THROMBOPOIETIN FOR AIDS RELATED THROMBOCYTOPOIESIS

用于艾滋病相关血小板生成的血小板生成素

• 批准号: 2233729
• 负责人: JEROME E GROOPMAN
• 金额: $ 24.15万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-04 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2233729
• 关键词: AIDS; HIV infections; antiAIDS agent; chemical structure function; clinical trials; cytokine; dosage; drug quality /standard; gene therapy; growth factor; human subject; human therapy evaluation; immunopathology chemotherapy; immunosuppression; megakaryocytes; recombinant proteins; thrombocytopenia; thrombopoiesis; tissue /cell culture; tumor necrosis factor alpha; virus replication

DESCRIPTION (Adapted from the applicant's abstract) Thrombopoietin (TPO) has recently been discovered and is a potent regulator of both megakaryocyte progenitor proliferation and terminal megakaryocyte maturation. In vivo studies in rodent and subhuman primate models demonstrate that TPO can markedly increase circulating platelet numbers and restore megakaryocytopoiesis following suppressive treatment with x-irradiation and/or chemotherapy. Interestingly, TPO was also able to augment platelet production following treatment of rodents with antiplatelet antibodies, a model for immune thrombocytopenia. TPO is thus an attractive potential growth factor therapy for HIV-associated thrombocytopenia. The investigators propose to pursue in vitro biological studies of TPO as a framework for initial clinical studies in HIV-infected patients with sever thrombocytopenia. Three different in vitro culture systems will be employed to assess the mechanisms of HIV suppression of megakaryocyte progenitor and progeny development, and to determine the effects of TPO alone and in conjunction with other growth factors and/or anti-HIV agents. The preliminary data demonstrate in such culture systems a potent suppressive effect of prototype HIV isolates on in vitro megakaryocytopoiesis. The effects of TPO on HIV replication, interactions between HIV-infected T cells and monocyte-macrophages with developing megakaryocytes, relative dosing information, and the role of inhibitory cytokines such as TNF-alpha and TGF-beta may be derived from studies in these in vitro model systems. Furthermore, the effects of TPO on a specific strategy of HIV gene therapy, utilizing adeno-associated virus vectors, will be addressed. A prototype phase I safety and hematological efficacy trial of recombinant human TPO in severe HIV- associated thrombocytopenia is presented with intensive laboratory studies aimed at characterizing the effects of this growth factor on megakaryocytopoiesis and on HIV replication in vivo. By linking in vitro studies utilizing newly developed liquid culture systems of human megakaryocytes with a phase I clinical trial, the investigators aim to develop insights into optimal clinical applications of TPO in the HIV- infected host.

描述（改编自申请人摘要）血小板生成素（TPO） 最近被发现，它是一种有效的调节剂， 巨核祖细胞增殖和终末巨核细胞 成熟啮齿动物和亚人灵长类动物模型的体内研究 证明TPO可显著增加循环血小板数量 并在用以下抑制剂治疗后恢复巨核细胞生成 X射线照射和/或化疗。有趣的是，TPO还能够 在啮齿类动物治疗后增加血小板生成， 抗血小板抗体，免疫性血小板减少症的模型。TPO是 因此，一种有吸引力的潜在的生长因子治疗HIV相关的 血小板减少症。研究人员建议在体外 TPO的生物学研究作为初步临床研究的框架 严重血小板减少的HIV感染患者。三种不同 体外培养系统将用于评估艾滋病毒的机制， 抑制巨核细胞祖细胞和后代发育，以及 确定TPO单独和与其他生长因子结合的影响 因子和/或抗HIV剂。初步数据显示， 培养系统的原型艾滋病毒分离株的有效抑制作用， 体外巨核细胞生成。TPO对HIV复制的影响， HIV感染的T细胞和单核细胞-巨噬细胞之间的相互作用 发育中的巨核细胞，相对剂量信息，以及 抑制性细胞因子如TNF-α和TGF-β可来源于 在这些体外模型系统中的研究。此外，TPO的效果 艾滋病毒基因治疗的具体策略，利用腺相关病毒， 病毒载体，将得到解决。第一阶段安全和 重组人血小板生成素治疗重症HIV-1患者血液学疗效试验 相关性血小板减少症表现为强化实验室检查 研究旨在表征这种生长因子对 巨核细胞生成和体内HIV复制。通过链接 利用新开发的人类液体培养系统的体外研究 巨核细胞与I期临床试验，研究人员的目标是 深入了解TPO在HIV中的最佳临床应用- 被感染的宿主