Toxicology and Efficacy Studies of Intrathecal VersaMab-101 for spinal cord injury treatment

项目总结/摘要 据估计，脊髓损伤（SCI）影响了249，000至363，000名美国人，其中约17，730人 每年都有新的伤病发生。在美国，大约有42000名SCI患者是退伍军人。 近一半的SCI发生在16岁至36岁的患者中，这导致患有SCI的患者 SCI几十年来脊髓损伤患者的终生费用平均可达510万美元， 高度四肢瘫痪的人。到目前为止，还没有FDA批准的SCI药物治疗，这突出了 这些病人的巨大医疗需求大多数脊髓损伤在解剖学上是不完整的，这意味着 通过重建脊髓的神经回路，这些患者将具有功能恢复的潜力。到 启动恢复过程时，来自损伤水平以上或附近的剩余神经元的受损轴突需要 再生生长绕过损伤部位，重新连接到损伤水平以下的神经元，然后重新建立 神经回路阻止轴突再生的主要障碍是化学和物理屏障， 损伤后在损伤部位迅速积聚，这阻碍了轴突的再生生长。比如说， 当轴突再生到损伤部位时，在那里重新诱导的Wnts蛋白将与Ryk受体相互作用， 在轴突上重新诱导，然后停止轴突再生。为了消除这一障碍， Ryk受体和Wnts蛋白必须被阻断。 由世界著名的大学研究小组进行的一流研究成果 （UCSD），我们开发了一种新的人源化单克隆抗体候选药物， VersaMab-101，其可阻断Wnt与Ryk受体之间的相互作用。大鼠注射后 在脊髓损伤时，这种抗体促进轴突再生生长，并通过阻止损伤部位的生长而绕过损伤部位。 Ryk和Wnts之间的毒性相互作用。重建的神经回路将促进功能性的 大鼠的恢复。 这种新的治疗方法将通过促进轴突生长而使急性脊髓损伤患者受益 再生和改善他们的行为恢复。这种治疗方法也将有利于整个社区， 降低长期护理的成本。根据FDA在IND前会议上的建议，我们建议 在本授权申请中进行大鼠GLP投诉毒性研究，以评价VersaMab-101的安全性 数据区.我们还将研究脊髓挫伤大鼠所需的最小有效剂量。

PROJECT SUMMARY/ABSTRACT Spinal cord injury (SCI) is estimated to affect between 249,000 and 363,000 Americans, with about 17,730 new injuries occurring each year. There are around 42000 SCI patients that are veterans in the United States. Nearly half of all SCIs occur in patients between the ages of 16 and 36, which results in individuals living with SCI for decades. The lifetime costs of living with spinal cord injury can average up to $5.1M per patient for individuals with high tetraplegia. So far, there are no FDA approved drug therapeutics for SCI, which highlights a huge unmet medical need for those patients. Most spinal cord injuries are anatomically incomplete, which means by reestablishing neural circuits in the spinal cord, those patients would have functional recovery potential. To initiate the recovery process, injured axons from the remaining neurons above or near the injury level need to regenerative growth to bypass the lesion site, reconnect to the neurons below the injury level, and then reestablish the neural circuits. The major obstruction that prevents axon regrowth is the chemical and physical barriers that accumulated at the lesion site quickly after injury, which blocks the axonal regenerative growth. For instance, when axons regrowth to the lesion site, the Wnts protein reinduced there will interact with Ryk receptor that reinduced on the axons, and then stop axon regeneration. To remove this obstruction, the interactions between Ryk receptor and Wnts protein must be blocked. Advanced from the first-in-class research conducted in a world-famous research group in the University of California, San Diego (UCSD), we developed a novel humanized monoclonal antibody drug candidate, VersaMab-101, which could block the interaction between Wnt and the Ryk receptor. After injection into rats with spinal cord injury, this antibody promoted axons regenerative growth and bypass the lesion site by stopping the toxic interaction between Ryk and Wnts. The re-established neural circuits would then promote functional recovery in rats. This novel therapeutic will benefits the patients with acute spinal cord injury by promoting axon regeneration and improving their behavior recovery. This therapeutic will also benefit the whole community by reducing the cost of long-term care. According to FDA recommendations in our pre-IND meeting, we propose to conduct GLP-complaint toxicity study in rats in this grant application to evaluate the VersaMab-101 safety profiles. We will also investigate the minimal required efficacy dose for rats with spinal cord contusion injuries.