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

• 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
• 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

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.

项目概要 抗病毒药物是对抗甲型流感病毒（IAV）的重要对策，特别是在以下情况下 IAV 发病率增加或没有疫苗（例如强毒 H5N1 IAV）。然而IAV的出现 对当前抗病毒药物 1-6 (H5N1) 具有抗药性的菌株强调需要新的治疗策略， 特别是那些修改宿主响应的。 IAV 感染了 5-20% 的美国人口，感染人数超过 200,000 每年约有 40,000 人住院治疗并死亡。发病率和死亡率是继发于强烈的系统性 对抗病毒免疫反应的压力，特别是对于那些患有合并症（即慢性病）的个体 呼吸系统疾病和心血管疾病）。此外，来自其他物种的地方性 IAV 毒株（例如 H5N1）可以 通过“细胞因子风暴”杀死健康个体。正如大多数人所见，大流行毒株的出现是不可避免的 最近爆​​发了 2009 年 H1N1 流感。此外，IAV 能够快速获得更高的毒力和有效的人际传播能力。 通过基因转变进行的人类传播对全球人口构成持续威胁，良性菌株可能 迅速发展并导致严重的发病率和死亡率。该应用程序建议开发用于患者 一种通过使用纳米复合物定位于呼吸道上皮的新型治疗基因敲除策略， 阳离子聚合物和阴离子核酸的静电复合物。我们的初步研究结果表明 这种抗病毒疗法可以抑制 IAV 复制，减少 IAV 引起的肺损伤并提高抗菌能力 主持人回应。这一阶段的 STTR 应用将优化纳米复合物的制造和交付， 确定其体外功效（抗病毒和 IFN I 刺激活性）和毒性。随后的 STTR II 期应用将利用耐药性确定其在小鼠和雪貂中的体内功效和毒性 实验室、流行病、大流行和致病菌株。