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Principal Investigator: Amir Kol
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2022
Award: $196,510
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
This R21 proposes to fill a major scientific gap by investigating a new therapeutic approach for multisystem
inflammatory syndrome in children (MIS-C) using an innovative and clinically relevant feline model. We
propose to test a novel multi-pronged therapeutic paradigm targeting viral replication, lymphoid tissue injury
and hyper-inflammatory host response in cats with naturally occurring feline infectious peritonitis (FIP) to
accelerate viral clearance and immune restoration. Our long-term objective is to develop new therapeutic
approaches for the treatment of MIS-C. The overall objectives of this proposal are to test a novel multi-pronged
chemo-biologic therapeutic strategy and determine its underlying mechanism of action in a clinically relevant
animal model. The central hypothesis is that a combined GS-441524-multipotent stem/stromal cells (MSC)
therapy synergistically restores injured lymphoid tissues, decreases systemic inflammation and enhances
specific anti-coronavirus (CoV) immunity in cats with FIP. The rationale for this project is supported by our
preliminary data indicating that GS-441524 is a potent anti-CoV agent, and that MSC have a novel role in viral
infections by enhancing anti-viral immunity, dampening systemic inflammation and regenerating lymphoid
tissue structure and function. The central hypothesis will be tested by pursuing two specific aims: 1) Determine
the effect of GS-441524-MSC combination treatment on viral loads, lymphoid tissue injury and repair, and
elucidate the molecular networks that govern its mechanism of action; and 2) Determine the effect of GS-
441524-MSC combination treatment on T cell activation/exhaustion, inflammation and lymphocyte depletion in
peripheral blood compartment of cats with FIP. To test our hypothesis we will enroll client owned cats with FIP
into a double blinded trial with two experimental groups: GS-441524 only, or a combined GS-441524 -MSC
treatment. Blood, effusion and lymph node tissue samples will be serially collected throughout the study
timeline. Parallel samples will be collected from healthy controls. We will further leverage our bio-banked
tissues from cats with FIP that succumbed to the disease. Under the first aim we will determine the role of the
combined treatment approach in inducing IL-7, IFN type-1 and antigen presentation pathways within lymphoid
tissues to mitigate lymphoid depletion and mount an effective and balanced immune response to CoV
infection. For the second aim, we will determine the role of the combined treatment approach in inhibiting
lymphocyte apoptosis and T cell exhaustion in peripheral blood, and reducing systemic inflammation. The
proposed research is innovative because it will determine how monotherapy is affecting immune recovery, and
if MSC can enhance and accelerate viral clearance and lymphoid tissue regeneration in a clinically relevant
animal model of MIS-C. The proposed research is significant because it is expected to provide a strong
scientific justification and mechanistic understanding for the continued development of combined chemo-
biologic therapeutic strategies for MIS-C.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21 year old><21 years of age><3-10C><AIDS Virus><AMCF-I><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antigen Presentation><Antigen Presentation Pathway><Antigen Processing and Presentation><Antiinflammatories><Antiinflammatory Agents><Atrophic><Atrophy><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor Gene><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor 2 Gene><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF-2 Gene><BSF2><BSF2 Gene><Beta-2 Gene Interferon><Biological Response Modifier Therapy><Biological Therapy><Blood><Blood Plasma><Blood Reticuloendothelial System><COVID><COVID-19 virus><COVID19 virus><CXCL8><Cats><Cats Mammals><Cell Therapy><Cell-Mediated Lympholytic Cells><Cellular biology><Child><Child Youth><Childhood><Children (0-21)><Client><Clinical Trials><CoV disease><CoV-2><CoV2><Combined Modality Therapy><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Development><Disease><Disorder><Domestic Cats><Double-blind trial><Drug Precursors><Enrollment><Family Felidae><Felidae><Felids><Feline Species><Feline infectious peritonitis><Felis catus><Felis domestica><Felis domesticus><Felis sylvestris catus><Fever><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><GCP1><GS-441524><GS-5734><Germinal Center><HIV><HPGF><HSF Gene><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper Viruses><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hepatocyte Stimulatory Factor Gene><Hepatocyte-Stimulating Factor><Hospital Admission><Hospitalization><Human Immunodeficiency Viruses><Hybridoma Growth Factor><Hybridoma Growth Factor Gene><IFN><IFN-beta 2><IFNB2><IFNB2 Gene><IL-6><IL-6 Gene><IL-7><IL-7 Gene><IL-8><IL6><IL6 Protein><IL6 gene><IL7><IL7 Protein><IL7 gene><IL8><IL8 gene><Immune><Immune mediated therapy><Immune response><Immune system><Immunes><Immunity><Immunoassay><Immunofluorescence><Immunofluorescence Immunologic><Immunological response><Immunologically Directed Therapy><Immunotherapy><Impairment><Inducer Cells><Inducer T-Lymphocytes><Infection><Inflammation><Inflammation Mediators><Inflammatory><Injury><Interferons><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin-6><Interleukin-6 Gene><Interleukin-7><Interleukin-7 Gene><K60><LAV-HTLV-III><Laboratories><Life><Lymph Node Reticuloendothelial System><Lymph Node Tissue><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphatic nodes><Lymphocyte Depletion><Lymphocyte Subpopulations><Lymphocyte Subset><Lymphocytopenia><Lymphoid><Lymphoid Tissue><Lymphopenia><Lymphopoietin-1><MGI-2><MIS-C><Mission><Modeling><Molecular><Multimodal Therapy><Multimodal Treatment><Multiorgan Inflammatory Syndrome in Children><Multisystem Inflammatory Syndrome in Children><Myeloid Differentiation-Inducing Protein><NICHD><National Institute of Child Health and Human Development><National Institute of Children's Health and Human Development><Natural regeneration><Organ><Outcome Study><Pathogenesis><Pathway interactions><Patients><Peripheral><Plasma><Plasma Serum><Plasmacytoma Growth Factor><Position><Positioning Attribute><Pro-Drugs><Prodrugs><Property><Public Health><Pyrexia><RNA Polymerase Inhibitor><RNA Seq><RNA sequencing><RNAseq><Recovery><Regeneration><Research><Reticuloendothelial System, Serum, Plasma><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYB8><Safety><Sampling><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-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><Stromal Cells><Structure><Structure of germinal center of lymph node><Subcutaneous Injections><Syndrome><T-Cell Activation><T-Cells><T-Lymphocyte><TSG-1><Testing><Therapeutic><TimeLine><Tissue Banks><Tissue Collection><Tissue Sample><Tissue repository><Veklury><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus><Virus Diseases><Virus Replication><Virus-HIV><Wuhan coronavirus><age 21><age 21 years><allergic/immunologic body system><allergic/immunologic organ system><anti-viral immunity><antiinflammatory><antiviral immunity><apoptosis in lymphocytes><apoptotic lymphocytes><b-ENAP><biological therapeutic><biological treatment><biologically based therapeutics><biotherapeutics><biotherapy><cell biology><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapy><child patients><clinical relevance><clinically relevant><combination therapy><combined modality treatment><combined treatment><corona virus><corona virus disease><coronavirus disease><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><developmental><disability><effusion><enroll><exhaustion><experience><experimental group><febrile><febris><feline><flow cytophotometry><hCoV19><host response><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><inflammatory mediator><injured><injuries><injury and repair><injury to organs><injury to tissue><innovate><innovation><innovative><interferon beta 2><killer T cell><lymph gland><lymph nodes><lymphnodes><lymphocyte apoptosis><lymphocyte depletion therapy><model of animal><model organism><multi-modal therapy><multi-modal treatment><multidisciplinary><multisystem inflammatory syndrome of children><nCoV2><new drug treatments><new drugs><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><next generation therapeutics><non-human primate><nonhuman primate><novel><novel drug treatments><novel drugs><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><nucleoside analog><organ injury><pathway><pediatric><pediatric inflammatory multisystem syndrome><pediatric patients><peripheral blood><regenerate><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><remdesivir><response><response to therapy><response to treatment><restoration><social role><stem><subdermal injection><systemic inflammation><systemic inflammatory response><therapeutic agent development><therapeutic candidate><therapeutic development><therapeutic response><therapy response><thymus derived lymphocyte><tissue injury><tissue regeneration><tissue regrowth><tissue renewal><tissue specific regeneration><transcriptome sequencing><treatment response><treatment strategy><twenty-one year old><twenty-one years of age><viral RNA><viral infection><viral multiplication><viral replication><virus RNA><virus infection><virus multiplication><virus-induced disease><youngster>