Phoenicia Biosciences, Inc. scientists have discovered a small family of low MW compounds (short-chain fatty acid derivatives (SCFADs) - designated "Hemokines") that stimulate proliferation of human hematopoietic progenitors, multi-lineage-hematopoietic cell lines, and have increased red blood cell counts in animal models, with oral administration. Recently, select Hemokines were also found to stimulate myelopoiesis in cytokine-dependent human and murine myeloid cell lines, in hematopoietic progenitors cultured from normal and chemotherapy- treated humans, and in sub-lethally-irradiated or chemotherapy-treated mice. These findings strongly suggest that Hemokines offer potential utility for enhancing recovery of protective blood cell counts in Acute Radiation Sickness, and other neutropenias. We propose to test the hypothesis that some compounds from a panel of orally-bioavailable SCFADs can stimulate myelopoiesis (the production of neutrophils) in vitro and in vivo in an animal model of neutropenia. Preclinical development of a lead Hemokine, ST7, was begun for a non- myelopoietic indication. However, our molecular modeling discovery program has produced five other candidate Hemokines, and an enantiomer of ST7, which appear in preliminary studies to show more activity or potency than ST7 for myelopoiesis, or to have better pharmacokinetics in non-human primates. The goal of this Phase I proposal is compare and select the best candidate Hemokine compound for development as a new therapeutic to stimulate recovery from marrow damage following chemotherapy or radiation exposure in disaster conditions and increase survival, with oral doses feasible for large-scale use in exposed civilians or soldiers. The Specific Aims are: I. Evaluate the myelopoietic activity of the new candidate Hemokines in vitro, using cytokine-dependent myeloid cell lines and progenitors cultured from chemotherapy- treated patients' peripheral blood and cord blood. II. Evaluate the myelopoietic activity of the new candidate Hemokines in vivo, using a mouse model of radiation-induced neutropenia and examining reconstitution of neutrophils and platelets. These proposed studies will determine the optimal Hemokine among the available candidates for preclinical development, and identify back-up compounds.
Public Health Relevance: The Acute Radiation Syndrome (ARS), also referred to as Acute Radiation Sickness, is an acute illness caused by irradiation of the entire, or a significant portion of, the body by a high dose of penetrating radiation in a relatively short time period. Bone marrow damage and resulting suppression of blood cell production is one of the primary acute toxicities and causes of mortality from exposure to ionizing radiation. Currently there are no approved therapeutics to mitigate ARS. The U.S. Government has a stated interest in identifying sources of therapeutics likely to be effective in preventing or reducing the development of neutropenia or thrombocytopenia when administered at times after acute exposure to radiation. The compounds we have developed are orally-available small molecules with the potential to stimulate blood cell production and ameliorate acute radiation syndrome, and are scalable to community-sized deployment.
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