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：
9313256
负责人：
DEEPAK SHUKLA
金额：
$ 39.98万
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 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313256
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 Development Disease Drug Kinetics Drug resistance Enhancers Epithelial Eye Eye Infections Eye diseases Glycoproteins Goals Growth Herpesviridae Infections Herpesvirus 1 Herpetic Keratitis Immunohistochemistry In Situ Hybridization In Vitro Infection Inflammation Keratitis Lead Macular degeneration Measures Modernization Molecular National Eye Institute Natural Immunity Nature Pain 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 nanomolar novel novel diagnostics nucleoside analog ocular pain ocular surface pegaptanib prevent prophylactic public health relevance 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.

描述（由申请人提供）：国家眼科研究所已将开发针对眼部疾病的新型分子疗法确定为 1 型单纯疱疹病毒（HSV-）感染眼睛（更具体地说是角膜）的高度优先研究目标。 1) 导致上皮或基质角膜炎，并导致严重炎症、疼痛、角膜浑浊，在某些情况下甚至导致失明。目前，这种眼睛病毒感染仍然无法治愈，也没有有效的疫苗或药物。目前尚不存在针对 HSV-1 的预防药物，包括阿昔洛韦在内的许多现有疱疹治疗药物未能在眼部表现出高效功效，因此通常不用于控制角膜感染。针对阿昔洛韦和类似核苷的耐药性也在不断增加。该提案将使用小鼠角膜感染模型同时测试两种针对 HSV-1 的替代分子疗法，并检查它们控制症状和减少症状的协同能力。第一种疗法将源于我们的假设，即对 HSV-1 包膜糖蛋白 gD 与其在角膜细胞表面上的同源受体之间的相互作用进行高亲和力抑制可以产生强效的预防作用。为了证明我们的假设，我们将测试一种 RNA 适体，该适体以纳摩尔亲和力与 gD 结合，并阻止 HSV-1 进入细胞并在细胞间传播的能力。 gD/受体相互作用对于启动病毒进入和细胞间病毒转移至关重要，因为这些步骤是通过 HSV-1 糖蛋白 gD、gB、gH/gL 和宿主细胞受体的协作和融合作用而发生的。源自一种小分子，我们将其鉴定为新型自噬增强剂，由于 HSV-1 倾向于抑制自噬，因此适度增强自噬的分子可以作为高效的病毒抑制剂展现出前所未有的前景。我们的初步结果表明，候选分子 Iazovir 可以增强自噬，从而导致病毒感染的显着消失，包括几乎完全消失。因此，该提案的第二个目标是检验自噬增强剂将限制病毒生长并在角膜中表现出高治疗效果的假设，最终，我们将测试包含这种成分的联合疗法的可能性。适体和Iazovir 将产生强大的协同效应，包括更高的疗效和更快的恢复时间，并定义一系列新的抗 HSV-1 感染的抗病毒药物。总之，我们建议测试一系列新的、有前途的分子治疗方法，并确定新的、更有效的方法。预防和控制眼部疱疹症状和疾病。