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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：
10612913
负责人：
KAMAL D MOUDGIL
金额：
$ 19.31万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612913
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 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 Lesion Libraries Ligands Liposomes Lymphoid Tissue Mediator 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 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.

自体免疫源性人后段葡萄膜炎是一种慢性疾病，可损害视力和视力