Improving Platelet Recovery After Radiation

改善放射后的血小板恢复

• 批准号: 7555473
• 负责人: GEORGE Earl GEORGES
• 金额: $ 66.67万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555473
• 关键词: Acute; Antibiotics; Blood; Blood Platelets; Canis familiaris; Cells; Cessation of life; Clinical; Data; Development; Dose; Goals; Granulocyte Colony-Stimulating Factor; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hemorrhage; Hour; Human; Ligands; Modeling; Neutropenia; Opportunistic Infections; Outcome; Peptides; Pharmaceutical Preparations; Radiation; Recovery; Risk; Sepsis; Severities; Staging; Supportive care; Thrombocytopenia; Thrombopoietin; Transfusion; Vascular Endothelial Growth Factor Receptor-1; Whole-Body Irradiation; cytokine; improved; irradiation; keratinocyte growth factor; mimetics; neutrophil; therapy development

DESCRIPTION (provided by applicant): Hematopoietic cells are highly sensitive to radiation damage and their loss after radiation exposure results in both neutropenia and thrombocytopenia. Severe neutropenia results in sepsis and death due to opportunistic infections and thrombocytopenia results in increased risk of hemorrhage and death due to bleeding. Development of treatment that substantially improves thrombocytopenia after radiation exposure would be a significant advance. The aim of this project is to study a very promising new drug, pegylated thrombopoietin mimetic peptide (Peg-TPO-mp) that will likely significantly improve platelet recovery after high dose total body irradiation (TBI) in the well established dog model. Peg-TPO-mp will initially be administered as a single agent drug beginning at 24 hours after TBI dose of 6 to 8 Gy. Supportive care administered to dogs will include empiric broad spectrum antibiotics and transfusions with irradiated blood products transfusions. Next, Peg-TPO-mp will be administered in combination with granulocyte colony stimulating factor (G-CSF), fms-like tyrosine kinase-3 ligand (Flt3 ligand [FL]) and keratinocyte growth factor (KGF) after lethal dose TBI. The aim is to study if Peg-TPO- mp has synergistic activity with these cytokines to improve survival and mitigate the duration and severity of thrombocytopenia. We will study Peg-TPO-mp in the dog since (1) the dog model of radiation exposure and hematopoietic recovery has been highly predictive of human clinical outcomes, (2) there are extensive preliminary data with cytokines for platelet and neutrophil recovery in the dog after acute irradiation, (3) all of the human cytokines we have proposed have established biologic activity in the dog, and (4) the cytokines have been studied in humans and are in advanced stages of clinical development. The study goal is to achieve survival of dogs after an otherwise lethal dose of irradiation with a significantly reduced period of thrombocytopenia without requiring hematopoietic stem cell transplantation.

描述（由申请人提供）：造血细胞对辐射损伤高度敏感，辐射暴露后造血细胞的损失会导致中性粒细胞减少症和血小板减少症。严重的中性粒细胞减少症会因机会性感染而导致败血症和死亡，而血小板减少症会导致出血和因出血而死亡的风险增加。开发出能够显着改善辐射暴露后血小板减少症的治疗方法将是一个重大进步。该项目的目的是研究一种非常有前途的新药，聚乙二醇化血小板生成素模拟肽（Peg-TPO-mp），它可能会在成熟的狗模型中显着改善高剂量全身照射（TBI）后的血小板恢复。 Peg-TPO-mp 最初将作为单剂药物在 TBI 剂量 6 至 8 Gy 后 24 小时开始施用。对狗的支持性护理将包括经验性广谱抗生素和输注经过辐照的血液制品。接下来，在致死剂量的 TBI 后，Peg-TPO-mp 将与粒细胞集落刺激因子 (G-CSF)、fms 样酪氨酸激酶 3 配体（Flt3 配体 [FL]）和角质形成细胞生长因子 (KGF) 联合施用。目的是研究 Peg-TPO-mp 是否与这些细胞因子具有协同活性，以提高生存率并减轻血小板减少症的持续时间和严重程度。我们将在狗身上研究 Peg-TPO-mp，因为 (1) 狗的辐射暴露和造血恢复模型可以高度预测人类临床结果，(2) 在狗体内有关于血小板和中性粒细胞恢复的细胞因子的广泛初步数据。狗在急性照射后，（3）我们提出的所有人类细胞因子都已在狗身上建立了生物活性，（4）这些细胞因子已在人类中进行了研究，并处于临床开发的后期阶段。该研究的目标是使狗在接受致命剂量的辐射后存活，并显着缩短血小板减少症的时间，而无需造血干细胞移植。