swine compromised with reduced ejection fraction If successful the evidence would form the foundation of an IND application to the FDA Our commercialization objective is to develop the drug in house as far as feasible including planned early clinical trials before ultimately out licensing to a large pharmaceutical interest With an estimated worldwide diagnosis of progressive heart failure in excess of million this therapy offers substantial commercial potential and has already attracted large pharma interest PROJECT NARRATIVE In this Fast Track proposal Exscien Corporation will perform pre clinical development of its novel mitochondrial repair protein which has demonstrated the ability to restore fundamental cellular metabolic function and if suitably administered will directly influence disrupt a root pathway for cardiac disease progression and heart failure This proposal represents a first in class therapeutic approach