We have obtained preliminary in vitro and in vivo evidence for the existence of a novel pathway of free radical- and oxidant-related injury. Peroxynitrite, and hydrogen peroxide, potent oxidants produced in myocardial reperfusion injury, trigger a cascade culminating in cellular energetic failure. DNA strand-breakage activates the nuclear enzyme poly (ADP-ribose) synthetase (PARS) and initiates an energy consuming, inefficient repair cycle, with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. The resultant depletion of dinucleotide pools slows the rate of glycolysis and mitochondrial respiration, reducing ATP synthesis and leading to cellular dysfunction. Moreover, we have obtained preliminary in vivo data showing the substantial, prolonged protective effect of pharmacological inhibition and genetic inactivation of PARS on myocardial reperfusion injury. PARS inhibition may be a novel effective concept for protection against myocardial ischemia-reperfusion injury. The applicants are developing a novel class of potent PARS inhibitors, which have substantial cardioprotective potential. In the current application, we propose to test the efficacy of PJ34, a member of a novel ultrapotent class of PARS inhibitors in a porcine model of myocardial ischemia-reperfusion injury. Inotek's long- term intention is to develop a potent PARS inhibitor as a drug for the treatment of various forms of reperfusion injury. Based on the results of the present application, Inotek will apply for Phase 2 to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA, and clinical trials. Based on the promising preliminary data by multiple laboratories with various non-proprietary PARS inhibitors in myocardial ischemia-reperfusion, and the applicant's recent preliminary data with PARS deficient mice, we expect that myocardial ischemia-reperfusion is one of the most promising indications of the PARS inhibitor technology for further development.
The annual anticipated revenue for an effective therapeutic to prevent and treat myocardial reperfusion injury is estimated at > $1 billion in the US per annum.
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| Khan, Tanveer A; Bianchi, Cesario; Araujo, Eugenio G et al. (2003) Activation of pulmonary mitogen-activated protein kinases during cardiopulmonary bypass. J Surg Res 115:56-62 |
| Bianchi, Cesario; Wakiyama, Hidetaka; Faro, Renato et al. (2002) A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs. Ann Thorac Surg 74:1201-7 |
| Faro, Renato; Toyoda, Yoshiya; McCully, James D et al. (2002) Myocardial protection by PJ34, a novel potent poly (ADP-ribose) synthetase inhibitor. Ann Thorac Surg 73:575-81 |
