RAP as a therapeutic compound for neuronal regeneration after spinal cord injury

描述(由申请人提供)：RAP是一种治疗脊髓损伤后神经元再生的化合物。Novoron Bioscience Inc.研究和相关其他项目信息7.项目摘要估计每年有12,000至20,000例新的脊髓损伤(SCI)病例，美国有128万人因脊髓损伤而以某种形式瘫痪。目前，还没有针对降解的髓鞘的临床可用的治疗方法，髓鞘降解是脊髓损伤后中枢神经系统(CNS)再生失败的原因之一。LRP1是最近发现的一种新型髓鞘相关抑制物(MAI)受体，MAI是降解的髓鞘成分，导致再生失败。我们已经在体内证明，将LRP1拮抗剂RAP注入损伤的脊髓导致RhoA的减弱，RhoA是参与外源性介导的再生失败的关键神经元信号。在啮齿动物模型中，直接抑制RhoA可促进脊髓损伤后神经元的再生，而泛Rho抑制剂在探索性临床试验中已显示出对人类有效的证据。然而，到目前为止，目前的治疗方法仅限于单剂给药。相比之下，RAP已被证明可从外周循环很容易地进入中枢神经系统，从而使其易于随着时间的推移重复给药，从而使其比目前的PAN-RhoA抑制剂具有治疗优势。由于直接输注到损伤部位已经观察到了有益的结果，我们首先希望评估外周注射RAP是否对与脊髓损伤后再生失败相关的信号事件具有类似的有益影响。要做到这一点，首先必须建立一种能够在中枢神经系统导致足够水平的RAP的静脉给药方案。然后，我们将进行长期研究(为期8周的损伤疗程)，以评估受损神经元的组织学再生，以及随着时间的推移评估行为方面的好处，如改善行走能力、增加爪子利用率以及对受影响肢体的外部刺激做出反应。我们还将评估RAP输注对免疫渗透和病变形成的影响。由于LRP1已被证明是髓鞘介导的神经再生衰竭的关键促进器，我们假设应用RAP来阻断LRP1/MAI相互作用将导致脊髓损伤后显著的神经元再生。此外，独特的生物学特性 对RAP如CNS生物利用度的研究可能使其成为当前PAN-RhoA抑制剂的一种更好的，或者可能是联合治疗方法。因此，对于急性脊髓损伤后的功能恢复，RAP似乎是一种很有价值的潜在治疗方法。S的这项技术受到美国专利申请(US2012/035125)的保护，该专利目前正在从加州大学圣地亚哥分校向Novoron Inc.授予独家许可。

DESCRIPTION (provided by applicant): RAP as a therapeutic compound for neuronal regeneration after spinal cord injury Novoron Bioscience Inc. RESEARCH & RELATED Other Project Information 7. Project Summary There are an estimated 12,000 to 20,000 new cases of spinal cord injury (SCI) each year and 1.28 million people in the United States are paralyzed in some form due to SCI. Currently, there are no clinically available treatments that target the degraded myelin, one of the causes of regenerative failure in the central nervous system (CNS) after SCI. LRP1 was recently identified as a novel receptor of myelin-associated inhibitors (MAIs), the components of degraded myelin responsible for regenerative failure. We have shown in vivo that infusion of the LRP1 antagonist RAP into the injured spinal cord results in attenuation of RhoA, the critical neuronal signal involved in extrinsically-mediated regenerative failure. Direct inhibition of RhoA has been shown to enhance neuronal regeneration after SCI in rodent models and a pan-Rho inhibitor has shown evidence of efficacy in humans in exploratory clinical trials. However, current therapeutics have so far been limited to single dose administration. In contrast, RAP has been demonstrated to be readily available to the CNS from the peripheral circulation therefore making it amenable to repeated administration over time giving it therapeutic advantages over current pan-RhoA inhibitors. As beneficial results have already been observed using direct infusion to the injury site, we first wish to assess whether peripheral administration of RAP has comparable beneficial effects on the signaling events associated with regenerative failure after SCI. To accomplish this, an intravenous administration protocol capable of resulting in sufficient levels of RAP in the CNS must first be established. We will then perform long term studies (8-week injury course) to assess histological regeneration of damaged neurons, as well as evaluate the behavioral benefits over time such as improved locomotion, increased paw utilization, and response to external stimuli in affected extremities. We will also evaluate the effects of RAP infusion on immune infiltration and lesion formation. As LRP1 has been shown to be a critical facilitator of myelin mediated neuroregenerative failure, we hypothesize that therapeutic application of RAP to block the LRP1/MAI interaction will result in significant neuronal regeneration after SCI. Additionally, the unique biological characteristics of RAP such as CNS bioavailability could make it a superior, or perhaps combinatorial, therapeutic approach to the current pan-RhoA inhibitors. As such, RAP appears to be a high-value potential therapeutic for restoring function after acute spinal cord injury. This technology s protected by US patent pending (US2012/035125), which is currently in process of exclusive license to Novoron Inc. from the University of California San Diego.