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

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，涉及中枢神经系统（CNS）的炎症和损伤。多种自身抗原，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）都与ms的发病机制有关。T细胞对这些抗原产生反应，通过血脑屏障进入中枢神经系统，引起炎症和组织损伤。在多发性硬化症领域工作的研究人员面临的两个主要挑战是：1)确定使中枢神经系统高度容易受到自身免疫攻击的潜在机制；2)设计新的方法，使口服或注射药物主要进入中枢神经系统，以提高其疗效，同时最大限度地减少不良反应。我们假设中枢神经系统的血管内皮具有独特的分子标记，可以促进致病性T细胞选择性迁移到靶器官（中枢神经系统），并与炎症和组织损伤的诱导剂/介质相互作用。我们与Erkki Ruoslahti博士（加州La Jolla的Sanford-Burnham研究所）合作，最近完成并发表了大鼠佐剂关节炎模型中滑膜血管系统的研究（PNAS 2011, 108: 12857）。该研究的目的是确定独特的

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.