Improving Platelet Recovery After Radiation

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和血小板减少。严重的中性粒细胞减少症导致败血症和机会性感染导致的死亡，血小板减少症导致出血和出血导致的死亡风险增加。治疗的发展，实质上改善血小板减少放射暴露后将是一个重大的进步。这个项目的目的是研究一种非常有前途的新药，聚乙二醇化的血小板生成素模拟肽（Peg-TPO-mp），它可能会显著改善高剂量全身照射（TBI）后的血小板恢复。Peg-TPO-mp最初将在TBI剂量为6至8 Gy后24小时开始作为单药给药。给予狗的支持性护理将包括经验性广谱抗生素和用辐照血液制品输血。接下来，在致死剂量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]）和角质细胞生长因子（KGF）联合给药。目的是研究Peg-TPO- mp是否与这些细胞因子具有协同作用，以提高生存率，减轻血小板减少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已经高度预测了人类的临床结果，(2)有大量的初步数据表明，急性辐射后狗的血小板和中性粒细胞恢复的细胞因子，(3)我们提出的所有人类细胞因子都在狗身上建立了生物活性，(4)细胞因子已经在人类身上进行了研究，并处于临床开发的后期阶段。该研究的目的是在不需要造血干细胞移植的情况下，使狗在接受致死剂量的照射后存活，并显著缩短血小板减少期。

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.