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

用于治疗 TBI 的促红细胞生成素模拟肽 (pHBSP)

• 批准号: 8703819
• 负责人: CLAUDIA S ROBERTSON
• 金额: $ 71.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703819
• 关键词: Acute; Adverse effects; American; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Applications Grants; Binding; Blood; Blood Vessels; Brain; Cell Surface Receptors; Cells; Central Nervous System Diseases; Clinical; Clinical Trials; Complex; Critical Illness; Data; Diabetic Neuropathies; Direct Costs; Disease; Dose; Dose-Limiting; Erythropoietin; Erythropoietin Receptor; Event; Experimental Models; Facilities and Administrative Costs; Goals; Grant; Hematopoietic; Human; Injury; Ischemia; Laboratories; Life; Limb structure; Mediating; Modeling; Neurological outcome; Organ; Outcome; Patients; Peptides; Pharmacologic Substance; Phase; Phase II Clinical Trials; Postoperative Period; Public Health; Pyroglutamate; Regimen; Reporting; Retina; Rheumatoid Arthritis; Risk; Safety; Severities; Sex Characteristics; Signal Transduction; Surface; Thrombosis; Time; Tissues; Toxic effect; Translating; Trauma; Traumatic Brain Injury; Work; age difference; cost; disability; effective therapy; hematopoietic tissue; improved; meetings; mimetics; nervous system disorder; neurological recovery; neuroprotection; novel; pre-clinical; protective effect; protein aminoacid sequence; public health relevance; receptor; response; three dimensional structure

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.

描述（由申请人提供）：促红细胞生成素 (EPO) 是目前正在研究的用于改善 TBI 预后的最具吸引力的药物之一。在实验模型中，EPO 改善了 TBI 和许多其他中枢神经系统疾病后的结果。 EPO 已被证明在受伤后早期给予时具有神经保护作用，并且即使在受伤后较晚时间给予时也具有增强神经功能恢复的作用。神经保护机制可能很复杂，涉及抗炎、抗凋亡和血管作用。 EPO 诱导的神经保护作用的时间窗至少为损伤后 6 小时。 尽管在实验室中观察到了这些积极特征，但将 EPO 转化为 TBI 的临床环境是因为神经保护和增强神经功能恢复所需的 EPO 剂量会对患者产生不良影响。几乎所有针对危重患者、创伤患者和术后患者的 EPO 研究均表明，使用 EPO 会增加血栓形成的风险。 然而，EPO 的造血作用和组织保护作用是可以分开的。 Araim Pharmaceuticals 开发了一种短的合成 EPO 模拟肽（焦谷氨酸螺旋 B 表面肽 [pHBSP]），它保留了 EPO 的神经保护活性，但不保留导致 EPO 不良反应的造血活性。初步数据表明，在 TBI 模型中，pHBSP 可以像 EPO 一样改善神经功能恢复。 该项目的目标是在资助期结束前完成必要的临床前工作，将 pHBSP 从实验室转移到 II 期临床试验。 Araim Pharmaceuticals（纽约州奥西宁）已经完成了第一阶段的人体安全/毒性研究。完成 TBI 临床前工作的具体目标包括以下内容： 1-确定 pHBSP 急性给药治疗 TBI 的最佳剂量水平、有效时间窗和最佳剂量方案，2-确认 pHBSP 最佳给药方案在一系列损伤严重程度中的功效，3-确认 pHBSP 最佳给药方案在第二个 TBI 损伤模型中的功效，4-研究性别 和年龄差异对pHBSP最佳给药方案的反应，5-提交II期临床试验的IND申请。