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（由申请人提供）：国家眼科研究所已将开发用于眼科疾病的新型分子疗法确定为高度优先的研究目标。1型单纯疱疹病毒（HSV-1）对眼睛，更具体地说是角膜的感染导致上皮或基质角膜炎，并导致严重的炎症、疼痛、角膜混浊，在某些情况下导致失明。目前，这种眼睛的病毒感染仍然是不可治愈的，并且不存在针对HSV-1的有效疫苗或预防剂。许多现有的疱疹治疗，包括阿昔洛韦未能证明在眼睛中的高疗效，因此通常不用于控制角膜感染。对目前一般用于控制HSV-1的阿昔洛韦和类似核苷类似物的耐药性也在增加。该提案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，并检查其控制症状和减少病毒在眼睛和三叉神经节中传播的协同能力。第一种疗法将源于我们的假设，即HSV-1包膜糖蛋白gD与角膜细胞表面上其同源受体之间的相互作用的高亲和力抑制可以产生强的预防和治疗效果。为了证明我们的假设，我们将测试RNA适体，其以纳摩尔亲和力结合gD并阻断HSV-1进入细胞和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是必不可少的，因为这些步骤通过HSV-1糖蛋白gD、gB、gH/gL和宿主细胞受体的协同和融合作用发生。第二种分子疗法将来自一种小分子，我们已经确定它是一种新型的自噬促进剂。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，作为对抗病毒感染的高效抑制剂，并且它们作为对抗眼部感染的局部药物的潜在用途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，这反过来又导致病毒感染的显著损失，包括病毒蛋白和DNA的几乎完全损失。因此，该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高治疗功效的假设。最终，我们将测试一种令人兴奋的可能性，即含有适体和Iazovir的联合治疗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和有前途的分子治疗，并确定新的和更有效的方法来预防和控制眼部疱疹症状和疾病。