Use of Multifunctional rhPRG4 Biologic for Treatment of TBI

项目总结 创伤性脑损伤(TBI)是一种毁灭性的医疗疾病，影响着美国170多万平民 并代表着一种未得到满足的临床需求。迫切需要有效的治疗方法，因为脑损伤与 高住院率、高死亡率和高致残率。之前的临床试验未能证明Thera- 颅脑损伤患者的临床疗效。 本课题致力于评价一种新型多功能生物重组材料的治疗效果。 人蛋白多糖4(RhPRG4)，在脑损伤中也称为润滑素。重组人PRG4有效地与两者相互作用 表面亲水、疏水，具有很强的抗粘性和消炎性。什么时候 在脑外伤大鼠模型中，外周给药后，重组人促性腺激素释放激素4能穿过伤者的血脑屏障 脑实质，但在未受损伤的脑组织中缺失。我们的初步数据显示，重组人PRG4 显著减少创伤后促炎介质和基质金属的产生。 蛋白水解酶，并减少炎症细胞进入受损的脑实质。重组人PRG4也有一个 独特的稳定血脑屏障的能力，其功能受到脑外伤的影响。这些观察结果表明， 重组人PRG4生物可以限制在脑外伤中观察到的神经组织的破坏，从而改善 损伤后的神经转归。 这项研究有两个主要目标：(1)评估重组人PRG4在参与其推定的 靶点和加深对重组人PRG4 S在创伤急性期稳定血脑屏障能力的认识 (2)获取重组人促性腺激素释放激素4减少和改善神经元损伤的远期疗效的临床前资料 颅脑损伤后的功能结局。

PROJECT SUMMARY Traumatic brain injury (TBI) is a devastating medical condition that affects more than 1.7 million civilians in the US and represents an unmet clinical need. Effective therapies are urgently needed, as TBI is associated with high rates of hospitalization, mortality, and disability. Previous clinical trials have failed to demonstrate thera- peutic efficacy in patients with TBI. This project focuses on evaluating the therapeutic efficacy of a novel multifunctional biologic—recombinant human proteoglycan 4 (rhPRG4), also known as lubricin—in TBI. rhPRG4 effectively interacts with both hydrophilic and hydrophobic surfaces, and has strong anti-adhesive and anti-inflammatory properties. When administered peripherally in a rat model of TBI, rhPRG4 crosses the blood-brain barrier (BBB) in the injured brain parenchyma, but is absent from the uninjured parts of the brain. Our preliminary data show that rhPRG4 dramatically decreases the post-traumatic production of proinflammatory mediators and matrix metallo- proteinases, and reduces the influx of inflammatory cells into the injured brain parenchyma. rhPRG4 also has a unique ability to stabilize the BBB, whose function is affected by TBI. These observations suggest that the rhPRG4 biologic could limit the destruction of neural tissue observed in TBI and, consequently, improve neurological outcome after injury. There are two major goals of this study: (1) to assess the efficacy of rhPRG4 in engaging with its putative targets and enhance our understanding of rhPRG4's ability to stabilize the BBB in acute phase of injury, and (2) to obtain preclinical data on long-term efficacy of rhPRG4 in reducing the neuronal loss and improving functional outcome after TBI.