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Principal Investigator: Renukaradhya Jayamurthy Gourapura
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $196,875
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
HEV is an emerged zoonotic pathogen. It infects nearly 20 million people annually, resulting in approximately
70,000 deaths yearly (2). In the U.S. the virus is believed to be endemic to swine herds with the virus making
its way into the commercial food supply (3, 4). Genotype 3 HEV is increasingly being seen as a pathogen
afflicting immunocompromised populations including those with HIV, cancer, and solid organ transplant (SOT)
recipients (5-9) and mortality can reach up to 30% in pregnant women (10) . Currently chronic HEV patients are
treated with reduction of immunosuppression risking organ rejection in SOT patients or with ribavirin therapy.
There have been reported incidents of ribavirin failure both during and post treatment leading to poor patient
outcomes and ribavirin is contraindicated during pregnancy (11-13). Additionally, single nucleotide variants
(SNVs) have been identified from ribavirin treatment failure that enhance HEV replication (14). New therapeutics
that specifically target HEV, are amenable to treating at risk populations, and prevent complications such as
organ rejection while combatting the emergence of new ribavirin resistant HEV strains are essential to improving
outcomes in HEV patients. Emerging technologies such as CRISPR/Cas13 which can specifically target and
degrade viral RNA along with liver targeting nanoparticles may be an ideal tool to treat HEV infections. Our
proposal will test rationally designed CRISPR RNA targets for efficacy using a newly developed cell culture
system from our laboratory followed by studies on efficient liver targeting of the therapeutic using cutting edge
lipid nanoparticle technologies in a natural host pig model. If successful, these new technologies could be placed
into clinical trials as new therapies to combat HEV infection.
Terms: <1-Beta-D-ribofuranosyl-1,2,4-triazolo-3-carboxamide><1-Beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide><A549><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><After Care><After-Treatment><Aftercare><Alveolar><Animal Model><Animal Models and Related Studies><Anti-viral Agents><Anti-viral resistance><CRISPR><CRISPR/Cas system><Cancers><Capsid><Capsid Proteins><Cell Body><Cell Culture System><Cell Culture Techniques><Cell Line><CellLine><Cells><Cessation of life><Chronic><Chronic Hepatitis><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Coat Proteins><Code><Coding System><DNA Helicases><DNA Unwinding Proteins><DNA unwinding enzyme><Death><Death Rate><Developing Countries><Developing Nations><Development><Disease><Disorder><EC 2.1.1><EC 2.7.7.48><Emergent Technologies><Emerging Technologies><Epithelial Cells><Escape Mutant><Evaluation><Failure><Family suidae><Food Supply><Formulation><Functional RNA><Genome><Genomic Segment><Genotype><Gestation><Groups at risk><HIV><Hepatic Cells><Hepatic Parenchymal Cell><Hepatitis E virus><Hepatocyte><Human><Human Cell Line><Human Immunodeficiency Viruses><Immunoblotting><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Individual><Infectious Pregnancy Complications><LAV-HTLV-III><Laboratories><Less-Developed Countries><Less-Developed Nations><Liver><Liver Cells><Lymphadenopathy-Associated Virus><Malignant Neoplasms><Malignant Tumor><Methyltransferase><Modern Man><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Nucleic Acids><ORFs><Open Reading Frames><Organ><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><People at risk><Persons><Persons at risk><Pigs><Population><Populations at Risk><Pregnancy><Pregnant Women><Protein Coding Region><Proteins><Public Health><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><RNA><RNA Gene Products><RNA Replicase><RNA Viruses><RNA-Dependent RNA Polymerase><RNA-Directed RNA Polymerase><Regulatory Regions><Reporting><Resistance><Ribavirin><Ribonucleic Acid><Ribovirin><Risk><Risk Factors><Sampling><Single Base Polymorphism><Single Nucleotide Polymorphism><Site><Solid><Strains Cell Lines><Suidae><Swine><System><Technology><Testing><Therapeutic><Therapeutic Uses><Third-World Countries><Third-World Nations><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transmission><Treatment Failure><Tribavirin><Under-Developed Countries><Under-Developed Nations><Untranslated RNA><Vaccines><Validation><Viral Coat Proteins><Viral Diseases><Viral Genome><Viral Outer Coat Protein><Viral Pathogenesis><Viral hepatitis><Virus><Virus Diseases><Virus Replication><Virus-HIV><Western Blotting><Western Immunoblotting><Zoonoses><Zoonotic><Zoonotic Infection><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral resistant><anti-viral therapeutic><anti-virals><cell culture><cell cultures><cell type><chronic infection><combat><cultured cell line><determine efficacy><develop a vaccine><develop vaccines><developing country><developing nation><development of a vaccine><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><expectant mother><expecting mother><genetic regulatory element><genome segment><genomic region><global health><helicase><hepatic body system><hepatic organ system><hepatitis virus infection><hepatoma cell><human pathogen><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressed patient><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><improved outcome><innovate><innovation><innovative><insight><lipid based nanoparticle><lipid nanoparticle><malignancy><methylase><model of animal><mortality><mortality rate><mortality ratio><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new technology><new therapeutics><new therapy><next generation therapeutics><noncoding><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel technologies><novel therapeutics><novel therapy><nuclease><nucleic acid delivery><nucleic acid therapy><nucleic acid-based therapeutics><organ rejection><organ transplant patient><organ transplant recipient><organ transplant rejection><overexpress><overexpression><pathogen><patient oriented outcomes><persistent infection><pig model><piglet model><porcine><porcine model><post treatment><pregnancy infection><pregnant mothers><prevent><preventing><promoter><promotor><protein blotting><qRTPCR><rational design><remediation><resistant><response><single nucleotide variant><stem><suid><swine model><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic nucleic acids><therapeutically effective><therapy failure><tool><transmethylase><transmission process><uptake><vaccine development><validations><viral RNA><viral infection><viral multiplication><viral replication><viricidal><virucidal><virucide><virus RNA><virus culture><virus genome><virus infection><virus multiplication><virus pathogenesis><virus-induced disease>