R24EY033598

Alleviation of ER Stress as a Translational Strategy to Curb Ocular Viral Infections

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, the 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 three 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 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, 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.

University Of Illinois

1) TO SUPPORT EYE AND VISION RESEARCH PROJECTS THAT ADDRESS THE LEADING CAUSES OF BLINDNESS AND IMPAIRED VISION IN THE U.S. THESE INCLUDE RETINAL DISEASES, CORNEAL DISEASES, CATARACT, GLAUCOMA AND OPTIC NEUROPATHIES, STRABISMUS, AMBLYOPIA, AND LOW VISION AND BLINDNESS REHABILITATION. 2) TO INCREASE UNDERSTANDING OF THE NORMAL DEVELOPMENT AND FUNCTION OF THE VISUAL SYSTEM IN ORDER TO BETTER PREVENT, DIAGNOSE, AND TREAT SIGHT-THREATENING CONDITIONS, AND, TO ENHANCE THE REHABILITATION, TRAINING, AND QUALITY OF LIFE OF INDIVIDUALS WHO ARE PARTIALLY-SIGHTED OR BLIND. 3) TO SUPPORT A BROAD PROGRAM OF BASIC VISION RESEARCH THROUGH GRANTS AND COOPERATIVE AGREEMENTS, TO ENCOURAGE HIGH QUALITY CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS, OTHER EPIDEMIOLOGICAL STUDIES, AND HEALTH SERVICES RESEARCH, TO ENCOURAGE RESEARCH TRAINING AND CAREER DEVELOPMENT IN THE SCIENCES RELATED TO VISION, AND TO SPONSOR SCIENTIFIC WORKSHOPS IN HIGH PRIORITY RESEARCH AREAS TO ENCOURAGE EXCHANGE OF INFORMATION AMONG SCIENTISTS. 4) SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENCOURAGE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.867 - Vision Research

National Eye Institute (NEI) [HHS - NIH]

Illinois United States

State-Wide

NEI Translational Research Program (TRP) on Therapy for Visual Disorders (R24 Clinical Trial Optional) (PAR-20-319)

Amendment Since initial award the total obligations have increased 300% from $1,081,173 to $4,325,995.