Improving Platelet Recovery After Radiation

描述（由申请方提供）：造血细胞对辐射损伤高度敏感，辐射暴露后造血细胞丢失导致中性粒细胞减少症和血小板减少症。重度中性粒细胞减少导致败血症和机会性感染导致死亡，血小板减少导致出血和出血导致死亡的风险增加。开发治疗，大大改善辐射暴露后血小板减少症将是一个重大的进步。本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），它可能会显着改善高剂量全身照射（TBI）后的血小板恢复在良好的狗模型。Peg-TPO-mp最初将在6至8戈伊的TBI剂量后24小时开始作为单药药物施用。给予犬的支持性护理将包括经验性广谱抗生素和输注辐照血液制品。接下来，在致死剂量TBI后，将Peg-TPO-mp与粒细胞集落刺激因子（G-CSF）、fms样酪氨酸激酶-3配体（Flt 3配体[FL]）和角质形成细胞生长因子（KGF）组合施用。目的是研究Peg-TPO- mp是否与这些细胞因子具有协同活性，以改善生存率并减轻血小板减少症的持续时间和严重程度。我们将在狗中研究Peg-TPO-mp，因为（1）辐射暴露和造血恢复的狗模型高度预测人类临床结果，（2）存在关于急性辐射后狗中血小板和中性粒细胞恢复的细胞因子的广泛初步数据，（3）我们提出的所有人细胞因子都在狗中建立了生物活性，和（4）细胞因子已经在人体中进行了研究，并且处于临床开发的后期阶段。本研究的目的是使接受致死剂量辐照的犬在无需造血干细胞移植的情况下存活，血小板减少症的发生时间显著缩短。

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.