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A new molecular therapy against ocular herpes

一种针对眼部疱疹的新分子疗法

基本信息

批准号：
8962978
负责人：
DEEPAK SHUKLA
金额：
$ 39.95万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8962978
关键词：
Acute Acute Myelocytic Leukemia Acyclovir Affinity Antiviral Agents Area Autophagocytosis Binding Biochemical Biological Assay Biological Availability Blindness Cell Culture Techniques Cell surface Cells Choroidal Neovascularization Clinical Clinical Trials Combined Modality Therapy Cornea Corneal pain Development Disease Drug Kinetics Drug resistance Enhancers Epithelial Eye Eye Infections Eye diseases Glycoproteins Goals Growth Herpesvirus 1 Herpetic Keratitis Immunohistochemistry In Situ Hybridization In Vitro Infection Inflammation Keratitis Lead Macular degeneration Modeling Molecular Mus National Eye Institute Natural Immunity Nature Patients Permeability Pharmaceutical Preparations Physicians Prevention therapy Prophylactic treatment Pyrrolidines RNA Receptor Cell Recovery Recurrence Refractory Disease Regulation Research Research Priority Resistance Scientist Series Simplexvirus Solubility Structure of trigeminal ganglion Symptoms Testing Therapeutic Therapeutic Effect Thiophenes Thrombus Time Topical agent Toxic effect Toxicology Treatment Efficacy Vaccines Validation Viral Viral Eye Infections Viral Proteins Virus Virus Diseases Virus Shedding acute coronary syndrome aptamer aqueous base chemokine combat cytokine drug development effective therapy improved in vivo inhibitor/antagonist mouse model novel novel diagnostics nucleoside analog ocular pain ocular surface pegaptanib prevent prophylactic public health relevance pyrrolidine receptor response small molecule tool treatment effect viral DNA

项目摘要

DESCRIPTION (provided by applicant): Developing novel molecular therapies for eye diseases has been identified as a high priority research goal by the National Eye Institute. Infection of the eye and more specifically, the cornea, by herpes simplex virus type-1 (HSV-1) results in epithelial or stromal keratitis and leads to severe inflammation, pain, corneal cloudiness and, in some cases, blindness. At present, this viral infection of the eye remains incurable and effective vaccines or prophylactic agents against HSV-1 do not exist. Many existing herpetic treatments including acyclovir fail to demonstrate high efficacy in the eye, and are therefore not commonly prescribed for controlling corneal infections. Emergence of drug resistance is also on the rise against acyclovir and similar nucleoside analogs that are currently used to control HSV-1 in general. This proposal will simultaneously test two alternate molecular therapies against HSV-1 using a murine model of corneal infection and examine their synergistic ability to control symptoms and reduce the spread of the virus in the eye and also to the trigeminal ganglion. The first therapy will originate from our hypothesis that high affinity inhibition of the interaction between HSV-1 envelope glycoprotein gD and its cognate receptors on the corneal cell surface can generate strong prophylactic as well as therapeutic effects. To prove our hypothesis we will test an RNA aptamer that binds to gD with nanomolar affinity and blocks the ability of HSV-1 to enter cells and spread from cell-to-cell. The gD/receptor interaction is essential to initiate viral entry and cell-to-cell virus transfer as these steps occr through the cooperative and fusogenic action of HSV-1 glycoproteins gD, gB, gH/gL and host cell receptors. The second molecular therapy will originate from a small molecule, which we have identified as a novel autophagy booster. Since HSV-1 tends to suppress autophagy, the molecules that moderately augment autophagy can show unprecedented promise as highly effective inhibitors against viral infections and their potential use as a topical agent to combat ocular infections can yield a very effective therapy. Our preliminary results show that the candidate molecule, Iazovir, enhances autophagy, which in turn, results in a significant loss of viral infection including an almost complete loss of viral proteins and DNA. Thus, the second goal of this proposal is to test the hypothesis that an autophagy enhancer will limit virus growth and demonstrate high therapeutic efficacy in the cornea. Ultimately, we will test the exciting possibility that a combination therapy containing the Aptamer and Iazovir will generate strong synergistic effects including higher efficacy and faster recovery time and define a new series of antiviral drugs against HSV-1 infection. To conclude, we propose to test a series of new and promising molecular treatments and define new and more effective ways to prevent and control ocular herpes symptoms and diseases.