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: 10576905
• 负责人: Abhijit A Date
• 金额: $ 106.13万
• 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/10576905
• 关键词: Acyclovir; Animal Model; Antiviral Agents; Antiviral Therapy; Behavioral; Binding Proteins; Biological Availability; Blindness; Cavia; Cell Death; Cells; Chemicals; 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; Mucous body substance; Mus; Oral; Orphan Drugs; Oryctolagus cuniculus; Pathology; Pathway interactions; Penetration; Periodicity; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Poloxamers; Process; Production; Proteins; R24; RNA Interference; Response Elements; 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; 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; synergism; 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.

在美国，由疱疹病毒引起的感染相关性失明是导致视力丧失的主要原因。