Novel Therapy for Multiple Sclerosis (SBIR-Phase II)

描述（由申请人提供）：多发性硬化（MS）是中枢神经系统（CNS）的破坏性炎症和神经退行性疾病。目前，对于原发性进展型MS（PP-MS）没有有效的治疗方法，并且超过一半的复发缓解型MS（RR-MS）对现有疗法无效，从而产生严重未满足的医疗需求。本研究的最终目标是开发一种新型MS治疗药物，干扰主要炎症通路并提供神经保护。我们的I期研究建立了Cognosci创新性抗炎/神经保护性ApoE模拟肽的原理验证，该肽在两种实验性自身免疫性脑脊髓炎（EAE）MS模型中显著改善疾病严重程度，促进功能恢复，减少疾病的组织病理学体征，并降低复发率，即使在疾病发作后给药。我们通过确定一种新的，更有效的类似物，COG 112，使EAE的缓解率接近100%，超过了我们的目标。该II期提案将利用我们先前工作的成功，以在已建立的MS模型中检查三种更有效和更像药物的COG化合物的机制和相对功效。在具体目标1和2中，我们将在模拟PP-MS和RR的髓鞘少突胶质细胞糖蛋白（MOG）和蛋白脂质蛋白（PLP）诱导的EAE模型中从三种COG化合物中鉴定最佳候选物。人MS的MS形式。在具体目标3中，我们将从以下几个方面阐明COG化合物有效性的分子和药理学机制：1）COG化合物是否可以在EAE模型中将Th 1应答转变为Th 2应答; 2）COG化合物如何影响抗原呈递细胞的功能; 3）COG化合物如何调节MAP激酶JNK、p38和转录因子NF-？B。本提案生成的数据将使我们能够选择治疗MS的主要候选药物。项目完成后，该主要药物将通过FDA提交IND申请所需的安全药理学进行。该项目的完成也将加深我们对该疾病的理解，并确认我们已经确定了MS的新治疗靶点。考虑到发病年龄早，患者人群的规模，这种疾病的衰弱性质以及惊人的医疗费用，目前开发MS新疗法的项目对MS患者及其家庭具有显着的个人，社会和经济效益。

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.