Alleviation of ER stress as a translational strategy to curb ocular viral infections

缓解内质网应激作为遏制眼部病毒感染的转化策略

• 批准号: 10392735
• 负责人: Abhijit A Date
• 金额: $ 108.12万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392735
• 关键词: Acyclovir; Animal Model; Antiviral Agents; Antiviral Therapy; Behavioral; Biological Availability; Blindness; CREB3 gene; Cavia; Cell Death; Cells; Chemicals; Clinical; Complement; Cornea; Cyclic AMP; DNA biosynthesis; Data; Development; Dose; Drug Kinetics; Drug resistance; Drug usage; Endoplasmic Reticulum; Ensure; Eye Infections; FDA approved; Film; Formulation; Frequencies; Goals; Guidelines; Health; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Herpetic Keratitis; Homologous Gene; Human; Infection; Modality; Modeling; Molecular Chaperones; Monoclonal Antibody R24; Mucous body substance; Mus; Oral; Orphan Drugs; Oryctolagus cuniculus; Pathology; Pathway interactions; Periodicity; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Poloxamers; Process; Production; Proteins; RNA Interference; Safety; Scientist; Simplexvirus; Sodium; Sodium phenylbutyrate; Testing; Therapeutic; Thymidine Kinase; Time; Topical application; Translating; Translations; United States; Urea cycle disorders; VP 16; Viral; Viral Eye Infections; Viral Proteins; Virus Diseases; Virus Replication; Work; anti-viral efficacy; corneal epithelium; dosage; drug development; efficacy study; endoplasmic reticulum stress; exhaustion; improved; in vivo; intraperitoneal; meetings; mouse model; multidisciplinary; nanoformulation; novel therapeutics; nucleoside analog; ocular surface; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; prevent; response; safety study; topical antiviral; trait; transcription factor; translational approach; viral DNA; viral resistance

Infection-associated blindness caused by herpesviruses is a leading cause of vision loss in the United States. Frontline therapies include the use of nucleoside analogs such as acyclovir which inhibit the viral thymidine kinase to restrict viral DNA replication. However, emergence of drug resistance and lack of strong corneal bioavailability have made it an urgent priority to develop alternative therapeutics. We have recently discovered a new mechanism through which herpesviruses, exemplified by herpes simplex virus type-1 (HSV-1), propagate in the corneal epithelium. We have shown that endoplasmic reticulum (ER)-localized host protein cyclic adenosine 3′,5′-monophosphate (cAMP) response element-binding protein 3 (CREB3) is essential to HSV-1 replication. Our findings shift the current understanding that CREB3 is only a cellular homolog of HSV-1 VP16. We showed that it is an important pro-viral factor that can be exploited to generate novel therapeutics against HSV infections. We for the first time showed that its modulation via a chemical chaperone 4- phenylbutyrate sodium (Na-PBA), can alleviate, ER stress, reduce CREB3 expression and inhibit viral replication. PBA is currently approved to treat urea cycle disorder. Our translational results are supported by strong in vivo murine data that suggests antiviral efficacy and topical dosage safety of Na-PBA. Due to the high sodium burden associated with Na-PBA administration, its unpalatability, and inability to penetrate sufficiently through corneal epithelium upon topical administration, we have developed various sodium-free PBA nanoformulations to overcome limitations associated with oral and topical delivery of Na-PBA. The purpose of this R24 application is to generate preclinical data in two animal models that support an IND application for repurposing PBA to treat ocular HSV infection. This will be achieved via 3 well thought, exhaustive specific aims. In the first aim, we will evaluate dose-dependent pharmacokinetics, and safety of orally and topically delivered Na-PBA solution and various sodium-free PBA nanoformulations. Furthermore, we will also determine oral and topical, and oral antiviral efficacy of Na-PBA and sodium-free PBA nanoformulations in murine models of ocular HSV-1 infection. The second aim will use the most effective oral and topical formulation(s) and test their safety, PK, and efficacy in guinea pig and rabbit models of primary and reactivated ocular HSV-1 infection. Finally aim 3, we will investigate the potential of Na-PBA and sodium-free PBA formulations to synergize with existing antiviral therapies to determine their potential as an add-on modality to the existing treatment. The latter is likely and significant since PBA is a rare drug that works via alleviating ER stress and aiding the host cell’s response to viral infection, and thereby reducing the chance for emergence of viral resistance. We have assembled a multidisciplinary team including scientists, clinicians, drug development and translation experts who can help us navigate through requisite FDA guidelines. PBA has the potential to become a safe and efficacious alternative to existing ocular antivirals very quickly.

疱疹病毒引起的与感染相关的失明是美国视力丧失的主要原因。 前线疗法包括使用核外侧类似物，例如acyclovir，抑制病毒胸苷 激酶限制病毒DNA复制。但是，耐药性紧急和缺乏强烈的角膜 生物利用度使得开发替代疗法的重点是重中之重。我们最近发现了 一种新机制，疱疹病毒以单纯疱疹病毒类型1（HSV-1）为例， 在角膜上皮中传播。我们已经表明内质网（ER）局部宿主蛋白 环状腺苷3'，5'-单磷酸（CAMP）反应元件结合蛋白3（CREB3）对于必不可少 HSV-1复制。我们的发现改变了当前的理解，即CREB3只是HSV-1的细胞同源物 VP16。我们表明，这是一个重要的促病毒因素，可以探索以生成新的治疗 反对HSV感染。我们首次表明其通过化学伴侣4-的调节 苯丁酸钠钠（Na-PBA）可以减轻，ER应力，降低CREB3表达并抑制病毒 复制。 PBA目前被批准用于治疗尿素周期障碍。我们的翻译结果得到了支持 强烈的体内鼠数据表明Na-PBA的抗病毒效率和局部剂量安全性。由于高 伯恩钠与NA-PBA给药相关，其不可观性和无法正确穿透 通过局部给药后的角膜上皮，我们开发了各种无钠的PBA 纳米制剂以克服与Na-PBA的口服和局部递送相关的限制。目的 此R24应用程序是在两个动物模型中生成临床前数据，这些模型支持IND应用 重新利用PBA治疗眼HSV感染。这将通过3个经过思考，详尽的特定于 目标。在第一个目标中，我们将评估剂量依赖性药代动力学以及口服和局部的安全性 递送NA-PBA溶液和各种无钠的PBA纳米形式。此外，我们还将 确定Na-PBA和无钠PBA纳米成型的口服和局部和抗病毒效率 眼HSV-1感染的鼠模型。第二个目标将使用最有效的口头和局部 配方奶粉并测试其安全性，PK和效率 眼HSV-1感染。最终AIM 3，我们将研究Na-PBA和无钠PBA的潜力 公式与现有抗病毒疗法协同作用，以确定其潜力作为附加形式的潜力 现有的治疗方法。后者可能和重要 压力和帮助宿主细胞对病毒感染的反应，从而减少了出现的机会 病毒抗性。我们组建了一个多学科团队，包括科学家，临床医生，毒品 可以帮助我们浏览必要的FDA指南的开发和翻译专家。 PBA有 可能很快成为现有眼病病毒的安全有效替代品的潜力。