Oral Agents to Stimulate Neutrophil Production

描述（由申请人提供）：Phoenicia Biosciences, Inc.的科学家发现了一个小家族的低分子量化合物（短链脂肪酸衍生物(SCFADs) -被称为“血液因子”），通过口服给药，可以刺激人类造血祖细胞、多谱系造血细胞系的增殖，并增加动物模型中的红细胞计数。最近，在细胞因子依赖的人类和小鼠骨髓细胞系、正常和化疗治疗的人类培养的造血祖细胞以及亚致死照射或化疗治疗的小鼠中，也发现了选择性的Hemokines刺激骨髓生成。这些发现强烈表明，在急性放射病和其他中性粒细胞减少症中，血液因子具有增强保护性血细胞计数恢复的潜在效用。我们建议在中性粒细胞减少症的动物模型中验证一种假设，即从一组口服生物可利用的SCFADs中提取的某些化合物可以在体外和体内刺激骨髓生成（中性粒细胞的产生）。一种导联血红素ST7的临床前开发已开始用于非髓系适应症。然而，我们的分子建模发现项目已经产生了另外五种候选血红素，以及ST7的一个对映体，它们在初步研究中显示出比ST7在骨髓生成方面更具活性或效力，或者在非人类灵长类动物中具有更好的药代动力学。这项I期研究的目标是比较和选择最佳候选血红素化合物，作为一种新的治疗药物，刺激灾难条件下化疗或辐射暴露后骨髓损伤的恢复，提高生存率，口服剂量可用于暴露的平民或士兵的大规模使用。具体目的是：1 .利用从化疗患者外周血和脐带血中培养的细胞因子依赖性骨髓细胞系和祖细胞，在体外评估新的候选Hemokines的骨髓生成活性。2。利用辐射诱导的中性粒细胞减少症小鼠模型，并检查中性粒细胞和血小板的重建，评估新的候选血红素在体内的骨髓生成活性。这些拟议的研究将在临床前开发的候选药物中确定最佳的血红素，并确定备用化合物。

DESCRIPTION (provided by applicant): 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.