Influenza pandemics are considered one of the world's most devastating public health threats. The challenge for public health departments worldwide is to have an effective therapy on hand to prevent deaths during a pandemic influenza outbreak. Vaccines are effective, but have a lead time. Anti-viral drugs are partially effective, but are in limited supply and failure-prone due to resistant strains. The distinct possibility that current therapy will fail when needed has prompted development of alternative therapeutic approaches. We hypothesize that during lethal infections, such as caused by Influenza A/H5N1, the virus induces a severe hyper-inflammatory response characterized as a 'cytokine storm' resulting in tissue damage and death. Therefore, an immunomodulatory agent that diminishes, but does not eliminate, the patient's cytokine response to influenza infection would be effective in preventing deaths. In support of this hypothesis we have demonstrated that the immunomodulatory agent, GP1001, increases the survival of mice subjected to experimental, lethal influenza H5N1 infection. We have obtained in vitro and in vivo data that the novel immunomodulatory candidate, GP1002, modulates the inflammatory response. Phase I of the project has three specific goals. We propose to evaluate this novel candidate in mouse models of influenza. We intend to correlate improvement in mouse survival associated with GP1002 treatment with the compound's immunomodulatory activity in vitro. We will determine whether combination therapy of GP1002 and an approved antiviral compound provides improved protection of influenza-infected mice from mortality. The Phase II studies would further probe the safety and treatment with GP1002.
Public Health Relevance: We propose that a G protein-coupled protein receptor (GPCR) agonist which modulates immune system response may be an effective therapeutic for influenza A infections, particularly lethal infections by highly pathogenic influenza A, such as H5N1. This investigational therapeutic is neither a vaccine nor a traditional anti-viral medication. The innovation of the proposed project relates to the specific GPCR as a new drug target for influenza, the GPCR agonist's potential to complement existing influenza therapeutics, and the GPCR agonist's possible use as a therapy for late-stage, severe influenza.
Thesaurus Terms: After Care; After-Treatment; Aftercare; Agonist; Agreement; Animal Disease Models; Animals; Antiviral Agents; Antiviral Drugs; Antivirals; Area; Body Tissues; Booklets; Brochures; Cd8 Cell; Cd8 Lymphocyte; Cd8+ T-Lymphocyte; Cd8-Positive Lymphocytes; Cd8-Positive T-Lymphocytes; Cellular Assay; Cessation Of Life; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Combined Modality Therapy; Communicable Diseases; Complement; Complement Proteins; Cytokines, Chemotactic; Data; Death; Development; Development And Research; Drug Costs; Drug Delivery; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug Targetings; Drugs; Evaluation; Flr; Faculty; Failure (Biologic Function); Feedback; Ferrets; Funding; Future; G-Proteins; Gtp-Binding Proteins; Gtp-Regulatory Proteins; German; German Population; Goals; Grant; Grippe; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Regulatory Proteins; Guidelines; H5n1; H5n1 Virus; Hand; Homologous Chemotactic Cytokines; Immune Response; Immune System; Immunity; In Vitro; Industry; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases And Manifestations; Infectious Disorder; Inflammatory Response; Influenza; Influenza A Virus, H5n1 Subtype; Influenza Therapeutic; Intercrines; Intermediary Metabolism; Investigators; Lead; Licensing; Licensure; Lung; Metbl; Mammals, Mice; Medication; Metabolic Processes; Metabolism; Mice; Mortality; Mortality Vital Statistics; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; Murine; Mus; Outcome; Pbo; Pamphlets; Patients; Pb Element; Performance; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase; Placebos; Public Health; R & D; R&D; Receptor Protein; Research Personnel; Research Resources; Researchers; Resources; Respiratory System, Lung; Risk; Sbir; Sbirs (R43/44); Sis Cytokines; Safety; Sales; Sham Treatment; Small Business Innovation Research; Small Business Innovation Research Grant; Staging; T8 Cells; T8 Lymphocytes; Testing; Therapeutic; Time; Tissues; Toxicology; Translating; Translatings; Universities; Vaccines; Viral; Virus; Viruses, General; Who; Weight; Work; World Health; World Health Organization; Body System, Allergic/Immunologic; Chemoattractant Cytokine; Chemokine; Clinical Investigation; Combination Therapy; Combined Modality Treatment; Combined Treatment; Cost; Cytokine; Design; Designing; Drug Discovery; Drug/Agent; Effective Therapy; Experience; Failure; Flu Infection; Flu Outbreak; Flu Therapeutic; Heavy Metal Pb; Heavy Metal Lead; Host Response; Immunopathology; Immunoresponse; Improved; In Vitro Activity; In Vivo; Influenza Infection; Influenza Outbreak; Innovate; Innovation; Innovative; Language Translation; Meetings; Mouse Model; Multimodality Therapy; New Therapeutics; Next Generation Therapeutics; Novel; Novel Therapeutics; Organ System, Allergic/Immunologic; Pandemic Flu; Pandemic Influenza; Phase 2 Study; Prevent; Preventing; Public Health Medicine (Field); Public Health Relevance; Pulmonary; Receptor; Research And Development; Resistant Strain; Response; Sham Therapy; Viral Resistance
