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Therapy for drug resistant influenza strains by nucleic acid targeting of respiratory airways

核酸靶向呼吸道治疗耐药流感病毒株

基本信息

批准号：
9406008
负责人：
Charles Houston Jones
金额：
$ 4.99万
依托单位：
ABCOMBI BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-02 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9406008
关键词：
Anti-Bacterial Agents Antiviral Agents Antiviral Response Antiviral Therapy Bacterial Pneumonia Benign Cardiovascular Diseases Cations Cells Cessation of life Charge Chitosan Chronic Comorbidity Complex Cytosol Disease Drug Utilization Drug resistance Ebola virus Effectiveness Electrostatics Epidemic Ferrets Formulation Genes Genetic Genetic Transcription Goals Guidelines Hospitalization Human IRF3 gene Immune Immune response In Vitro Incidence Individual Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A virus Innate Immune Response Interferon Type I Interferons Laboratories Ligands Lung diseases Messenger RNA Morbidity - disease rate Mus Nonstructural Protein Nucleic Acids Pathogenicity Patients Phase Phase I Clinical Trials Polymers Population Production RNA RNA Interference Resistance Risk Safety Secondary to Signal Transduction Small Business Technology Transfer Research Stress Structure of respiratory epithelium Surface TLR3 gene TRIM25 gene Testing Therapeutic Time Toxic effect Treatment Efficacy Ubiquitination Vaccines Vent Viral Virulence Virulence Factors Virulent Virus Diseases Virus Replication anti-influenza biomaterial compatibility cytokine design drug resistant influenza flu improved in vivo killings knock-down lung injury mRNA Transcript Degradation mortality nano nanoparticle novel novel therapeutics pandemic disease resistant strain respiratory response sensor small hairpin RNA success therapeutic gene transmission process treatment strategy viral RNA

项目摘要

PROJECT SUMMARY Antiviral drugs are a crucial countermeasure for influenza A virus (IAV), particularly in circumstances of increased IAV incidence or if a vaccine is unavailable (e.g., virulent H5N1 IAV). However, the emergence of IAV strains that are resistant to current antivirals1-6 (H5N1) underscores the need for new treatment strategies, particularly those that modify the host response. IAVs infect 5-20% of the US population with >200,000 hospitalizations and ~40,000 deaths annually. Morbidity and mortality are secondary to an intense systemic stress to the antiviral immune response particularly in those individuals with co-morbidities (i.e., chronic respiratory and cardiovascular diseases). Additionally, endemic IAV strains from other species (e.g., H5N1) can kill healthy individuals by a “cytokine storm”. The emergence of pandemic strains is inevitable, as seen most recently with 2009 H1N1. Moreover, IAV’s ability to rapidly acquire increased virulence and efficient human-to- human transmission through genetic shift is a constant threat to the global population, and benign strains may rapidly evolve and cause severe morbidity and mortality. This application proposes to develop for use in patients a novel therapeutic gene knockdown strategy localized to respiratory epithelium by employing nanoplexes, an electrostatic complex of cationic polymers and anionic nucleic acids. Our preliminary findings have demonstrated that this antiviral therapy, inhibits IAV replication, decreases IAV induced lung injury and improves antibacterial host responses. This Phase I STTR application will optimize the fabrication and delivery of the nanoplexes and establish its in vitro efficacy (with respect to antiviral and IFN I stimulating activity) and toxicity. The subsequent Phase II STTR application will determine its in vivo efficacy and toxicity in mice and ferrets utilizing drug-resistant laboratory, epidemic, pandemic, and pathogenic strains.

项目总结