Research Project
7804235
DESCRIPTION (provided by applicant) 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.
