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

项目总结 抗病毒药物是对抗甲型流感病毒(IAV)的关键对策，特别是在 IAV发病率增加或无法获得疫苗(例如，强毒H5N1 IAV)。然而，IAV的出现 对当前抗病毒药物1-6(H5N1)具有抗药性的菌株突出表明需要新的治疗策略， 尤其是修改主机响应的那些。IAV感染了5-20%的美国人口，感染了20万人 每年住院人数和约40,000人死亡。发病率和死亡率仅次于强烈的全身性 对抗病毒免疫反应的压力，特别是在那些患有共病(即慢性 呼吸系统和心血管疾病)。此外，来自其他物种(例如H5N1)的地方性IAV毒株可以 通过一场“细胞因子风暴”杀死健康的人。正如大多数人所见，大流行毒株的出现是不可避免的。 最近感染了2009年甲型H1N1流感。此外，IAV迅速获得更强的毒力和有效的人传人的能力 人类通过基因转移传播是对全球人口的持续威胁，而良性菌株可能 迅速演变并导致严重的发病率和死亡率。这一应用程序计划开发用于患者 一种新的治疗性基因敲除策略，通过使用纳米丛定位于呼吸道上皮细胞 阳离子聚合物和阴离子核酸的静电络合物。我们的初步调查结果表明 这种抗病毒疗法可以抑制IAV的复制，减少IAV引起的肺损伤，并提高抗菌能力 主机响应。这项第一阶段STTR应用将优化纳米网络的制造和交付，并 确定其体外效力(关于抗病毒和干扰素I刺激活性)和毒性。随后的 二期STTR应用将确定其在小鼠和利用耐药雪貂的体内疗效和毒性 实验室、流行病、大流行和致病菌株。

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.