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.

由疱疹病毒引起的感染相关失明是美国视力丧失的主要原因。 一线疗法包括使用核苷类似物，例如抑制病毒胸苷的阿昔洛韦 限制病毒 DNA 复制的激酶。然而，耐药性的出现和角膜强度的缺乏 生物利用度使得开发替代疗法成为当务之急。我们最近发现 疱疹病毒（以 1 型单纯疱疹病毒 (HSV-1) 为代表）通过一种新机制， 在角膜上皮中繁殖。我们已经证明内质网（ER）定位的宿主蛋白 环腺苷 3′,5′-单磷酸 (cAMP) 反应元件结合蛋白 3 (CREB3) 对于 HSV-1 复制。我们的发现改变了目前的认识，即 CREB3 只是 HSV-1 的细胞同源物 副总裁16。我们证明它是一种重要的促病毒因子，可用于产生新的疗法 对抗 HSV 感染。我们首次表明它通过化学伴侣 4- 进行调节 苯丁酸钠（Na-PBA），可以缓解内质网应激，降低CREB3表达并抑制病毒 复制。 PBA 目前被批准用于治疗尿素循环障碍。我们的翻译结果得到以下支持 强有力的小鼠体内数据表明 Na-PBA 的抗病毒功效和局部剂量安全性。由于高 与 Na-PBA 给药相关的钠负荷、其难吃性和无法充分渗透 通过局部给药，通过角膜上皮，我们开发了各种无钠PBA 纳米制剂克服了与口服和局部给药 Na-PBA 相关的局限性。目的 该 R24 应用程序旨在在两种动物模型中生成临床前数据，以支持 IND 申请 重新利用 PBA 治疗眼部 HSV 感染。这将通过 3 个深思熟虑、详尽的具体措施来实现 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用药的安全性 提供Na-PBA溶液和各种无钠PBA纳米制剂。此外，我们还将 确定 Na-PBA 和无钠 PBA 纳米制剂的口服和局部以及口服抗病毒功效 眼部 HSV-1 感染的小鼠模型。第二个目标将使用最有效的口服和局部用药 制剂并在原发和再激活的豚鼠和兔模型中测试其安全性、PK 和功效 眼部 HSV-1 感染。最后目标 3，我们将研究 Na-PBA 和无钠 PBA 的潜力 与现有抗病毒疗法协同作用的制剂，以确定其作为附加疗法的潜力 现有的治疗方法。后者很可能而且意义重大，因为 PBA 是一种通过缓解 ER 发挥作用的稀有药物 应激并帮助宿主细胞对病毒感染做出反应，从而减少出现的机会 病毒抵抗力。我们组建了一支多学科团队，包括科学家、临床医生、药物 开发和翻译专家可以帮助我们了解必要的 FDA 指南。 PBA 具有 有潜力很快成为现有眼部抗病毒药物的安全有效替代品。