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: 10599904
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599904
• 关键词: Acute Lung Injury; Adverse effects; Antiviral Agents; Antiviral resistance; Avian Influenza; Bacterial Pneumonia; Birds; Cardiac; 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; Inflammatory; Inflammatory Infiltrate; 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; 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; Persons; Pharmaceutical Preparations; Phase I Clinical Trials; Polymerase; Population; Production; RNA; RNA Binding; RNA Interference; Recommendation; Resistance development; Respiratory System; Risk; Seasons; Secondary to; Severities; Standardization; Symptoms; Therapeutic; Time; Translations; Treatment Efficacy; Vaccines; Viral; Viral Physiology; 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; immunoregulation; improved; in vivo; influenza virus strain; influenzavirus; inhibitor; injured airway; lung injury; mortality; nano; nanoparticle; nanoprocess; novel; novel strategies; novel therapeutic intervention; pandemic disease; pandemic potential; product development; prophylactic; resistant strain; response; seasonal influenza; sensor; swine flu; transmission process; tripolyphosphate; viral resistance

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.

项目摘要/摘要 人类影响力抗药性菌株（IAV）和B病毒的出现以及禽类H5N1的出现 具有流行潜力的病毒，唯一认可的抗病毒药强调了发展的重要性 新颖的抗病毒策略。我们已经在阳离子纳米颗粒之间设计了静电复合物（即 壳聚糖）和阴离子RNA在IAV感染过程中靶向体内气道上皮细胞。这些纳米旋转 诱导针对IAV的抗病毒生物活性，几乎没有或没有肺部或肺 回答。纳米旋转构建体刺激了早期的I型干扰素（IFN）细胞反应通过5'-- 三磷酸（PPP） - 细胞内传感器的RNA结合，RIG-I。另外，5'ppp-ns1shrna Nanoplex公式抑制IAV病毒因子NS1的翻译，该因子抑制RIG-I和宿主 细胞RNA成熟。肺非常适合抗病毒纳米旋转策略，因为它为门户提供了门户 吸入生物活性纳米旋转。我们已经证明，该策略抑制了体内IAV 复制并避免“ IFN悖论”，特别减少IAV肺损伤，而IAV 肺部细菌清除受损。当前建议的重点是优化治疗性 5'ppp-NS1SHRNA纳米旋转公式在体外，然后在体内的作用。此外，我们建议携带 FDA文章推荐的题为“抗病毒产品开发：进行和 将病毒学研究提交给该机构。”这包括体外和体内实验以评估 治疗效率（抗病毒活性），药代动力学，药物相互作用和病毒的发展 反抗。另外，因为5'ppp-ns1shrna纳米旋转可调节免疫反应，所以FDA 建议检查由免疫系统作用引起的可能的意外不良影响。 这是，我们还将确定所改变的特定免疫系统成分，并评估 IAV感染的免疫介导的并发症，包括增加呼吸道损伤的严重程度， 以及与IAV相关的继发性细菌性肺炎的风险，这是影响力病例中的主要死亡原因。 具体而言，我们将检查5'ppp-NS1SHRNA纳米插曲刺激先天抗病毒免疫（a）的能力， 从而改变炎性细胞的浸润，炎性细胞因子环境，适应性免疫反应， 以及减少呼吸道损伤和IAV相关细菌清除率的损伤。此外 评估IAV从呼吸道的清除率，我们预测纳米旋转构建体将减少 抗药性季节性和大流行菌株的发病率和影响症状的严重程度，高度 致病性H1N1猪原生IAV病毒（S-OIV）和H5N1“鸟流感”。这些纳米技术方法 还可以可能治疗其他感染性（即埃博拉病毒）或非感染性肺损伤。我们的建议是设计的 为了生产一种新型的抗病毒纳米纳普利公式，用于1阶段临床试验作为研究新药。

项目成果

Human Innate Lymphoid Cells in Influenza Infection and Vaccination.

• DOI: 10.1615/critrevimmunol.2021040801
• 发表时间: 2021
• 期刊: CRITICAL REVIEWS IN IMMUNOLOGY
• 影响因子: 1.3
• 作者: Kumar, Amrita;Kumari, Rashmi;Liu, Timothy;Cao, Weiping;Davidson, Bruce A.;Knight, Paul R.;Sambhara, Suryaprakash
• 通讯作者: Sambhara, Suryaprakash