Development of thrombopoietin mimetic (TPOm) as a mitigator against Radiation-induced endovascular injuries

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Abstract Radiation-induced vascular injury (RIVI) is a critical component of the multi-organ failure (MOF) seen in acute radiation syndrome (ARS), following exposure to whole or partial body irradiation. The pathophysiology of ARS results from a combination of direct cytocidal effects of irradiation (IR) on tissue stem and progenitor cells (TSPC) and niche cells with varying radiosensitivity. While several growth and differentiation agents targeting TSPCs are being actively pursued as therapeutics to treat ARS, it is evident that rapid restoration of the sinusoidal endothelial cells (SEC) in the stem cell niche cells is critical for improving survival in ARS and in ameliorating the delayed effects of acute radiation exposure (DEARE). SECs provide a conduit for nutrition and secrete angiocrine growth factors that support the proliferation of perivascular niche cells, such as, mesenchymal cells and TSPCs. Studies have implicated the essential role of the vascular component in acute radiation injuries of the bone marrow (BM) and intestine, as well as, in late effects in lung, liver and kidneys. In the bone marrow, the peri-arteriolar NG2+Nestinbright pericytes support hematopoietic stem cell (HSC) quiescence, while the peri-sinusoidal LepR+Nestindim mesenchymal cells promote HSC proliferation. Following exposure to IR, there is regression of BM-SEC with destruction of peri-sinusoidal niche cells and HSCs. VEGFR2-mediated regeneration of the marrow SECs is necessary for BM regeneration in ARS. We are collaborating with Janssen Pharmaceuticals on the development of a novel radiation countermeasure, thrombopoietin (TPO) mimetic (TPOm, aka JNJ-26366821), which is a Phase II ready, fully synthetic, PEGylated TPO receptor, c-MPL agonist peptide that reduces mortality and morbidity associated with BM-ARS. TPOm is unique amongst radiomitigators because of two distinct pharmacodynamic effects: (1) Mitigation of radiation-induced thrombocytopenia, anemia, and leukopenia upon binding and activation of the c-Mpl receptor on megakaryocytes and HSC, and (2) protection and regeneration of vascular endothelium, particularly SEC. A single dose of TPOm, administered 24 h post-whole body irradiation (WBI) improved survival significantly in multiple animal models of ARS, including mouse, rat, dog and non-human primates (NHP). TPO has also been shown to promote mobilization of vascular endothelial progenitor cells to sites of vascular injury. We, therefore, hypothesize that in addition to treating radiation-induced thrombocytopenia, TPOm would promote regeneration of SEC in multiple tissue stem cell niches, including bone marrow and intestine, thereby, accelerating tissue regeneration after radiation exposure. The proposal entails a step-wise plan to determine the radiomitigating efficacy of TPOm in vascular injuries at peripheral and tissue level under specific aim 1 using acute radiation injury model. These studies will focus on peripheral vascular damage, endothelial injury of the hematopoietic and perivascular niche (H-ARS model), and vascular endothelial injury in the crypt and villi (GI-ARS model). We will also validate the efficacy of TPOm in mice, determine its dose modification factor and its effect of inflammatory cytokine profiles under specific aim 2. Finally, we will determine its effects against DEARE of the lungs and kidney, identify early biomarkers of endothelial injury at systemic and tissue level and develop imaging techniques to assess the injury using high contrast micro-CT scanner.