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.

项目摘要抗病毒药物是影响力病毒（IAV）的关键对策，尤其是在 IAV发病率增加或疫苗不可用（例如有毒H5N1 IAV）。但是，IAV的出现对当前抗病毒药1-6（H5N1）抗性的菌株强调了对新治疗策略的需求，特别是那些修改主机响应的人。 IAV感染了5-20％的美国人口，> 200,000 每年住院和约40,000人死亡。发病率和死亡率是强度的系统性的抗病毒免疫反应的压力，特别是在那些合并症的个体中（即慢性病）呼吸道和心血管疾病）。此外，来自其他物种的内粒IAV菌株（例如，H5N1）可以通过“细胞因子风暴”杀死健康的个体。正如大多数人所见，大流行菌株的出现是不可避免的最近有2009 H1N1。此外，IAV能够快速获得病毒和有效的人类对人的能力通过遗传转移的人类传播是对全球人口的持续威胁，良性菌株可能迅速发展并引起严重的发病率和死亡率。该申请提案用于患者使用一种新型的热基因敲低策略，通过使用纳米插曲，将其定位于呼吸上皮阳离子聚合物和阴离子核酸的静电复合物。我们的初步发现已经证明了这种抗病毒疗法抑制IAV复制，减少IAV诱导的肺损伤并改善抗菌主机响应。此I阶段ISTTR应用程序将优化纳米旋转的制造和交付建立其体外效率（相对于抗病毒和IFN I刺激活性）和毒性。随后的序列 II期STTR应用将确定其体内效率和使用耐药性的小鼠的体内效率和毒性实验室，流行病，大流行和致病菌株。