Oral Agents to Stimulate Neutrophil Production

描述（由申请人提供）：Phoenicia Biosciences，Inc.科学家们已经发现了一小类低MW化合物（短链脂肪酸衍生物（SCFAD）-命名为“血细胞因子”），其通过口服给药刺激人类造血祖细胞、多谱系造血细胞系的增殖，并且在动物模型中增加了红细胞计数。最近，还发现所选的造血因子在精氨酸依赖性人和鼠骨髓细胞系中、在从正常人和化疗处理的人培养的造血祖细胞中以及在亚致死剂量照射或化疗处理的小鼠中刺激骨髓生成。这些发现有力地表明，血细胞因子为促进急性放射病和其他贫血症中保护性血细胞计数的恢复提供了潜在的效用。我们建议在中性粒细胞减少症的动物模型中测试来自一组口服生物可利用SCFAD的一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）的假设。已开始针对非骨髓生成适应症进行先导性造血因子ST 7的临床前开发。然而，我们的分子建模发现计划已经产生了五种其他候选的造血因子和ST 7的对映异构体，它们在初步研究中显示出比ST 7更强的骨髓生成活性或效力，或者在非人灵长类动物中具有更好的药代动力学。该I期提案的目标是比较和选择最佳候选Hemokine化合物，以开发作为一种新的治疗药物，以刺激在灾难条件下化疗或辐射暴露后骨髓损伤的恢复，并增加生存率，口服剂量可用于暴露的平民或士兵的大规模使用。具体目标是：一。使用从化疗患者的外周血和脐带血培养的精氨酸依赖性髓样细胞系和祖细胞，在体外评价新候选造血因子的骨髓生成活性。二.使用放射诱导的中性粒细胞减少症的小鼠模型并检查中性粒细胞和血小板的重建，评价新候选造血因子的体内骨髓生成活性。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Hemokine，并确定备用化合物。 公共卫生相关性：急性辐射综合征（ARS），也称为急性辐射病，是由在相对短的时间内由高剂量的穿透辐射照射整个身体或身体的重要部分而引起的急性疾病。骨髓损伤和由此导致的血细胞生成抑制是电离辐射照射的主要急性毒性和死亡原因之一。目前还没有批准的治疗方法来缓解ARS。美国政府已声明有意确定在急性辐射暴露后给药时可能有效预防或减少中性粒细胞减少症或血小板减少症发生的治疗剂来源。我们开发的化合物是口服小分子，具有刺激血细胞生成和改善急性辐射综合征的潜力，并且可扩展到社区规模的部署。

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.