Elastase Inhibition as a Novel Therapeutic Approach for Neuromyelitis Optica

弹性蛋白酶抑制作为视神经脊髓炎的新型治疗方法

• 批准号: 8715193
• 负责人: Jack Tzu-Chiao Lin
• 金额: $ 22.41万
• 依托单位: ANVIL BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715193
• 关键词: 1-Phosphatidylinositol 4-Kinase; Affect; Animal Model; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Automobile Driving; Biological Markers; Blindness; Blood; Body Weight decreased; Brain; CCL2 gene; CCL20 gene; CXCL10 gene; CXCL5 gene; Candida; Cathepsin G; Cellular Infiltration; Clinical; Clinical Research; Clinical assessments; Collaborations; Data Analyses; Data Set; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Combinations; Elastases; Enzyme-Linked Immunosorbent Assay; Eotaxin; Experimental Autoimmune Encephalomyelitis; Goals; Harvest; Hematoxylin and Eosin Staining Method; Histology; Human; IL8 gene; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Infiltrate; Institutes; Interferons; Interleukin-17; Joint Ventures; Lead; Leukocyte Elastase; Limb structure; Measures; Mediator of activation protein; Methods; Methylprednisolone; Mission; Modeling; Motor; Multiple Sclerosis; Mus; National Institute of Allergy and Infectious Disease; National Institute of Neurological Disorders and Stroke; Nerve; Neuromyelitis Optica; Optics; Outcome; Paralysed; Pathology; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physicians; Play; Proteinase 3; Rare Diseases; Regimen; Research; Research Proposals; Role; Serine Protease; Serum; Severity of illness; Small Business Innovation Research Grant; Spinal Cord; Staining method; Stains; System; Testing; Therapeutic; Therapeutic Effect; Tissues; Translating; Translational Research; Treatment Efficacy; United States National Institutes of Health; Wit; alpha 1-Antitrypsin; aquaporin 4; arm; chemokine; cohort; combinatorial; cost effective; cytokine; design; disability; drug candidate; efficacy testing; improved; in vivo; inhibitor/antagonist; interest; interleukin-12 subunit p40; mouse model; neutrophil; neutrophil elastase inhibitor; novel therapeutic intervention; novel therapeutics; patient population; pre-clinical; preclinical study; programs; public health relevance; standard of care; synergism

DESCRIPTION (provided by applicant): Neuromyelitis Optica (NMO) is a rare autoimmune inflammatory disease that affects the spinal cord and optical nerves leading to limb paralysis and loss of vision. Despite advances in the understanding of underlying disease mechanisms and patient diagnostic criteria there is a lack of treatment options. A specific cellular component of NMO disease was found to be neutrophils as they play a pathogenic role in causing the observed inflammation. We propose targeting a recently discovered pathogenic mediator secreted by neutrophils in NMO disease by using inhibitors of neutrophil elastase as a therapeutic approach. Various neutrophil elastase inhibitors have been used for other indications and our strategy seeks to re-purpose these drugs for NMO to find an optimal therapeutic. Our first aim will test the efficacy of two neutrophil elastase inhibitors using a Th1 mouse EAE transfer model that recapitulates the pathogenic features seen in NMO patients. We will measure therapeutic effect by EAE disease scoring and blood will be collected to assess levels of serum neutrophil elastase and other serine proteases, cytokines, and chemokines for potential biomarkers. Spinal cord and optical tract will also be harvested for histology to assess cellular infiltration. Our second aim builds upon the first by using the identified optimal candidae therapeutic in combinatorial studies with current NMO standard of care methylprednisolone. These studies will again use the Th17 mouse EAE transfer model to measure efficacy and will specifically test for synergistic therapeutic effect using the combination of drugs. Blood will agan be collected for serum biomarker analysis and spinal cord and optical tract for histology. The overall goal of these studies is to re-purpose a neutrophil elastase inhibitor as a novel therapeutic for NMO whether as stand-alone or add-on combinatorial therapy. This Phase I proposal seeks to demonstrate proof of efficacy and prepares the project for additional research and pre-clinical studies in Phase II as well as potential research collaboration joint ventures wit interested pharmaceutical companies.

描述(申请人提供)：视神经脊髓炎(NMO)是一种罕见的自身免疫性炎症性疾病，影响脊髓和视神经，导致肢体瘫痪和视力丧失。尽管在对潜在疾病机制和患者诊断标准的理解方面取得了进展，但仍然缺乏治疗选择。特定的蜂窝组件 NMO疾病的一部分被发现是中性粒细胞，因为它们在引起观察到的炎症中起着致病作用。我们建议通过使用中性粒细胞弹性蛋白酶抑制剂作为治疗方法，来靶向最近发现的由中性粒细胞在NMO疾病中分泌的致病介质。各种中性粒细胞弹性蛋白酶抑制剂已被用于其他适应症，我们的策略旨在为NMO重新调整这些药物的用途，以找到最佳的治疗方法。我们的第一个目标是使用Th1小鼠EAE转移模型来测试两种中性粒细胞弹性蛋白酶抑制剂的疗效，该模型概括了NMO患者的致病特征。我们将通过EAE疾病评分来衡量疗效，并将采集血液以评估血清中性粒细胞弹性蛋白酶和其他丝氨酸蛋白酶、细胞因子和趋化因子的潜在生物标志物的水平。脊髓和视束也将被采集用于组织学检查，以评估细胞浸润。我们的第二个目标建立在第一个目标的基础上，在与当前NMO标准治疗甲基强的松龙的联合研究中使用已确定的最佳念珠菌治疗。这些研究将再次使用Th17小鼠EAE转移模型来衡量疗效，并将专门测试使用联合药物的协同治疗效果。将采集血液进行血清生物标记物分析，并采集脊髓和视束进行组织学检查。这些研究的总体目标是将中性粒细胞弹性蛋白酶抑制剂作为一种新的治疗NMO的方法，无论是单独治疗还是附加联合治疗。这项第一阶段的提案旨在证明有效性，并为第二阶段的其他研究和临床前研究以及与感兴趣的制药公司建立潜在的研究合作合资企业做准备。