Currently there are very few antiviral drugs, and no broad-spectrum antiviral drugs. For example, Influenza A virus (IAV) causes 12,000-56,000 deaths and 150,000-750,000 hospitalizations annually in the US alone, despite the availability of vaccines and five FDA-approved drugs 1, 2. Resistance to two of the five existing drugs has already emerged 13. Second, SARS-CoV-2 a virus which causes COVID19 led to unprecedented death toll worldwide. Currently there are no anti-SARS-Cov-2 drugs that can target other corona viruses. Type I interferons (IFNs) are host cytokines providing protection against viral infections. There are several different layers of IFN negative regulation, and the ISG15/USP 18 host protein 4, 5, 6, 7 complex is responsible for suppressing the tail end of IFN inflammation. Human ISG15 knockouts have been identified and shown to control IAV and SARS-CoV-2 replication better than WT counterparts. Based on the evidence of efficacy and safety provided by these ISG15-deficient individuals, Lab11 Therapeutics is developing new drugs, transient host-mimicking modified mRNA therapies aimed at enhancing control of IAV and SARS-CoV-2 infection in the general population 4, 6, 7. Candidate drugs are recreating antiviral state identified and tested in the human system, but, for FDA approval, Lab11 Therapeutics must demonstrate safety and efficacy in an animal model, before proceeding with human in vivo studies. This STTR aims to test our modRNA cocktail drugs in animal models of IAV and SARS-CoV2 infection. The phase I hypothesis is that modRNA cocktail delivered intranasally will restrict IAV replication in mice and SARS- CoV-2 infection in hamsters. We will test this hypothesis in Specific Aim 1, by evaluating the effects of modRNAs on IAV in human and murine cell lines followed by in vivo testing in mice. In Specific Aim 2, we will evaluate the effects modRNAs have on SARS-CoV-2 in human and hamster cell lines followed by in vivo testing in hamsters. In Phase II, we propose to test different delivery modes and encapsulations of modRNAs to optimize the most effective delivery and antiviral protection. The global influenza market is valued at about 5 billion dollars, about a fifth of which relates to non-vaccine products. The patient population targeted by Lab11 Therapeutics will be hundreds of millions of individuals in the general population. Given the crucial role of IFN in the control of many viral infections (ISG15-deficient cells control have been shown to control the replication of 14 different viruses more effectively than WT cells), the lead drugs developed here for IAV and SARS-CoV2 are likely to be effective against other viral diseases too. This will provide Lab11 Therapeutics with opportunities for the licensing of different products with identical mechanisms of action on an indication-by-indication basis. Public Health Relevance Statement Project Narrative In this STTR, Lab11 Therapeutics LLC plans to develop modified mRNA (modRNA) drugs for treating Influenza A virus (IAV) and SARS-CoV-2 infections. This drug will significantly decrease the annual rates of mortality and morbidity due to these infections.
Project Terms: Animals ; Antiviral Agents ; Antiviral Drugs ; Antivirals ; anti-viral agents ; anti-viral drugs ; anti-virals ; Biotechnology ; Biotech ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cells ; Cell Body ; Cessation of life ; Death ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Emergency Situation ; Emergencies ; gene therapy ; DNA Therapy ; Gene Transfer Clinical ; Genetic Intervention ; gene-based therapy ; genetic therapy ; genomic therapy ; Genes ; Goals ; Hamsters ; Cricetinae ; Hamsters Mammals ; Hospitalization ; Hospital Admission ; Human ; Modern Man ; Immune system ; allergic/immunologic body system ; allergic/immunologic organ system ; Natural Immunity ; Innate Immunity ; Native Immunity ; Non-Specific Immunity ; Nonspecific Immunity ; In Vitro ; Incidence ; Infection ; Inflammation ; Influenza ; Grippe ; Interferon Type I ; Interferons ; IFN ; Laboratories ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Maps ; Morbidity - disease rate ; Morbidity ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Proteins ; Messenger RNA ; mRNA ; Role ; social role ; Safety ; medical schools ; medical college ; school of medicine ; Tail ; Target Populations ; Technology ; Testing ; Vaccines ; Virus Diseases ; Viral Diseases ; viral infection ; virus infection ; virus-induced disease ; Virus Replication ; viral multiplication ; viral replication ; virus multiplication ; Virus ; Work ; cytokine ; base ; Phase ; Coronavirus ; Coronaviridae ; corona virus ; Germ-Line Mutation ; Germline Mutation ; Hereditary Mutation ; Individual ; Licensing ; Biological Process ; Biological Function ; Therapeutic ; Knowledge ; Hereditary ; Inherited ; Complex ; System ; Viral ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; novel ; Human Cell Line ; General Public ; General Population ; Regulation ; vulnerable group ; Vulnerable Populations ; Influenza A ; Influenza Viruses Type A ; Influenzavirus A ; Orthomyxovirus Type A ; Type A Influenza ; Influenza A virus ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Preparedness ; Readiness ; Dose ; Symptoms ; Data ; Hamster Cell Line ; in vivo ; Small Business Technology Transfer Research ; STTR ; Knock-out ; Knockout ; Development ; developmental ; anti-influenza ; anti-flu ; antiflu ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Outcome ; Antiviral resistance ; Antiviral resistant ; anti-viral resistance ; anti-viral resistant ; flu ; Resistance ; resistant ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; commercial application ; high risk ; FDA approved ; patient population ; resistant strain ; resistance strain ; drug candidate ; phase 1 study ; Phase I Study ; phase 2 study ; phase II study ; Formulation ; ISG15 gene ; ISG15 ; Interferon-Induced Protein IFI-15K ; in vivo evaluation ; in vivo testing ; COVID-19 ; COVID19 ; CV-19 ; CV19 ; corona virus disease 2019 ; coronavirus disease 2019 ; 2019-nCoV ; 2019 novel corona virus ; 2019 novel coronavirus ; COVID-19 virus ; COVID19 virus ; CoV-2 ; CoV2 ; SARS corona virus 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 ; 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 ; Wuhan coronavirus ; coronavirus disease 2019 virus ; hCoV19 ; nCoV2 ; vaccine access ; access to vaccination ; access to vaccines ; vaccination access ; vaccination availability ; vaccine availability ; SARS-CoV-2 infection ; COVID-19 infection ; COVID19 infection ; SARS-CoV2 infection ; Severe acute respiratory syndrome coronavirus 2 infection ; coronavirus disease 2019 infection ; infected with COVID-19 ; infected with COVID19 ; infected with SARS-CoV-2 ; infected with SARS-CoV2 ; infected with coronavirus disease 2019 ; infected with severe acute respiratory syndrome coronavirus 2 ;
