THERAPEUTIC USE OF INTER-ALPHA INHIBITOR IN SEPSIS

描述（由申请人提供）： 拟议研究的目标是证明Inter-alpha丝氨酸蛋白酶抑制剂蛋白（IaIp）是脓毒症的有效疗法。在脓毒症中，成人和新生儿患者中正常高的IaIp血浆水平急剧下降。我们假设IaIp被消耗，同时减轻循环蛋白酶的破坏作用。我们假设IaIp的给药将纠正IaIp和血浆蛋白酶之间的不平衡，从而防止脓毒症中的器官损伤和高死亡率。在用于脓毒症的大鼠盲肠结扎/穿刺模型中的动物研究已经证明，IaIp有助于维持血液动力学稳定性，防止器官损伤，并提高存活率。使用高度纯化的Ialp的SBIR I期研究证实Ialp为预防剂，并且即使当给药延迟达10小时时也显示Ialp的有益作用。脓毒症诱导后。这些结果强烈支持Ialp作为新型抗炎剂的进一步开发。在本研究中，我们将扩大人Ialp的生产，用于动物和人类的临床前研究，以评估其在脓毒症患者中的安全性、药代动力学特性和疗效。这些试验性I/IIa期研究将导致开发用于管理脓毒症的新型抗炎药。

DESCRIPTION (provided by applicant): The goal of the proposed research is to demonstrate that Inter-alpha serine protease inhibitor proteins (IaIp) are an effective therapy for sepsis. In sepsis, normally high plasma levels of IaIp drop dramatically in adult and newborn patients. We hypothesize that IaIp are consumed while mitigating the damaging effects of circulating proteases. We hypothesize that administration of IaIp will correct the imbalance between IaIp and plasma proteases, thereby preventing organ injuries and high mortality rates in sepsis. Animal studies in a rat cecal ligation/puncture model for sepsis have demonstrated that IaIp helps maintain hemodynamic stability, prevents organ injury, and improves survival. SBIR Phase I studies with highly purified Ialp confirmed Ialp as the preventive agent and showed beneficial effects of Ialp even when administration was delayed up to 10 hrs. after sepsis induction. These results strongly support further development of Ialp as a novel anti-inflammatory agent. In this study, we will scale up the production of human Ialp for preclinical studies in animals and humans to assess its safety, pharmacokinetic properties and efficacy in septic patients. These pilot Phase I/IIa studies will lead to development of novel anti-inflammatory agents for management of sepsis.