AN ERYTHROPOIETIN-MIMETIC PEPTIDE (pHBSP) FOR TREATMENT OF TBI

描述（由申请人提供）：促红细胞生成素（EPO）是目前正在研究的改善TBI结局的最有吸引力的药物之一。在实验模型中，EPO改善了TBI和许多其他中枢神经系统疾病的结果。EPO已被证明在损伤后早期给予时具有神经保护作用，并且即使在损伤后较晚的时间给予也具有促进神经恢复的作用。神经保护机制可能是复杂的，涉及抗炎，抗凋亡和血管作用。EPO诱导的神经保护的时间窗为损伤后至少6小时。 尽管在实验室中观察到这些积极的特征，但难以将EPO转化为 因为神经保护和增强神经恢复所需的EPO剂量在患者中具有不利影响。几乎所有的EPO在危重病、创伤和术后患者中的研究都表明，使用EPO会增加血栓形成的风险。 然而，EPO的造血和组织保护作用可以分开。Araim Pharmaceuticals已经开发了一种短的合成EPO模拟肽（焦谷氨酸抑制剂B表面肽[pHBSP]），其保留EPO的神经保护活性，但不保留引起EPO副作用的造血活性。初步数据表明，在TBI模型中，pHBSP改善神经恢复类似于EPO。 该项目的目标是在资助期结束前完成将pHBSP从实验室转移到II期临床试验所需的临床前工作。Araim Pharmaceuticals（Ossining，NY）已经完成了人体I期安全性/毒性研究。完成TBI临床前工作的具体目标包括：1-确定用于治疗TBI的pHBSP的急性给药的最佳剂量水平、有效时间窗和最佳剂量方案，2-确认pHBSP的最佳给药方案在损伤严重程度谱中的功效，3-确认pHBSP的最佳给药方案在第二TBI损伤模型中的功效，4-研究pHBSP最佳给药方案的性别和年龄差异，5-提交II期临床试验的IND申请。

DESCRIPTION (provided by applicant): Erythropoietin (EPO) is one of the most attractive agents currently being studied to improve outcome from TBI. In experimental models, EPO has improved outcome after TBI, and many other central nervous system disorders. EPO has been shown to have neuroprotective effects when given early post-injury, and to have effects that enhance neurological recovery even when given at later times after injury. The neuroprotective mechanisms are probably complex, involving anti-inflammatory, anti-apoptotic, and vascular actions. The time window for EPO-induced neuroprotection is at least 6 hr post-injury. Despite these positive features observed in the laboratory, it has been difficult to translate EPO into the clinical setting for TBI because the doses of EPO required for neuroprotection and enhancement of neurological recovery have adverse effects in patients. Almost all studies of EPO in critically ill, trauma, and post-operative patients have shown an increased risk of thrombosis with EPO administration. The hematopoietic and tissue protective effects of EPO, however, can be separated. Araim Pharmaceuticals has developed a short, synthetic EPO-mimetic peptide (pyroglutamate Helix B surface peptide [pHBSP]) that retains EPO's neuroprotective activities, but not the hematopoietic activities responsible for the adverse effect of EPO. Preliminary data demonstrates in a TBI model that pHBSP improves neurological recovery similar to EPO. The goal of this project is to perform the preclinical work necessary to move pHBSP from the laboratory to a phase II clinical trial by the end of the grant period. Araim Pharmaceuticals (Ossining, NY) has already completed phase I safety/toxicity studies in humans. The specific aims to accomplish the preclinical work in TBI include the following: 1-To determine the optimal dose level, effective time window, and optimal dose regimen for acute dosing of pHBSP for treatment of TBI, 2-To confirm efficacy of optimal dosing regimen of pHBSP in a spectrum of injury severities, 3-To confirm efficacy of optimal dosing regimen of pHBSP in a second TBI injury model, 4-To study gender and age differences in response to optimal dosing regimen of pHBSP, 5-To submit an IND application for phase II clinical trial.