Thrombopoietin mimetic (TPOm) as a medical countermeasure for GI-ARS

ABSTRACT Acute Radiation Syndrome (ARS) is a potentially lethal multi-organ failure syndrome resulting from whole or partial-body exposure to irradiation due to accidents or nuclear terrorism. Currently, four FDA-approved radiation medical countermeasures (MCMs) are available for treating hematopoietic ARS (H-ARS). However, there is a significant gap in approved drugs for non-hematopoietic organ systems such as the gastrointestinal (GI). In collaboration with BioConvergent Health, we are developing a Phase 2 ready, 29-amino acid, fully synthetic, PEGylated peptide (TPOm), which binds to the thrombopoietin (TPO) receptor, c-Mpl, acting as a TPO mimetic. TPOm has been shown to induce regeneration of megakaryocytes, platelets, and HSPCs in mice, with or without exposure to total body irradiation (TBI). Our preliminary studies indicate that TPOm administered 24 hours post- partial body irradiation (PBI) significantly improves 30-day survival and reduces gut barrier dysfunction, while promoting intestinal crypt and epithelial regeneration. We have identified several unique pharmacodynamic effects of TPOm among radiomitigators: stimulating regeneration of c-Mpl-expressing HSPCs, megakaryocytes, and mesenchymal stromal cells (MSCs) in irradiated BM; inducing proliferation of c-Mpl-expressing microvascular lung and liver sinusoidal endothelial cells; activating a novel Leptin Receptor (LepR+)/c-Mpl+ MSCs to promote secretion of Wnt ligands and angiogenic growth factors; and promoting mobilization of histidine decarboxylase (HDC)-expressing granulocytic immature myeloid cells (IMCs) from BM to irradiated organs like the intestine, stimulating repair and regeneration of tissue stem cells. Based on these features, we hypothesize that TPOm will mitigate GI-ARS by regenerating HSPCs in irradiated BM, stimulating the secretion of growth factors, and mobilizing BM-derived IMCs and MSCs into circulation. These cells could home in on irradiated organs, like the intestine, to promote repair and regeneration of intestinal stem cells (ISCs), thereby mitigating GI-ARS. Four specific aims are proposed to further develop TPOm as MCM for GI-ARS: 1) Mitigation of GI-ARS and determining the dose modification factor (DMF) of TPOm; 2) Mechanisms of action (MOA) of TPOm for radio-mitigation of GI-ARS; 3) Pharmacokinetics/Pharmacodynamics (PK/PD) of TPOm in unirradiated and irradiated animals; and 4) Comparison of TPOm effectiveness with FDA-approved radiation MCMs and intestinal mitogens for GI-ARS treatment. This study will illuminate TPOm's mechanisms of action in mitigating GI injury post-irradiation and provide comprehensive characterization information about TPOm. This could lead to filing TPOm with the FDA as an investigational new drug (IND) for GI-ARS.