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Principal Investigator: PHILIP J SANTANGELO
Organization: EMORY UNIVERSITY
Fiscal Year: 2023
Award: $723,501
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
There are over 200 viruses known to infect humans and they contribute to 6.6% of global mortality. We have
approximately 91 drugs for 10 viral species and vaccines for only 16. Reassortment and antigenic changes pose
challenges to vaccine efficacy; this has clearly been demonstrated during the COVID pandemic. Current drug
development is focused on small molecules and neutralizing antibodies, which require high doses or frequent
re-dosing to obtain functional outcomes and have also been challenged by antigenic changes. Thus, it is crucial
to address the need for higher efficiency and broader spectrum antivirals. To address this need we are proposing
an entirely different paradigm for antiviral development, an mRNA-encoded activatable RNase, Cas13, as a
platform for a pan-respiratory treatment. Cas13 represents a programmable RNase that can directly target and
degrade multiple viral messenger or genomic RNA. Synthetic mRNA is being used to deliver the RNase, as it
allows for transient, non-viral delivery, with an improved safety profile over other gene therapy vectors1. Given
achieving pan-respiratory results with a single mRNA-encoded Cas13 based drug is not trivial, critical steps
towards that goal can be achieved by focusing on the three most impactful respiratory viruses in circulation,
RSV, influenza and SARS-CoV-2. To date, our team was the first to demonstrate efficacy of mRNA-encoded
Cas13 in vitro and in vivo via nebulizer-based lung delivery against influenza in the mouse model and SARS-
CoV-2 in the hamster model in our recent publication in Nature Biotechnology. In order to achieve one drug for
RSV, influenza and SARS-CoV-2 there are important questions/challenges that will need to be met. Thus, we
will determine the optimal Cas13 species for multiple respiratory pathogens and investigate the mechanism of
action of Cas13 for each virus. We will also demonstrate single drug efficacy against RSV, influenza and SAR-
CoV-2 in vivo in mouse and hamster models, given as treatments for the individual viral infections, during co-
infection (influenza and SAR-CoV-2), and to mitigate transmission of SARS-CoV-2.
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Vectors><Goals><Grippe><Hamsters><Hamsters Mammals><Human><In Vitro><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A><Influenza A virus><Influenza B><Influenza B Virus><Influenza Viruses Type A><Influenza Viruses Type B><Influenzavirus A><Innate Immune Response><Medication><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Nature><Nebulizer><Non-Polyadenylated RNA><Organ><Orthomyxovirus Type A><Orthomyxoviruses Type B><Pathogenesis><Ph.D.><PhD><Pharmaceutic Preparations><Pharmaceutical Preparations><Predisposition><Publications><Pulmonary Body System><Pulmonary Organ System><Qualifying><RNA><RNA Degradation><RNA Gene Products><RNA Nucleases><RNA Seq><RNA sequencing><RNAseq><RNase><Resistance><Respiratory System><Respiratory Tracts><Respiratory tract structure><Ribonuclease Family Protein><Ribonucleases><Ribonucleic Acid><Rodent><Rodentia><Rodents Mammals><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 transmission><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-Related Coronavirus><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><Safety><Scientific Publication><Seasons><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Surface><Susceptibility><Time><Transmission><Type A Influenza><Universities><Vaccines><Variant><Variation><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus><Virus Diseases><Work><Wuhan coronavirus><anti-viral agents><anti-viral compound><anti-viral development><anti-viral drug development><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-viral therapeutic development><anti-viral therapy development><anti-virals><antiviral compound><antiviral development><antiviral drug development><antiviral medication><antiviral therapeutic><antiviral therapeutic development><antiviral therapy development><co-infection><coinfection><compare effectiveness><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 transmission><coronavirus disease 2019 virus><coronavirus disease 2019 virus transmission><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><developing anti-viral agent><developing anti-viral drug><developing anti-viral therapeutic><developing anti-viral therapy><developing antiviral agent><developing antiviral drug><developing antiviral therapeutic><developing antiviral therapy><drug development><drug efficacy><drug/agent><fluorescence imaging><fluorescent imaging><functional outcomes><genomic RNA><hCoV19><improved><in vitro Assay><in vivo><innovate><innovation><innovative><lung basal segment><lung base><mRNA><mRNA delivery><model of animal><mortality><mouse model><murine model><nCoV2><nebulization><nebulize><neutralizing antibody><nuclease><pathogen><resistance mutation><resistant><resistant mutation><respiratory><respiratory pathogen><respiratory virus><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 transmission><severe acute respiratory syndrome-CoV><small molecule><success><super high resolution><superresolution><transcriptome sequencing><transcriptomic sequencing><transmission process><transmitted COVID-19><transmitted SARS-CoV-2><transmitted coronavirus disease 2019><transmitted severe acute respiratory syndrome coronavirus 2><ultra high resolution><vaccine efficacy><viral RNA><viral infection><viral respiratory infection><virus RNA><virus infection><virus-induced disease>