Improving Platelet Recovery After Radiation

说明(申请人提供)：造血细胞对辐射损伤高度敏感，辐射后它们的丢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会导致败血症和机会性感染导致的死亡，而血小板减少会增加出血和因出血而死亡的风险。能显著改善辐射暴露后的血小板减少症的治疗方法的开发将是一个重大的进步。本项目的目的是研究一种非常有前景的新药，聚乙二醇化的血小板生成素模拟肽(Peg-TPO-MP)，它可能显著改善大剂量全身照射(TBI)后犬的血小板恢复。PEG-TPO-MP最初将作为单药给药，从6-8GyTBI剂量后24小时开始。对狗的支持性护理将包括经验性的广谱抗生素和与辐射血液产品输血。接下来，在致死剂量的颅脑损伤后，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(FL)和角质形成细胞生长因子(KGF)联合应用。目的是研究Peg-TPO-MP是否与这些细胞因子具有协同作用，以提高存活率，缓解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)辐射暴露和造血恢复的狗模型一直高度预测人类的临床结果，(2)有大量关于狗急性辐射后血小板和中性粒细胞恢复的细胞因子的初步数据，(3)我们提出的所有人类细胞因子在狗身上都具有生物活性，(4)这些细胞因子已经在人类中进行了研究，并处于临床开发的后期阶段。这项研究的目标是在不需要造血干细胞移植的情况下，在显著缩短血小板减少的时间的情况下，实现狗在其他致命剂量的照射后存活。

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.