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

描述（由申请人提供）：RAP作为脊髓损伤后神经元再生的治疗化合物Novoron Bioscience Inc。研究及相关的其他项目信息据估计，每年有1.2万至2万例脊髓损伤（SCI）新发病例，美国有128万人因SCI而出现某种形式的瘫痪。髓磷脂降解是脊髓损伤后中枢神经系统（CNS）再生衰竭的原因之一，目前尚无针对髓磷脂降解的临床治疗方法。LRP1最近被鉴定为髓磷脂相关抑制剂（MAIs）的一种新型受体，MAIs是降解髓磷脂的成分，负责再生失败。我们已经在体内证明，将LRP1拮抗剂RAP输注到受损脊髓中会导致RhoA的衰减，RhoA是参与外部介导的再生衰竭的关键神经元信号。在啮齿动物模型中，直接抑制RhoA已被证明可以增强脊髓损伤后的神经元再生，在探索性临床试验中，一种泛rho抑制剂已显示出对人类有效的证据。然而，目前的治疗方法到目前为止仅限于单剂量给药。相比之下，RAP已被证明很容易从外周循环中进入中枢神经系统，因此可以随着时间的推移反复给药，这使其比目前的泛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有益的结果，我们首先希望评估外周给药RAP是否对脊髓损伤后再生衰竭相关的信号事件具有类似的有益影响。为了实现这一点，必须首先建立一个能够在中枢神经系统中产生足够水平RAP的静脉给药方案。然后，我们将进行长期研究（8周的损伤过程），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益处，如改善运动，增加爪子的使用，以及对受影响肢体外部刺激的反应。我们还将评估RAP输注对免疫浸润和病变形成的影响。由于LRP1已被证明是髓磷脂介导的神经再生失败的关键促进者，我们假设治疗性应用RAP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，具有独特的生物学特性

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.