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Principal Investigator: Abhijit A Date
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $1,094,442
Funding agency: National Eye Institute
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.
Terms: <3'5'-cyclic ester of AMP><Acicloftal><Aclovir><Acycloguanosine><Acyclovir><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Animal Model><Animal Models and Related Studies><Anti-viral Agents><Anti-viral Therapy><Basal Transcription Factor><Basal transcription factor genes><Behavioral><Binding Proteins><Bioavailability><Biological Availability><Blindness><Cargosil><Cavia><Cell Body><Cell Death><Cells><Chaperone><Chemicals><Cornea><Cyclic AMP><Cyclicity><DNA Replication><DNA Synthesis><DNA biosynthesis><Data><Deoxypyrimidine Kinase><Deoxythymidine Kinase><Development><Domestic Rabbit><Dose><Drug Kinetics><Drug resistance><Drug usage><Drugs><ER stress><Early-Stage Clinical Trials><Endoplasmic Reticulum><Ensure><Ergastoplasm><Eye Infections><FDA approved><Film><Formulation><Frequencies><GeneHomolog><General Transcription Factor Gene><General Transcription Factors><Goals><Guidelines><Guinea Pigs><Guinea Pigs Mammals><HSV><HSV-1><HSV1><Health><Herpes Simplex Keratitis><Herpes Simplex Type 1><Herpes Simplex Virus><Herpes Simplex Virus 1><Herpes Simplex Virus Type 1><Herpes infection><Herpes labialis Virus><Herpesviridae><Herpesviridae Infections><Herpesviridae disease><Herpesvirus 1><Herpesvirus Infections><Herpesviruses><Herpetic Keratitis><Homolog><Homologous Gene><Homologue><Human><Infection><Ligand Binding Protein><Ligand Binding Protein Gene><Medication><Mice><Mice Mammals><Modality><Modeling><Modern Man><Molecular Chaperones><Mucous body substance><Mucus><Murine><Mus><Na element><Ocular Herpes Simplex><Ocular Herpetic Disease><Ocular Infections><Oral><Orphan Drugs><Oryctolagus cuniculus><PK/PD><Pathology><Pathway interactions><Penetration><Periodicity><Permeability><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phase 1 Clinical Trials><Phase I Clinical Trials><Physiologic Availability><Poloxamers><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Poviral><Process><Production><Protein Binding><Proteins><R24><RNA Interference><RNA Silencing><RNAi><Rabbits><Rabbits Mammals><Response Elements><Rhythmicity><Safety><Scientist><Sequence-Specific Posttranscriptional Gene Silencing><Simplexvirus><Sodium><Sodium 4-phenylbutyrate><Sodium Salt 4-Phenylbutyric Acid><Sodium phenylbutyrate><Testing><Therapeutic><Thymidine Kinase><Time><Topical Drug Administration><Topical application><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Translations><United States><Urea cycle disorders><VP 16><VP16><Viral><Viral Diseases><Viral Eye Infections><Viral Gene Products><Viral Gene Proteins><Viral Ocular Infections><Viral Proteins><Virorax><Virus Diseases><Virus Replication><Work><Zovirax><adenosine 3'5' monophosphate><administer topically><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral therapeutic><anti-virals><apply topically><bound protein><cAMP><corneal><corneal epithelial><corneal epithelium><corneal herpetic disease><deliver topically><developmental><dosage><drug development><drug resistant><drug use><drug/agent><efficacy study><emergent virus><emerging virus><endoplasmic reticulum stress><herpes simplex i><herpes simplex virus keratitis><herpes simplex-1><herpes virus><hsv keratitis><improved><in vivo><intraperitoneal><meeting><meetings><model of animal><mouse model><mucous><multidisciplinary><murine model><nano formulation><nanoformulation><necrocytosis><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nucleoside analog><ocular herpes><ocular surface><pathway><pharmacokinetics and pharmacodynamics><phase I protocol><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><resistance to Drug><resistant to Drug><response><safety study><synergism><topical administration><topical anti-viral><topical antiviral><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><trait><transcription factor><translation><translation strategy><translational approach><translational strategy><treat topically><viral DNA><viral emergence><viral infection><viral infectious disease treatment><viral multiplication><viral replication><viral resistance><virus DNA><virus infection><virus multiplication><virus protein><virus resistance><virus-induced disease><vision loss><visual loss>