Novel Therapy for Multiple Sclerosis (SBIR-Phase II)

多发性硬化症新疗法（SBIR-II 期）

基本信息

批准号：
7495597
负责人：
FENG-QIAO LI
金额：
$ 19.85万
依托单位：
COGNOSCI, INC.
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-10 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7495597
关键词：
Affect Age of Onset Age-Years Animal Model Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Antigen-Presenting Cells Antigens Apolipoprotein E Autoimmune Diseases Axon Blood - brain barrier anatomy Brain Cells Characteristics Chronic Class Clinical Copaxone Data Data Reporting Demyelinations Dendritic Cells Development Disadvantaged Disease Disease remission Drug Design Economics Effectiveness Encephalomyelitis End Point Equilibrium Etiology Exhibits Experimental Autoimmune Encephalomyelitis Family Funding Goals Health Care Costs Histocompatibility Antigens Class II Human In Vitro Inflammation Inflammatory Inflammatory Infiltrate Interferon beta-1a Investigational New Drug Application Investments Knowledge Lead MAP Kinase Gene MAPK14 gene MAPK8 gene Macrophage Activation Maintenance Marketing Medical Membrane Proteins Mitogen-Activated Protein Kinases Mitoxantrone Mitroxone Modeling Molecular Multiple Sclerosis Mus Myelin Myelin Associated Glycoprotein Myelin Sheath Nature Nerve Degeneration Neuraxis Neurodegenerative Disorders Nitric Oxide Oligodendroglia Onset of illness Pathogenesis Pathway interactions Patients Penetration Peptides Peripheral Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Phase I Clinical Trials Phase II Clinical Trials Phosphorylation Population Preventive Primary Progressive Multiple Sclerosis Property Proteins Proteolipids Rate Recombinant interferon beta-1b Recovery of Function Recurrence Relapse Relative (related person)Resources Safety Series Severity of illness Signal Transduction Spinal Cord TNFRSF5 gene Testing Therapeutic Tissues Toxic effect Trauma Tysabri United States United States Food and Drug Administration Work analog avonex copolymer 1 cost cytokine disability experience fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether human relapse in vivo in vivo Model innovation lymphocyte proliferation macrophage migration mimetics nervous system disorder neuroprotection neutralizing antibody novel novel therapeutics oligodendrocyte-myelin glycoprotein pre-clinical repaired response size social success therapeutic target transcription factor young adult

项目摘要

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.

描述（由申请人提供）：多发性硬化症（MS）是一种破坏性的中枢神经系统（CNS）炎症和神经退行性疾病。目前，原发进展型多发性硬化症 (PP-MS) 尚无有效治疗方法，超过一半的复发缓解型多发性硬化症 (RR-MS) 无法对现有疗法产生反应，从而产生了严重未满足的医疗需求。这项研究的最终目标是开发一种新型多发性硬化症治疗药物，干扰主要炎症途径并提供神经保护。我们的第一阶段研究利用 Cognosci 的创新抗炎/神经保护 ApoE 模拟肽建立了原理验证，该肽可显着改善两种实验性自身免疫性脑脊髓炎 (EAE) 疾病的严重程度，促进功能恢复，减少疾病的组织病理学体征，并降低复发率）多发性硬化症模型，即使是在疾病发作后施用。我们发现了一种新的、更有效的类似物 COG112，超出了我们的目标，它使 EAE 的缓解率接近 100%。该 II 期提案将利用我们之前工作的成功，在已建立的 MS 模型中检查三种更有效、更类似药物的 COG 化合物的机制和相对功效。在具体目标 1 和 2 中，我们将从模拟人类 MS 的 PP-MS 和 RR-MS 形式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 模型中的三种 COG 化合物中确定最佳候选化合物，分别。在具体目标3中，我们将从以下几个方面解读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Th1反应转变为Th2反应； 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-κB 的磷酸化。该提案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。项目完成后，该先导药物将通过 FDA 提交 IND 申请所需的安全药理学进展。该项目的完成也将加深我们对该疾病的了解，并确认我们已经确定了多发性硬化症的新治疗靶点。考虑到多发性硬化症的发病年龄早、患者群体规模大、该疾病使人衰弱的性质以及令人震惊的医疗费用，当前开发多发性硬化症新疗法的项目对多发性硬化症患者及其家人具有显着的个人、社会和经济利益。