Identification of eye-homing peptides and their use for targeted liposomal drug delivery in posterior uveitis

眼归巢肽的鉴定及其在后葡萄膜炎靶向脂质体药物递送中的应用

基本信息

批准号：
10452321
负责人：
KAMAL D MOUDGIL
金额：
$ 23.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452321
关键词：
Address Adjuvant Arthritis Adverse effects Affect Alzheimer&apos s Disease Amino Acids Animal Cancer Model Animals Antibodies Antigens Arthritis Attention Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Bacteriophages Binding Biological Availability Biology Blindness Blood Vessels Blood-Retinal Barrier Cells Characteristics Choroid Chronic Disease Code Collaborations Cyclic Peptides Cysteine Disease Drug Delivery Systems Drug Targeting Encapsulated Endothelium Experimental Autoimmune Encephalomyelitis Eye Eye diseases Gene Expression Profiling Hemorrhage Heterogeneity Home Homing Human Hypoxia Immune Immunization Individual Inflammation Inflammation Mediators Joints Lead Lesion Libraries Ligands Liposomes Lymphoid Tissue Mediator of activation protein Methodology Methods Methotrexate Modeling Molecular Molecular Profiling Multiple Sclerosis Neural Retina Organ Oxygen Pathogenesis Pathogenicity Pathology Peptide Library Peptide Phage Display Library Peptides Peripheral Pharmaceutical Preparations Pharmacodynamics Posterior Uveitis Procedures Process Proteins Publishing Rattus Reporting Retina Retinal Detachment Retinal Diseases Rheumatoid Arthritis Rodent Site Specificity T-Lymphocyte Testing The Sun Tissues Topical application Toxic effect Uvea Uveitis Vascular Endothelium Visual impairment Work anterior chamber autoimmune pathogenesis autoimmune uveitis autoreactive T cell design human model improved in vivo innovation interstitial retinol-binding protein intravitreal injection medication safety migration molecular marker nanoparticle neoplastic cell novel novel therapeutics posterior eyeball chamber protein aminoacid sequence screening systemic toxicity tool trafficking tumor

项目摘要

Human posterior segment uveitis of autoimmune origin is a chronic disease that can impair vision and result in blindness. A variety of autoantigens, including interphotoreceptor retinoid binding protein (IRBP), have been implicated in uveitis pathogenesis. The T cells reactive against these antigens access the eye through the blood-retinal barrier and cause local inflammation and tissue damage. Two of the main challenges in non- infectious posterior uveitis are – 1) to define the molecular changes induced during uveitis in endothelium of the choroidal and retinal vasculature, and 2) to devise novel ways to direct the systemically-administered drugs primarily into the eye to enhance their efficacy but minimize adverse effects. We hypothesize that the vascular endothelium of the eye in uveitis is characterized by unique molecular markers that facilitate both selective migration of the pathogenic T cells into the target organ and cellular interaction with the inducers/ mediators of inflammation and tissue damage. Accordingly, the identification of peptide ligands (by phage peptide library screening) that interact with such markers would be invaluable tools to study disease pathogenesis. Furthermore, these peptide ligands can be exploited for targeted drug delivery to the eye with the objective of enhancing efficacy, but reducing systemic toxicity of those drugs. In collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham, La Jolla), who pioneered the concept of vascular ‘address molecules’ or ‘zip codes’, we published a study on the molecular profiling of the synovial vasculature in adjuvant arthritis in rats (PNAS 2011). We identified unique joint-homing peptide ligands using an innovative approach of ex vivo/ in vivo enrichment of clones from a phage peptide-display library. Recently, we also reported CNS-homing peptides in the EAE model of human multiple sclerosis. The advantage of using phages to detect tissue-specific markers is that there is no a priori bias in predicting the peptide sequences/motifs. And, unlike antibodies, phage peptides interact with functional domains of target molecules. We now plan to apply this methodology to rat experimental autoimmune uveitis (EAU). The aims of our study in collaboration with experts in EAU (Dr. Caspi and Dr. Sun), [in vascular biology (Dr. Teesalu from Ruoslahti group), and in pharmacodynamics (Dr. Swaan)] are: Aim 1. To identify peptide ligands homing to the diseased eye in EAU using the ex vivo/ in vivo screening of phage peptide library. (a) To identify unique peptide-encoding phages that home to the vasculature and retina of the diseased eye; and (b) to determine the relative specificity of select phages/ peptides [for other tissues within the eye as well as other organs in EAU versus control (healthy/EAE) rats.] Aim 2. To use the eye-homing peptides for targeted drug delivery to the diseased sites in EAU. To use a specific peptide to guide liposomes encapsulating a drug (e.g., methotrexate) [to the diseased sites in eyes in EAU, and compare the pharmacodynamics and safety of that drug] with that using plain liposomes or free drug. The results would advance understanding of pathogenesis of human uveitis and designing of novel therapies.

自身免疫性起源的人类后节葡萄膜炎是一种慢性疾病，可以损害视力和导致失明。多种自身抗原，包括protoreceptor类维生素类似结合蛋白（IRBP），具有在葡萄膜炎发病机理中隐含。 T细胞反应针对这些抗原通过血视网膜屏障并引起局部炎症和组织损伤。非 - 传染性后葡萄膜炎是 - 1）定义在葡萄膜炎期间诱发的分子变化脉络膜和视网膜脉管系统，以及2）设计新颖的方法来指导系统化的药物首先，以提高其有效性，但最大程度地减少不良影响。我们假设血管葡萄膜炎中眼内皮的特征是独特的分子标记物，可促进既有选择性病原T细胞迁移到靶器官，并与影响者/介体的细胞相互作用炎症和组织损伤。彼此之间，鉴定肽配体（通过噬菌体肽库与此类标记相互作用的筛选将是研究疾病发病机理的宝贵工具。此外，可以探索这些胡椒配体以靶向药物的目的，目的是提高效率，但会降低这些药物的全身毒性。与Erkki Ruoslahti博士合作（La Jolla Sanford-Burnham），他启用了血管“地址分子”或“邮政编码”的概念发表了一项关于大鼠调节性关节炎滑膜脉管系统分子分析的研究（PNAS 2011）。我们使用Ex Vivo/ Intente的创新方法鉴定了独特的联合居住肽配体从噬菌体肽 - 播放库中富集克隆。最近，我们还报道了中枢神经系统融合的肽人类多发性硬化症的EAE模型。使用噬菌体检测组织特异性标记的优点是预测胡椒序列/基序没有先验偏见。而且，与抗体不同，噬菌体肽与靶分子的功能结构域相互作用。我们现在计划将这种方法应用于老鼠实验性自身免疫性葡萄膜炎（EAU）。我们研究的目的与EAU专家合作（Caspi博士和Sun博士），[in Vascular Biology（Ruoslahti Group的Teesalu博士）和药效学（Swaan博士）] 是：目标1。使用ex ex -ex -invo/ in Vivo识别向EAU中解散的眼睛的肽配体筛选噬菌体胡椒库。（a）确定家乡的独特肽编码噬菌体脉管和视网膜的视网膜；（b）确定选择噬菌体/的相对特异性肽[对于眼睛内的其他组织以及EAU与对照（健康/EAE）大鼠的其他器官。] AIM 2。要使用令人眼花pec乱的肽将靶向药物递送到EAU的患病部位。使用一种特定的肽来指导脂质体封装药物的脂质体（例如，方法邻二酸）[ EAU，并将该药物的药物脱脂动力学和安全性与使用普通脂质体或免费药物进行比较。结果将提高人们对人葡萄膜炎的发病机理的了解和新型疗法的设计。