Novel Therapy for Multiple Sclerosis (SBIR-Phase II)

描述(申请人提供)：多发性硬化症(MS)是一种破坏性的中枢神经系统(CNS)炎症性和神经退行性疾病。目前，对原发进展型多发性硬化症(PP-MS)没有有效的治疗方法，超过一半的复发缓解型多发性硬化症(RR-MS)对现有的治疗方法无效，导致严重的医疗需求未得到满足。这项研究的最终目标是开发一种新的治疗多发性硬化症的药物，它可以干扰主要的炎症途径，并提供神经保护。我们的第一阶段研究建立了Cognosci创新的抗炎/神经保护ApoE模拟多肽的原则证明，即使在疾病发作后服用，这些多肽也可以显著改善MS的两种实验性自身免疫性脑脊髓炎(EAE)模型的疾病严重程度，促进功能恢复，减少疾病的组织病理学迹象，并降低复发率。我们超过了我们的目标，发现了一种新的、更有效的类似物COG112，它导致了EAE近100%的缓解率。这项第二阶段的建议将利用我们先前工作的成功，在已建立的MS模型中研究三种更有效和更类似药物的COG化合物的机制和相对疗效。在特定的目标1和2中，我们将从髓鞘少突胶质细胞糖蛋白(MOG)和蛋白脂蛋白(PLP)诱导的EAE模型中分别模拟PP-MS和RR-MS形式的髓鞘少突胶质细胞糖蛋白(MOG)和蛋白质脂蛋白(PLP)诱导的EAE模型中确定最佳候选者。在具体目标3中，我们将从以下几个方面破译COG化合物有效的分子和药理学机制：1)COG化合物是否能在EAE模型中将Th1反应转移到Th2；2)COG化合物如何影响抗原提呈细胞的功能；以及3)COG化合物如何调节MAP激酶JNK、p38和转录因子NF-B的磷酸化？B。这项提议产生的数据将使我们能够选择治疗多发性硬化症的主要候选药物。在项目完成后，这种领先将通过FDA提交IND申请所需的安全药理学进行进展。该项目的完成还将加深我们对这种疾病的理解，并确认我们已经为MS确定了一个新的治疗目标。考虑到MS的早期发病年龄、患者群体的规模、这种疾病的衰弱性质以及惊人的医疗成本，目前开发MS新疗法的项目对MS患者及其家人具有显著的个人、社会和经济利益。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a devastating inflammatory and neurodegenerative disorder of the central nervous system (CNS). Currently, there are no effective treatments for Primary Progressive forms of MS (PP-MS) and more than half of Relapsing Remitting forms of MS (RR-MS) fail to respond to existing therapies generating a critically unmet medical need. The ultimate goal of this study is to develop a novel therapeutic drug for MS that interferes with the major inflammatory pathways and provides neuroprotection. Our phase I study established proof-of-principle with Cognosci's innovative anti- inflammatory/neuroprotective ApoE-mimetic peptides that significantly ameliorated disease severity, promoted functional recovery, decreased histopathological signs of disease, and reduced the relapse rate in two experimental autoimmune encephalomyelitis (EAE) models of MS, even when administered after the onset of disease. We EXCEEDED our aims by identifying a new, more potent analog, COG112, which resulted in nearly 100% remission rate in EAE. This Phase II proposal will capitalize on the success of our previous work to examine the mechanism and relative efficacy of three more potent and more drug-like COG compounds in established models of MS. In specific aims 1 and 2, we will identify the optimal candidate from the three COG compounds in myelin oligodendrocyte glycoprotein (MOG)- and proteolipid protein (PLP)-induced EAE models mimicking the PP-MS and RR-MS forms of human MS, respectively. In specific aim 3, we will decipher the molecular and pharmacological mechanisms underlying the effectiveness of COG compounds in the following aspects: 1) if COG compounds can shift Th1 response to Th2 in EAE model; 2) how COG compounds affect the function of antigen-presenting cells; and 3) how COG compounds modulate the phosphorylation of MAP kinase JNK, p38 and transcription factor NF-?B. The data generated by this proposal will enable us to select a lead candidate for the treatment of MS. After the project is completed, this lead will be progressed through the safety pharmacology required by the FDA for submission of an IND application. The completion of the project will also deepen our understanding of the disease and confirm that we have identified a novel therapeutic target for MS. Considering the early age of onset, size of the patient population, debilitating nature of this disease, and the startling healthcare costs, the current project to develop a novel therapy for MS has significant personal, social, and economic benefit to MS patients and their families.