Immunotherapy for acute lung injury secondary to influenza

流感继发急性肺损伤的免疫治疗

• 批准号: 10133140
• 负责人: PAUL R KNIGHT III
• 金额: $ 43.68万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133140
• 关键词: Acute Lung Injury; Address; Adverse effects; Antiviral Agents; Antiviral resistance; Avian Influenza; Bacterial Pneumonia; Birds; Cardiac; Cations; Cause of Death; Cell Line; Cells; Cessation of life; Chitosan; Clinical; Communicable Diseases; Complex; Coupled; Development; Disease; Disease Outbreaks; Drug Interactions; Drug Kinetics; Drug resistance; Ebola; Ebola virus; Electrostatics; Engineering; Epidemic; Epithelial Cells; Etiology; Formulation; Foundations; Genes; Genetic Drift; Hospitalization; Human; Immune; Immune response; Immune system; Immunotherapy; Impairment; In Vitro; Incidence; Infection; Infiltration; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza B Virus; Inhalation; Inhalation Drug Administration; Injury; Innate Immune Response; Interferon Type I; Interferons; Investigational Drugs; Investigational New Drug Application; Ligands; Lung; Mediating; Morbidity - disease rate; Mus; Nanotechnology; Natural Immunity; Neuraminidase inhibitor; Nonstructural Protein; Nucleic Acids; Oseltamivir; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Polymerase; Population; Preventive treatment; Process; Production; RNA; RNA Binding; RNA Interference; Resistance development; Respiratory System; Risk; Secondary to; Severities; Standardization; Symptoms; Therapeutic; Time; Translations; Treatment Efficacy; Vaccines; Viral; Viral Pneumonia; Virulence; Virulence Factors; Virulent; Virus; Work; Zika Virus; adaptive immune response; airway epithelium; antiviral immunity; biomaterial compatibility; comorbidity; cytokine; cytokine release syndrome; design; drug resistant influenza; experimental study; feasibility testing; gene product; improved; in vivo; influenza virus strain; influenzavirus; inhibitor/antagonist; lung injury; mortality; nanoparticle; novel; novel strategies; pandemic disease; product development; prophylactic; resistant strain; respiratory; response; seasonal influenza; sensor; swine flu; transmission process; treatment strategy; tripolyphosphate; viral resistance; virology

PROJECT SUMMARY/ABSTRACT The emergence of drug-resistant strains of human influenza A (IAV) and B viruses, as well as avian H5N1 virus with pandemic potential, to the only approved antiviral agents underscores the importance of developing novel antiviral strategies. We have engineered electrostatic complexes between cationic nanoparticles (i.e., chitosan) and anionic RNA that target airway epithelial cells in vivo during an IAV infection. These nanoplexes induce antiviral bioactivity directed against IAV in vivo with little or no untoward cellular or pulmonary responses. The nanoplex constructs stimulate early type I interferon (IFN) cellular responses through 5’- triphosphate (PPP)-RNA binding of the intracellular sensor, RIG-I. Additionally, the 5’PPP-NS1shRNA nanoplex formulation suppresses the translation of the IAV virulence factor, NS1, which inhibits RIG-I and host cell RNA maturation. The lung is well suited for an antiviral nanoplex strategy since it provides a portal for inhalation administration of bioactive nanoplexes. We have demonstrated that this strategy inhibits in vivo IAV replication therapeutically and avoids the “IFN paradox”, specifically, decreasing IAV lung injury, and IAV impairment of bacterial clearance from the lung. The focus of the current proposal is to optimize the therapeutic action of the 5’PPP-NS1shRNA nanoplex formulation in vitro and then in vivo. Additionally, we propose to carry out experiments recommended by the FDA article entitled “Antiviral Product Development: Conducting and Submitting Virological Studies to the Agency.” This includes in vitro and in vivo experiments to assess therapeutic efficacy (antiviral activity), pharmacokinetics, drug-drug interactions, and development of viral resistance. Additionally, because the 5’PPP-NS1shRNA nanoplex modulates the immune response, the FDA recommends examining possible unintended adverse effects resulting from actions on the immune system. Thus, we will also identify the specific immune system components that are altered, as well as assess the immune-mediated complications of an IAV infection including increased severity of the respiratory tract injury, and the risk of IAV-associated secondary bacterial pneumonia, a major cause of death in influenza cases. Specifically, we will examine the ability of 5’PPP-NS1shRNA nanoplexes to stimulate innate antiviral immunity, thereby changing infiltration of inflammatory cells, inflammatory cytokine milieu, adaptive immune responses, as well as decrease respiratory injury and IAV-associated impairment of bacterial clearance. In addition to assessing the clearance of IAV from the respiratory tract, we predict that the nanoplex construct will reduce the morbidity and severity of symptoms of influenza from drug resistant seasonal and pandemic strains, the highly pathogenic H1N1 swine-origin IAV virus (S-OIV) and H5N1 “bird flu”. These nano-technological approaches can also potentially treat other infectious (i.e., Ebola) or non-infectious lung injuries. Our proposal is designed to produce a novel antiviral nanoplex formulation for Phase 1 clinical trials as an Investigational New Drug.

项目概要/摘要 人类甲型流感病毒 (IAV) 和乙型流感病毒以及禽流感 H5N1 耐药株的出现 具有大流行潜力的病毒，对唯一批准的抗病毒药物强调了开发的重要性 新的抗病毒策略。我们设计了阳离子纳米颗粒之间的静电复合物（即， 壳聚糖）和阴离子 RNA 在 IAV 感染期间靶向体内气道上皮细胞。这些纳米复合物 在体内诱导针对 IAV 的抗病毒生物活性，很少或没有不良的细胞或肺部不良反应 回应。纳米复合物结构通过 5'- 刺激早期 I 型干扰素 (IFN) 细胞反应 细胞内传感器 RIG-I 的三磷酸 (PPP)-RNA 结合。此外，5'PPP-NS1shRNA 纳米复合物制剂可抑制 IAV 毒力因子 NS1 的翻译，从而抑制 RIG-I 和宿主 细胞RNA成熟。肺非常适合抗病毒纳米复合物策略，因为它提供了一个门户 生物活性纳米复合物的吸入给药。我们已经证明这种策略可以抑制体内 IAV 复制治疗并避免“IFN悖论”，特别是减少IAV肺损伤和IAV 肺部细菌清除受损。当前提案的重点是优化治疗 5'PPP-NS1shRNA 纳米复合物制剂在体外和体内的作用。此外，我们建议携带 FDA 题为“抗病毒产品开发：进行和 向该机构提交病毒学研究。”这包括体外和体内实验来评估 治疗效果（抗病毒活性）、药代动力学、药物相互作用和病毒的发展 反抗。此外，由于 5’PPP-NS1shRNA 纳米复合物可调节免疫反应，FDA 建议检查对免疫系统的作用可能产生的意外不良影响。 因此，我们还将识别发生改变的特定免疫系统成分，并评估 IAV 感染的免疫介导并发症，包括呼吸道损伤严重程度增加， 以及 IAV 相关继发性细菌性肺炎的风险，这是流感病例死亡的主要原因。 具体来说，我们将检查 5'PPP-NS1shRNA 纳米复合物刺激先天抗病毒免疫的能力， 从而改变炎症细胞的浸润、炎症细胞因子环境、适应性免疫反应， 以及减少呼吸道损伤和 IAV 相关的细菌清除损伤。此外 评估 IAV 从呼吸道的清除率，我们预测纳米复合物构建体将减少 耐药季节性和大流行毒株引起的流感症状的发病率和严重程度， 致病性 H1N1 猪源 IAV 病毒 (S-OIV) 和 H5N1“禽流感”。这些纳米技术方法 还可以治疗其他传染性（即埃博拉）或非传染性肺损伤。我们的建议是这样设计的 生产一种新型抗病毒纳米复合制剂，作为研究新药用于一期临床试验。