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Principal Investigator: Bryan Berube
Organization: HDT BIO CORPORATION
Fiscal Year: 2022
Award: $299,984
Funding agency: National Center for Immunization and Respiratory Diseases
Project summary:
Despite widespread availability of vaccines, the SARS-CoV-2 pandemic continues to wreak havoc on our
healthcare system and our economy. High numbers of unvaccinated individuals combined with vaccine
breakthrough cases continues to allow the virus to spread throughout the community and cause morbidity and
mortality at high rates. There continues to be an urgent need for innovative therapeutics to address the current
pandemic, as well as those which will inevitably arise in the future.
Host-directed therapies (HDTs) offer a promising approach in this regard. Rather than targeting the virus itself,
HDTs target the host to either restrict an essential growth factor or upregulate innate defenses. By targeting the
host to attack the virus, traditional mechanisms of antiviral resistance are circumvented. We are developing a
broad-spectrum antiviral RNA molecule targeting retinoic acid inducible gene-I (RIG-I), a host pattern recognition
receptor (PRR) evolved to recognize viral RNA to trigger innate antiviral immune responses, an approach
validated in preclinical studies to protect mice from multiple RNA and DNA viruses. Our preliminary data show
the RIG-I agonist, PAMP105, prevents SARS-CoV-2 replication in vitro and can be effectively delivered to the
lung to completely prevent disease from influenza and SARS-CoV-2 infection. In the proposed studies herein,
we will perform critical formulation optimization to create a final product to be tested for efficacy against SARS-
CoV-2 challenge in vitro and in vivo. We will optimize parameters of four clinically relevant nanoparticle
formulations, including our novel nano-structured lipid carrier, which effectively protects and delivers RNA in
vivo. We will optimize formulation parameters and downselect a final formulation by measuring cytokine release
patterns in vivo from the blood, lung, and liver following innate immune agonist delivery. The lead formulated
PAMP molecule will be tested for efficacy against a SARS-CoV-2 challenge in Syrian hamsters.
To this point, little progress has been made clinically in developing innate immune agonists as therapeutics. Our
expertise formulating agonists and vaccine platforms (including RNA) for preclinical and clinical trials will allow
us to use a variety of nanoparticle formulations to deliver this RNA RIG-I agonist safely and effectively in a
pressurized metered-dose inhaler to treat SARS-CoV-2 infection following exposure or after symptom onset.
With results from this Phase I project, we will advance our formulated host-directed RNA molecule into clinical
development as a as part of our Phase II research. Once developed, our therapeutic can be quickly pivoted for
use against any number of current or emerging viruses, including influenza, Hepatitis B Virus, Hepatitis C Virus,
Dengue Virus, or West Nile Virus, all of which are susceptible to PAMP in preclinical studies.
Terms: <(IFN) α><(IFN)-α><(IFN)α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ATRA><Address><Adjuvant><Agonist><Alferon><Animals><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antiviral resistance><Antiviral resistant><Antivirals><Bacterial Infections><Basal Transcription Factor><Basal transcription factor genes><Binding><Blood><Blood Circulation><Blood Reticuloendothelial System><Bloodstream><Breakbone Fever Virus><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 positive><COVID-19 positivity><COVID-19 prevention><COVID-19 public health crisis><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 positive><COVID19 positivity><COVID19 prevention><COVID19 public health crisis><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Circulation><Clinical><Clinical Trials><CoV-2><CoV2><Communities><Complement><Complement Proteins><DNA Viruses><Data><Defensins><Dengue Virus><Dengue fever virus><Development><Diagnosis><Disease><Disorder><Egypt 101 virus><Epidemiology><Epithelial Cells><Event><Formulation><Future><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genes><Goals><Golden Hamsters><Golden Syrian Hamsters><Grippe><Growth Agents><Growth Factor><Growth Substances><HBV><HCV><Health Care Systems><Health system><Healthcare Systems><Hepatitis B Virus><Hepatitis C virus><Homologous Serum Hepatitis Virus><Human><Hybrids><IFN Alpha><IFN α><IFN-α><IFNa><IFNα><Immune><Immune response><Immunes><Immunological response><In Vitro><Individual><Influenza><Innate Immune 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Acid><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 positive><SARS-CoV-2 positivity><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 positive><Severe acute respiratory syndrome coronavirus 2 positivity><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Speed><Structure of respiratory epithelium><Symptoms><Syrian Hamsters><Therapeutic><Trans Vitamin A Acid><Transcription Factor Proto-Oncogene><Transcription factor genes><Transfection><Translating><Transmission><Tretinoin><Tretinoinum><Vaccines><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus><Virus Diseases><Virus Replication><Vitamin A Acid><WNV><West 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therapeutic target><novel therapeutics><novel therapy><novel therapy target><pandemic><pandemic disease><pathogen><pathway><post SARS-CoV-2 infection><pre-clinical study><pre-clinical trial><preclinical study><preclinical trial><pressure><prevent><prevent COVID-19><prevent COVID19><prevent coronavirus disease 2019><preventing><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><product development><programs><protective efficacy><pulmonary><receptor><resistant><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><sound><structured 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