A new molecular therapy against ocular herpes

一种针对眼部疱疹的新分子疗法

• 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
• 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

 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(申请人提供)：开发治疗眼病的新分子疗法已被国家眼科研究所确定为高度优先的研究目标。单纯疱疹病毒1型(HSV-1)感染眼睛，更具体地说是角膜，会导致上皮性或间质性角膜炎，并导致严重的炎症、疼痛、角膜混浊，在某些情况下还会失明。目前，这种眼部病毒感染仍然无法治愈，也不存在针对HSV-1的有效疫苗或预防性药物。许多现有的疱疹治疗方法，包括阿昔洛韦，都未能证明对眼睛有很高的疗效，因此并不是通常用于控制角膜感染的处方。对阿昔洛韦和类似的核苷类似物的耐药性也在上升，目前这些药物通常用于控制HSV-1。这项提议将使用角膜感染的小鼠模型同时测试两种针对HSV-1的替代分子疗法，并检查它们在控制症状和减少病毒在眼睛和三叉神经节传播的协同能力。第一种疗法源于我们的假设，即高亲和力抑制HSV-1包膜糖蛋白gD与其在角膜细胞表面的同源受体之间的相互作用可以产生强烈的预防和治疗效果。为了证明我们的假设，我们将测试一种RNA适配子，它以纳摩尔亲和力结合到GD上，并阻止HSV-1进入细胞并在细胞间传播的能力。GD/受体的相互作用是启动病毒进入和细胞间病毒转移的关键步骤，因为这些步骤是通过HSV-1糖蛋白gD、gB、Gh/g1和宿主细胞受体的协同和融合作用进行的。第二种分子疗法将起源于一种小分子，我们已经确定它是一种新的自噬助推器。由于HSV-1倾向于抑制自噬，适度增强自噬的分子可以显示出前所未有的前景，成为对抗病毒感染的高效抑制剂，它们作为局部药物对抗眼部感染的潜在用途可以产生非常有效的治疗方法。我们的初步结果表明，候选分子Iazovir可以增强自噬，进而导致病毒感染的显著丧失，包括几乎完全丧失病毒蛋白质和DNA。因此，这项提议的第二个目标是测试自噬增强剂将限制病毒生长并在角膜中显示出高疗效的假设。最终，我们将测试令人兴奋的可能性，即包含适体和Iazovir的联合疗法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病毒药物来对抗HSV-1感染。总之，我们建议测试一系列新的和有希望的分子治疗方法，并定义新的和更有效的方法来预防和控制眼部疱疹症状和疾病。