Oral Agents to Stimulate Neutrophil Production

刺激中性粒细胞产生的口服药物

• 批准号: 7802424
• 负责人: SUSAN Park PERRINE
• 金额: $ 35.06万
• 依托单位: PHOENICIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-07 至 2012-05-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802424
• 关键词: Acute; Animal Model; Animals; Back; Bioavailable; Blood; Blood Cell Count; Blood Cells; Blood Platelets; Bone Marrow; Cell Culture Techniques; Cell Line; Communities; Development; Disasters; Dose; Drug Kinetics; Erythroid; Erythropoiesis; Exposure to; Family; Goals; Government; Growth Factor; Hematopoietic; Human; In Vitro; Ionizing radiation; Lead; Marrow; Medical; Methods; Molecular Models; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Neutropenia; Oral; Oral Administration; Papio; Patients; Phase; Population; Prevention; Primates; Production; Radiation; Radiation Sicknesses; Radiation Syndromes; Recovery; Red Blood Cell Count; Relative (related person); Research; ST7 gene; Sampling; Scientist; Soldier; Source; State Interests; Testing; Therapeutic; Thrombocytopenia; Time; Toxic effect; Transplantation; Umbilical Cord Blood; Volatile Fatty Acids; chemotherapy; cytokine; enantiomer; in vivo; irradiation; molecular modeling; mortality; mouse model; neutrophil; nonhuman primate; novel therapeutics; peripheral blood; pre-clinical; prevent; progenitor; programs; prototype; public health relevance; reconstitution; small molecule

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.

描述（由申请人提供）：Phoenicia Biosciences, Inc. 的科学家发现了一小类低分子量化合物（短链脂肪酸衍生物 (SCFAD) - 称为“血因子”），可刺激人类造血祖细胞、多谱系细胞的增殖。造血细胞系，并通过口服给药增加了动物模型中的红细胞计数。最近，还发现某些血因子可以刺激细胞因子依赖性人类和鼠类骨髓细胞系、正常和化疗治疗人类培养的造血祖细胞以及亚致死照射或化疗治疗小鼠的骨髓生成。这些发现强烈表明，血因子在增强急性放射病和其他中性粒细胞减少症中保护性血细胞计数的恢复方面具有潜在的用途。我们建议测试以下假设：一组口服生物可利用的 SCFAD 中的一些化合物可以在中性粒细胞减少症动物模型中体外和体内刺激骨髓生成（中性粒细胞的产生）。主要血因子 ST7 的临床前开发已开始用于非骨髓生成适应症。然而，我们的分子建模发现计划已经产生了其他五种候选血因子和 ST7 的一种对映体，它们在初步研究中显示出比 ST7 更强的骨髓生成活性或效力，或者在非人类灵长类动物中具有更好的药代动力学。该第一阶段提案的目标是比较并选择最佳的候选血红素化合物，作为一种新的治疗方法来开发，以刺激灾难条件下化疗或放射暴露后骨髓损伤的恢复，并提高生存率，口服剂量可用于大规模使用暴露在外的平民或士兵。具体目标是： I. 使用从化疗患者的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，在体外评估新候选血因子的骨髓生成活性。二.使用辐射诱导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，评估新候选血因子的体内骨髓生成活性。这些拟议的研究将确定临床前开发可用候选药物中的最佳血红蛋白，并确定备用化合物。 公众健康相关性：急性辐射综合症 (ARS)，也称为急性放射病，是由于在相对较短的时间内高剂量的穿透性辐射照射整个或大部分身体而引起的急性疾病。时间段。骨髓损伤和由此产生的血细胞生成抑制是电离辐射暴露导致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可以缓解 ARS。美国政府明确表示有兴趣确定在急性暴露于辐射后不时施用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症的潜力，并且可扩展到社区规模的部署。