Identification of CNS-homing peptides for therapeutic use in multiple sclerosis

鉴定用于治疗多发性硬化症的中枢神经系统归巢肽

• 批准号: 8897016
• 负责人: KAMAL D MOUDGIL
• 金额: $ 19万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897016
• 关键词: Address; Adjuvant Arthritis; Adverse effects; Adverse reactions; Alanine; Animal Model; Antibodies; Antigens; Area; Arginine; Arthritis; Asparagine; Aspartic Acid; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteriophages; Binding; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Cells; Characteristics; Chronic; Clinical; Code; Collaborations; Detection; Development; Disease; Drug Delivery Systems; Drug Targeting; Encapsulated; Experimental Autoimmune Encephalomyelitis; Glutamine; Glycine; Health; Heterogeneity; Home environment; Homing; Human; Immune; Individual; Inflammation; Inflammation Mediators; Institutes; Integrins; Interferons; Joints; Leukocyte Trafficking; Libraries; Ligands; Liposomes; Lysine; Methodology; Methods; Mitoxantrone; Modeling; Multiple Sclerosis; Mus; Myelin Basic Proteins; Neuraxis; Normal tissue morphology; Organ; Paralysed; Pathogenesis; Pathology; Peptide Phage Display Library; Peptides; Phage Display; Pharmaceutical Preparations; Physiological; Play; Process; Proteins; Proteolipids; Publishing; RGD (sequence); Rattus; Reporting; Research Personnel; Role; SJL Mouse; Site; Spinal Cord; Study models; System; T-Lymphocyte; Techniques; Therapeutic; Therapeutic Agents; Therapeutic Index; Therapeutic Uses; Tissues; Toxic effect; Translational Research; Tysabri; Vascular Endothelial Cell; Vascular Endothelium; Work; angiogenesis; autoreactive T cell; base; copolymer 1; design; disability; in vivo; innovation; insight; lymph nodes; migration; molecular marker; mouse myelin oligodendrocyte glycoprotein; natalizumab; neoplastic cell; novel; novel strategies; novel therapeutic intervention; oligodendrocyte-myelin glycoprotein; receptor binding; screening; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic debilitating autoimmune disease involving inflammation and damage to the central nervous system (CNS). A variety of autoantigens, including myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), and myelin basic protein (MBP) have been implicated in the pathogenesis of MS. The T cells reactive against these antigens access the CNS through the blood-brain barrier and cause inflammation and tissue damage. Two of the main challenges for researchers working in the field of MS are - 1) to define the underlying mechanisms that render the CNS highly prone to an autoimmune attack, and 2) to devise novel ways to direct the orally-administered or injected drugs primarily into the CNS to enhance their efficacy while minimizing adverse effects. We hypothesize that the vascular endothelium of the CNS is characterized by unique molecular markers that facilitate both selective migration of the pathogenic T cells into the target organ (the CNS) as well as cellular interaction with the inducers/mediators of inflammation and tissue damage. In collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham Institute at La Jolla, CA), we recently completed and published (PNAS 2011, 108: 12857) study of the synovial vasculature in the rat adjuvant arthritis model. The objective of that study was to identify unique joint-specific vascular markers using an innovative approach of in vivo enrichment of clones from a phage peptide-display library. The advantage of the phage system for detection of tissue-specific markers is that there is no a priori bias in predicting the ligand in the vascular endothelium. In addition, unlike antibodies, the phage-displayed peptides interact with the functional domain of the target molecule. This approach has been pioneered by Dr. Ruoslahti, who has developed the concept of vascular 'address molecules' or 'zip codes'. His group and other investigators have examined several organs in this regard except the inflamed CNS. We hypothesize that the vascular endothelium of the brain and the spinal cord in EAE is characterized by unique molecular markers, and that the targeting of drugs via one or more of these markers would downregulate inflammation and tissue damage in the CNS without undue adverse reactions or systemic toxicity. The aims of our study based on MOG-EAE and PLP-EAE models (and in collaboration with Dr. Ruoslahti, and EAE experts- Drs. Scott and Lees) are as follows: Aim 1, to identify unique 'address molecules' for vascular endothelium of the inflamed CNS in mice with EAE using the in vivo screening of phage peptide-display library method. Aim 2, to use CNS-homing peptides for vasculature-targeted drug delivery into sites of CNS inflammation and tissue damage. We believe that the results of this study would advance our understanding of the pathogenesis of EAE/MS, and pave the way for designing novel peptide-directed therapeutics for MS through translational research.

描述（由申请人提供）：多发性硬化症（MS）是一种慢性衰弱性自身免疫性疾病，涉及炎症和中枢神经系统（CNS）损伤。各种自身抗原，包括髓鞘少突胶质细胞糖蛋白（MOG），蛋白脂质蛋白（PLP），和髓鞘碱性蛋白（MBP）已涉及MS的发病机制。T细胞对这些抗原的反应通过血脑屏障进入中枢神经系统，并引起炎症和组织损伤。在MS领域工作的研究人员面临的两个主要挑战是：1）定义使CNS高度倾向于自身免疫攻击的潜在机制，以及2）设计新的方法来将口服给药或注射的药物主要引导到CNS中，以增强其功效，同时最小化不良反应。我们假设CNS的血管内皮的特征在于独特的分子标记物，其促进致病性T细胞选择性迁移到靶器官（CNS）以及与炎症和组织损伤的诱导物/介质的细胞相互作用。与Erkki Ruoslahti博士（Sanford-Burnham Institute at拉霍亚，CA）合作，我们最近完成并发表了（PNAS 2011，108：12857）大鼠佐剂性关节炎模型中滑膜血管系统的研究。这项研究的目的是确定独特的 关节特异性血管标志物，使用体内富集来自噬菌体肽展示文库的克隆的创新方法。用于检测组织特异性标志物的噬菌体系统的优点在于，在预测血管内皮中的配体时没有先验偏差。此外，与抗体不同，噬菌体展示肽与靶分子的功能结构域相互作用。这种方法是由Ruoslahti博士开创的，他开发了血管“地址分子”或“zip代码”的概念。他的研究小组和其他研究人员已经检查了几个器官，除了发炎的中枢神经系统。我们假设EAE中脑和脊髓的血管内皮以独特的分子标记物为特征，并且通过这些标记物中的一种或多种靶向药物将下调CNS中的炎症和组织损伤，而不会产生过度的不良反应或全身毒性。我们基于MOG-EAE和PLP-EAE模型（并与Ruoslahti博士和EAE专家-Scott博士和Lees博士合作）的研究的目的如下：目的1，使用噬菌体肽展示文库方法的体内筛选来鉴定患有EAE的小鼠中发炎CNS的血管内皮的独特“地址分子”。目的2：利用CNS归巢肽作为靶向药物，将药物递送至CNS炎症和组织损伤部位。我们相信，这项研究的结果将促进我们对EAE/MS的发病机制的理解，并通过转化研究为设计新的肽导向的MS治疗方法铺平了道路。