Broad-spectrum prophylaxis and therapeutics for respiratory viral infections are highly desirable due to the immense socioeconomic burden imposed by the respiratory viruses. Human parainfluenza viruses (HPIV) represent a significant portion of respiratory viral disease. There are currently no approved treatments for the prevention or treatment of HPIV. The aims of this proposal are the first steps in a clinical development program to address this unmet medical need. The long-term objective of this project is to bring DAS181 into clinical trials in an HPIV indication. DAS181 is a recombinant fusion protein composed of a sialidase catalytic domain fused with an epithelium-anchoring sequence which functions by eliminating sialic acids on the airway epithelium. DAS181 is currently in clinical development for treatment of influenza virus (IFV) infection. IFVs and HPIVs share a common pathway of virus binding to sialic acids on the surface of cells as the initial step in infection. Since DAS181 works by inactivating sialic acid, the drug potentially confers very broad protection against any virus utilizing binding to sialic acid to gain entry into the cell. There are two specific aims of this proposal: first, to demonstrate the in vitro efficacy and pharmacodynamics of DAS181 against clinical isolates of HPIV and second, to demonstrate the in vivo efficacy of DAS181 against HPIV using a cotton rat model with DAS181 prophlyaxis and treatment. To establish the proof-of-principle in vitro, clinical isolates confirmed to be HPIV1, 2 or 3 will be obtained. At least 20 different clinical isolates will be established for testing sensitivity to DAS181. The ability of DAS181 to inhibit HPIV infection in LLC-MK cells will be evaluated. The susceptibility of various HPIV isolates to DAS181 will be compared by EC50 and EC90 values at an equal level of viral challenge. The potential anti- HPIV effect of DAS181 against clinical HPIV isolates will also be evaluated using the well-differentiated human airway epithelium culture (HAE). This model will allow the assessment of time of DAS181 exposure on the infection of HPIV. The cotton rat model of HPIV will be used to determine in vivo efficacy. Following the establishment of the model to determine the optimum infection of HPIV isolates, the efficacy of DAS181 will be evaluated in the prophylaxis, pre-HPIV inoculation model. Subsequent in vivo studies in cotton rats will define the time course of DAS181 treatment for existing HPIV infection. Accomplishing these two aims of defining pharmacological efficacy of DAS181 in HPIV infection will provide the rationale for engaging in pre-INS development, IND submission, and eventually the conduct of clinical trials in this indication. As DAS181 is already in a Phase I clinical trial for an influenza indication, the development path forward into an HPIV indication could be quite rapid upon this demonstration of potent activity against HPIV.
Public Health Relevance: There is currently no treatment for human parainfluenza viral (HPIV) infection and no vaccine for prevention of infection. Yet HPIV represents a significant disease burden, especially for children, and represents a large unmet medical need. The proposed studies will establish Fludase(R), a novel recombinant fusion protein, as a potential drug for HPIV infections.
Thesaurus Terms: 0-11 Years Old; Acylneuraminyl Hydrolase; Address; Applications Grants; Binding; Binding (Molecular Function); Catalytic Core; Catalytic Domain; Catalytic Region; Catalytic Site; Catalytic Subunit; Cell Surface; Cells; Child; Child Youth; Children (0-21); Clinical; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Conduct Clinical Trials; Cotton Rats; Development; Drugs; Early-Stage Clinical Trials; Epithelium; Goals; Grant Proposals; Grants, Applications; Grippe; Ha2; Hemadsorption Type 2 Virus; Hemadsorption Virus 2; Human; Human Parainfluenza Virus 1; Human, Child; Human, General; In Vitro; Infection; Infection Prevention; Influenza; Influenza Virus; Laboratory Animals; Man (Taxonomy); Man, Modern; Medical; Medication; Modeling; Molecular Interaction; Morbidity; Morbidity - Disease Rate; Mortality; Mortality Vital Statistics; N-Acetylneuraminic Acids; N-Acylneuraminate Glycohydrolases; Neuraminidase; Oligosaccharide Sialidase; Parainfluenza; Parainfluenza Virus 1, Human; Parainfluenza Virus Infections; Pathway Interactions; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Predisposition; Prevent Infection; Prevention; Prevention Measures; Program Development; Prophylactic Treatment; Prophylaxis; Protocols, Treatment; Rgm; Receptor Protein; Recombinant Fusion Proteins; Regimen; Sbir; Sbirs (R43/44); Safety; Sialic Acids; Sialidase; Small Business Innovation Research; Small Business Innovation Research Grant; Susceptibility; Testing; Therapeutic; Time; Treatment Protocols; Treatment Regimen; Treatment Schedule; Vaccines; Viral; Viral Diseases; Virus; Virus Diseases; Viruses, General; Work; Airway Epithelium; Burden Of Disease; Burden Of Illness; Children; Clinical Investigation; Disease Burden; Drug/Agent; Exo Alpha Sialidase; Flu Infection; In Vivo; Influenza Infection; Influenzavirus; Influenzavirus (Unspecified); Intervention Development; Novel; Parainfluenza Virus; Pathway; Phase 1 Study; Phase 1 Trial; Phase I Trial; Prophylactic; Protocol, Phase I; Public Health Relevance; Receptor; Respiratory; Respiratory Virus; Socioeconomic; Socioeconomically; Socioeconomics; Therapy Development; Treatment Development; Viral Infection; Virus Infection; Years Of Life Lost To Disability; Years Of Life Lost To Disease; Youngster
