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.

描述（适用提供）：国家眼科研究所（National Eye Institute）已将开发新型眼病分子疗法确定为高优先研究目标。眼睛的感染，更具体地说，是由单纯疱疹病毒1型（HSV-1）引起的角膜会导致上皮或基质角膜炎，并导致严重的感染，疼痛，角膜云彩以及在某些情况下，在某些情况下会导致失明。目前，眼睛的这种病毒感染仍然无法治愈，有效的疫苗或预防剂对HSV-1不存在。许多现有的疱疹疗法在内，包括阿西克罗维尔（Acyclovir）无法表现出眼睛的效率很高，因此通常不适合控制角膜感染。耐药性的出现也在对阿昔洛韦和类似的核核苷类似物中的增长，目前用于控制HSV-1。该建议将使用角膜感染的鼠模型对HSV-1进行两种替代分子疗法，并检查其控制症状并减少病毒在眼睛以及三叉神经节上的传播的协同能力。第一种疗法将源于我们的假设，即高亲和力抑制HSV-1包膜糖蛋白GD与角膜细胞表面上的同源受体之间的相互作用可以产生强烈的预防性和治疗作用。为了证明我们的假设，我们将测试具有纳摩尔亲和力与GD结合的RNA APATMER，并阻止HSV-1进入细胞并从细胞到细胞扩散的能力。 GD/受体相互作用对于通过HSV-1糖蛋白GD，GB，GH/GH/GH/GH/GH/GH和宿主细胞受体的合作和融合作用进行了这些步骤OCCR，对于启动病毒进入和细胞间病毒转移至关重要。第二个分子疗法将起源于小分子，我们已将其确定为一种新型的自噬增强剂。由于HSV-1倾向于抑制自噬，因此适度增强自噬的分子可以表现出前所未有的前景，因为对病毒感染的高度抑制剂以及它们作为局部用作抗击眼感染的潜在使用可以产生非常有效的治疗。我们的初步结果表明，候选分子Iazovir增强了自噬，这又导致病毒感染的显着丧失，包括病毒蛋白和DNA几乎完全丧失。这是该提案的第二个目标是检验以下假设：自噬增强子将限制病毒的生长并证明角膜的高治疗效率。最终，我们将测试含有纠纷和Iazovir的组合疗法的令人兴奋的可能性，将产生强大的协同作用，包括更高的效率和更快的恢复时间，并定义了针对HSV-1感染的一系列新系列的抗病毒药物。包括，我们建议测试一系列新的和有望的分子治疗，并定义预防和控制眼疱疹症状和疾病的新的，更有效的方法。