A Bifunctional Katp Channel Activator and Redox Mimetic for BPD

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DESCRIPTION (provided by applicant): Radikal Therapeutics is developing a novel small molecule therapy (R-801) for neonatal prematurity that triggers an endogenous cytoprotective defense and thereby blocks pulmonary inflammation and acute lung injury (ALI). R-801 is formed from the covalent fusion of 2 moieties with demonstrated tissue protective properties: 1) a mito-K+-ATP channel activating domain derived from pinacidil, and 2) a pyrrolidine nitroxide domain (hydroxymethylproxyl, "HMP") that acts as a broad-spectrum redox decomposition catalyst. R-801 is more potent than classic K+-ATP channel openers (e.g. pinacidil) and is free of the classic side-effects of sarcolemmal K+-ATP channel activation (hyperglycemia, ventricular fibrillation, hypotension). Our overarching hypothesis is that R-801 will prophylactically block th progression of neonatal respiratory distress syndrome to bronchopulmonary dysplasia (BPD). In a murine model of hypohalous redox lung injury induced by Cl2 inhalation, R-801 resuscitation reduced histologic injury, diminished neutrophil (PMN) infiltration, blocked nuclear translocation of NF-kB, and diminished the degradation of the anti-inflammatory cytoplasmic protein IkB¿ (p<0.01). R-801 does not activate the sarcolemmal K+-ATP channel, as shown by its failure in rats to induce hypotension, hyperglycemia, or ventricular fibrillation. We now seek to establish that R-801 attenuates changes of pulmonary vascular and alveolar structure in a hyperoxic model of BPD in neonatal rats. In conjunction with the Abman laboratory (University of Colorado), RTX will carry out a prospective dose-escalation study wherein lung injury is induced by subjecting 2-day old rat pups to hyperoxia for 10 days. A sham control (no hyperoxia, no R-801) will be compared to a drug control (R-801, no hyperoxia), R-801 (3, 10, 30 mg/kg qd), and vehicle control (D5W) administered by an intraperitoneal (IP) route for 3 weeks, a period characterized in this model system by progressive lung fibrosis, pulmonary arterial hypertension (PAH), and hypoalveolarization. Lung tissue taken at necropsy will be analyzed for pulmonary vascular structure and growth, alveolarization, lipid peroxidation (malondialdehyde), glutathione (GSH/GSSG ratio), peroxynitrite formation (3-nitrotyrosine), poly(ADP-ribose) formation, fibrosis (Mason Trichrome staining for collagen), R- 801 levels, and the protein expression of pro-inflammatory genes, including eotaxin, G-CSF, GM-CSF, IFN-?, IL-1¿, IL-2, IL4, IL-3, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, MCP-1, M-CSF, MIG, MIP-1¿, MIP-1¿, MIP-2, RANTES, TNF-¿, and VEGF. The heart will also be analyzed for evidence of PAH (as evidenced by right ventricular hypertrophy). Progression to the Phase 2 NIH SBIR will require that treatment with R-801 dose-dependently demonstrates (at p<0.05 2-tailed) relative to the vehicle control: > 30% increase in alveolar density, and > 30% reductions in pulmonary fibrosis, pulmonary arteriolar smooth muscle hypertrophy, right ventricular mass, PMN infiltration, lipid peroxidation, peroxynitrite and poly(ADP-ribose) formation, pro-inflammatory gene expression, and oxidized glutathione.