Development of the PTP1B inhibitor MSI-1436 for therapeutic stimulation of heart regeneration following acute myocardial infarction

PROJECT SUMMARYHeart disease is the leading cause of mortality and morbidity in the worldCoronary heart disease is the most common type of heart disease and results from the blockage of blood vessels that supply blood to the heartA heart attack or myocardial infarctionMIoccurs when loss of blood flow causes the death of oxygenstarved cardiomyocytesIn humansthere is little or no significant cardiac muscle regeneration after an injury like a heart attackInsteaddead cardiomyocytes are replaced by nonfunctional scar tissuewhich weakens the heart and can lead ultimately to heart failure and deathCurrent therapies for heart attack are limited to reducing post MI heart damagepreventing secondary heart attacks and treating resultant heart failureDevelopment of therapies that stimulate regeneration of the heart is a strategic priority for the National Heart Lung and Blood InstituteWhile under intensive studyno such therapies currently existMSIis potent and specific inhibitor of the tyrosine phosphatase PTP BPTP B inactivates diverse receptor tyrosine kinases that regulate innate tissue repair and regeneration processesUsing blinded and randomized experimental and data analysis protocolswe have shown that MSIstimulates regeneration of adult zebrafish heartconnectivenerveskinbone and vascular tissues after amputationand reverses genetically induced cardiac scar formationIn adult miceMSIstimulates stem celI activation in injured skeletal muscle and increases survivalimproves heart functionfoldreduces infarct size byand stimulates cellular proliferationfold atweeks post MIMSIwas previously shown to be well tolerated by patients in Phaseandb clinical trials as a potential treatment for obesity and typediabetesThe effects of MSIon regeneration occur at concentrationsfold lower than the maximum well tolerated human doseThe demonstrated safety of MSIand extensive knowledge of its target greatly reduce the time and costs associated with developing this drug as a regenerative medicine therapy for treating acute MIWe will test the efficacy of MSIin the restoration of heart function in a clinically relevant pig ischemia reperfusion MI modelPorcine models have become the standard large animal system for studies of cardiac function due to similarities in heart morphology and metabolism to humansCardiac function will be measured by echocardiography and infarct sizecardiomyocyte regeneration and cardiomyocyte hypertrophy will be assessed by histologyTesting the efficacy of MSIin the pig is the required next step towards potential clinical trialsAs with all our previous workproposed pig studies will be blinded and randomized and will be performed in collaboration with lead investigators of the NIH NHLBI sponsored Consortium for preclinicAl assESsment of cARdioprotective therapiesCAESARDemonstrated efficacy in the pig will form an essential component of an FDA IND application for MSIclinical trials in MI patients