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Principal Investigator: WEI WENG
Organization: INGENIOUS TARGETING LABORATORY, INC.
Fiscal Year: 2022
Award: $292,710
Funding agency: National Institute of Allergy and Infectious Diseases
With the initial wave of zoonotic transmission firmly established in the human population worldwide, severe
acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) poses an eminent threat to individuals, health
care systems and societies. Various degrees of disease severity (from asymptomatic to lethal) combined with
challenging infection metrics ‒ in the absence of widespread testing coverage, as well as lack of established
vaccination and treatment options ‒ have triggered massive and urgent biomedical efforts to counter the
associated human disease that is COVID-19. Founded in the complexities of virus/host interactions, it is
imperative to utilize experimental infections with virus or viral material in translational platforms with a focus on
viral and/or host modeling in order to establish preventive as well as control strategies. In this experimental
setting, animal models play a central role as in vivo hosts for evaluation purposes of antiviral drugs,
immunotherapy and vaccines ‒ foremost in preclinical, but also in parallel-to-clinical, studies. A single type of
organism, either wildtype or genetically-modified, will however likely not be sufficient for studies of all relevant
physiological mechanisms. In this project, we propose reverse genetic designs in the mouse by introducing
genetically humanized components on large and medium scales, enabling viral binding and cellular infection
with the aim to mimic human COVID-19 disease susceptibility during early stages of the SARS-CoV-2
replication cycle. Rodent species, although favorable as small animal research objects, are generally refractory
to displaying SARS and the COVID-19 pathology upon simple infection. One way to address this species
boundary so far was to create random transgenic mouse lines carrying small-scale partially humanized gene
expression units for the human ACE2 receptor. These models, however, display partial phenotypes
characterized by: (a) no terminal-lung outcomes, (b) undesired replication in the brain and (c) lack of multi-
organ failure upon infection (exemplified by SARS-CoV, with similar outcomes expected for SARS-CoV-2). In
order to enable a distinct lung and other human phenotypes, we hypothesize that extended genomic
humanization in the form of the human ACE2 receptor alone (see Spec. Aim 1) or in combination with lung-
specific human cofactors, i.e., TMPRSS2/Furin (see Spec. Aim 2) ‒ based on their human-like expression
(verified in Spec. Aim 3) ‒ will thus improve viral infection and tissue tropism measured by timely progression
of viral titers in different organs (in Spec. Aim 4). Fluorescent reporting as well as site-specific recombination
will be enabled in an alternative Cre-recombinase fusion model of ACE2, while intrinsic features of the
TMPRSS2/Furin model will provide a fluorescent signal upon expression. Our broad SARS/COVID-19 mouse
model platform utility (consisting of three individual models at the Phase I stage) will significantly support cross-
species translational investigations into the development of disease and the testing of intervention measures
by specialists in the biomedical field ‒ thus, addressing their short-term and long-term research needs.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Address><Animal Experimental Use><Animal Experimentation><Animal Model><Animal Models and Related Studies><Animal Research><Animals><Antiviral Agents><Antiviral Drugs><Antivirals><BAC clone><BACs><Bacterial Artificial Chromosomes><Binding><Body Weight decreased><Brain><Brain Nervous System><COVID-19><COVID-19 virus><COVID19><COVID19 virus><CRE Recombinase><CV-19><CV19><Causality><Cell Communication and Signaling><Cell Signaling><Clinical Research><Clinical Study><Clone Cells><CoV emergence><CoV-2><CoV2><Cofactor Protein S><Communities><Complementary DNA><Containment><Coronaviridae><Coronavirus><DNA Recombination><Detection><Development><Diathesis><Disease><Disease Outbreaks><Disease Progression><Disease susceptibility><Disorder><Drugs><ES cell><Embryo><Embryonic><Enabling Factors><Encephalon><Engineering><Enterobacteria phage P1 Cre recombinase><Epitheliasin Gene><Esteroproteases><Etiology><Evaluation><Exons><Experimental Therapies><Future><GEM model><GEMM model><Gene Expression><Genes><Genetic><Genetic Recombination><Genetically Engineered Mouse><Genome><Genomics><Genotype><Health><Health Care Systems><Healthcare Systems><Host Factor><Host Factor Protein><Human><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Individual><Infection><Infectious Agent><Integration Host Factors><Intervening Sequences><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Introns><Investigation><Investigational Therapies><Investigational Treatments><Investigators><Isoforms><K-18><K-18 conjugate><K18><K18 combination><Kinetics><Knowledge><Laboratories><Licensing><Life Cycle><Life Cycle Stages><Logic><Lung><Lung Respiratory System><MOF syndrome><Measures><Mediating><Medical><Medication><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular Interaction><Monitor><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Organ><Organism><Outbreaks><Outcome><PRSS10><Pathogenesis><Pathology><Peptidases><Peptide Hydrolases><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Phenotype><Physiologic><Physiological><Play><Population><Predisposition><Preventative measure><Prevention><Preventive><Preventive measure><Production><Protease Gene><Proteases><Protein Isoforms><Protein S><Proteinases><Proteins><Proteolytic Enzymes><Public Health><RNA Splicing><RT-PCR><RTPCR><Receptor Protein><Recombination><Refractory><Regulation><Regulatory Element><Reporter><Reporting><Reproducibility><Research><Research Personnel><Researchers><Reverse Transcriptase Polymerase Chain Reaction><Rodent><Rodentia><Rodents Mammals><Role><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV disease><SARS-CoV-1><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SBIR><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><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 related corona virus 2><Severity of illness><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Business Innovation Research><Small Business Innovation Research Grant><Societies><Specialist><Splicing><Structure><Susceptibility><System><TMPRSS2><TMPRSS2 gene><Testing><The Jackson Laboratory><Time><Transcript><Transgenic Mice><Transgenic Organisms><Transmission><Tropism><Vaccination><Vaccines><Validation><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virion><Virus><Virus Diseases><Virus Particle><Vitamin K-Dependent Protein S><Weight Loss><Weight Reduction><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><bacteriophage P1 recombinase Cre><base><biological signal transduction><body weight loss><cDNA><causation><cofactor><corona virus><corona virus disease 2019><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus of pandemic concern><coronavirus of pandemic potential><coronavirus with pandemic potential><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><discover vaccines><disease causation><disease severity><drug discovery><drug/agent><embryonic stem cell><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><experimental therapeutic agents><experimental therapeutics><genetically engineered mouse model><genetically engineered murine model><hCoV19><human disease><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in vivo><infectious organism><innovate><innovation><innovative><interest><interventional strategy><liability to disease><life course><living system><model of animal><model organism><mouse genome><mouse model><multiorgan failure><multiple organ system failure><murine model><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><novel CoV><novel corona virus><novel coronavirus><offspring><pandemic coronavirus><pandemic threat coronavirus><particle><pathogen><pre-clinical><preclinical><promoter><promotor><pulmonary><receptor><response><reverse genetics><reverse transcriptase PCR><severe acute respiratory syndrome-CoV><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><stem cell of embryonic origin><stressor><tissue tropism><tool><transgenic><transmission process><vaccine development><vaccine discovery><vector><viral infection><virus host interaction><virus infection><virus-induced disease><wt-loss>