Nanomicellar antiviral strategies for RSV infection

RSV 感染的纳米胶束抗病毒策略

• 批准号: 10516004
• 负责人: Shyam S Mohapatra
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516004
• 关键词: 3-Dimensional; Adult; Aging; Antibiotic Therapy; Antibodies; Arrhythmia; Asthma; Atrial Tachycardia; Attenuated; Biodistribution; Biological Availability; Biological Models; Biology; Bone Marrow; Bronchiolitis; Cause of Death; Cell fusion; Cell membrane; Cells; Cessation of life; Chimeric Proteins; Chronic Obstructive Pulmonary Disease; Clinical Trials; Cyclophosphamide; DNA; Development; Drug Screening; Elderly; Epithelial Cells; FDA approved; Formulation; Future; Genes; Goals; Health; Hospitalization; Human; Immunocompromised Host; Immunologic Deficiency Syndromes; In Vitro; Incidence; Infant; Infection; Investigational Drugs; Knowledge; Lead; Lung; Lung diseases; Mesenchymal; Mesenchymal Stem Cells; Micelles; Modeling; Mus; Organ Transplantation; Palivizumab; Pathology; Peptides; Persons; Pharmaceutical Preparations; Phospholipids; Plasmids; Pneumonia; Pre-Clinical Model; Property; Prophylactic treatment; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Ribavirin; Safety; Small Interfering RNA; Solid; Surface; Testing; Therapeutic; Translating; Treatment Efficacy; United States; Vaccines; Veterans; Virus; base; comorbidity; effective therapy; high risk; high risk infant; human old age (65+); humanized antibody; humanized mouse; immunopathology; improved; inhibitor; innovation; molecular modeling; mortality; mouse model; multidisciplinary; nanoformulation; nanomedicine; nanoparticle; nanotherapy; novel; novel vaccines; pathogen; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; prevent; programs; prophylactic; respiratory pathogen; scaffold; self assembly; side effect; small molecule; translational study

The major goal of this program is to further develop and translate recent discoveries in biology of respiratory syncytial virus (RSV), an important pathogen that infects an estimated 64 million people and causes ~200, 000 deaths globally every year. In the US, RSV causes >11,000 deaths of elderly annually. There is no effective treatment or vaccine against RSV infection. Currently, only high-risk infants receive antibody-based prophylaxis, which is expensive and moderately effective in reducing hospitalization. Therefore, a broadly applicable, effective and inexpensive approach to prevent or treat RSV-bronchiolitis or -pneumonia remains an urgent unmet need. This proposal to develop and test a novel prophylaxis and/or therapy against RSV infection was inspired by the following discoveries. i) A platform of phospholipid micellar nanoparticles (PMN) was developed, which when given intranasally delivers payload predominantly to the lung. ii) A decoy short heptad repeat (HR)2 peptide was identified, which effectively inhibits the RSV-cell fusion. iii) Human mesenchymal cells were found to be highly susceptible to RSV. The latter aided in establishing a novel 3D scaffold for anti-RSV drug screens, which consisted of creating a naked mouse lung scaffold (nMLS) by decellularization followed by recellularization of the nMLS with desired human cells, such as hMSCs and epithelial cells and then infecting the cells in scaffold with RSV. iv) A robust immunocompromised mouse model was created by combining cyclophosphamide treatment with infection by a highly mucogenic strain, RSV-L19F. These developments have led to the hypothesis that a RSV-targeted PMN (RTPMN), combining HR2D anti-fusion peptide, and plasmid encoded siRNAs against RSV-NS1 and/or RSV-P gene can provide a safe, effective and inexpensive anti-RSV prophylaxis and/or therapy. Three specific aims (SAs) will test these hypotheses. In SA#1, multifunctional and smart RTPMNs will be synthesized with plasmids encoding siRNAs for RSV-NS1and RSV-P genes in the core and anti-fusion HR2D peptides on the surface and be characterized in vitro. In SA#2, RTPMNs will be examined for their biodistribution, pharm-tox and PK/PD properties. SA#3 will examine the prophylactic and therapeutic potential of RTPMN- HR2D-psiNS1-P against RSV infection in an in vitro 3D lung scaffold and in immunocompromised mice to investigate the mechanism of action. The results of these highly innovative multidisciplinary translational studies are expected to increase the understanding of RSV pathology in humanized mouse lung model and in a model using adult immunocompromised mice. A successful completion of preclinical formulation of anti- RSV PMN-based prophylactics and therapeutics is expected to pave the way to IND-driven studies and clinical trials.

该计划的主要目标是进一步发展和翻译生物学的最新发现 呼吸综合病毒（RSV），这是一种重要的病原体，估计有6400万人 每年全球造成约200,000人死亡。在美国，RSV导致> 11,000人死亡 每年老年人。没有有效的治疗方法或针对RSV感染的疫苗。目前，只有 高风险的婴儿接受基于抗体的预防，这是昂贵且有效的 在减少住院。因此，一种广泛适用，有效且廉价的方法 预防或治疗RSV-支气管炎或-Pneumonia仍然是紧迫的未满足需求。 这项开发和测试针对RSV感染的新型预防和/或治疗的建议是 受到以下发现的启发。 i）磷脂胶束纳米颗粒（PMN）的平台 是开发的，当鼻内提供有效载荷时，主要为肺部提供有效载荷。 ii）a 鉴定了诱饵短赫普特重复（HR）2肽，这有效地抑制了RSV细胞 融合。 iii）发现人间质细胞高度易于RSV。后者有助于 在建立抗RSV药物屏幕的新颖的3D支架时，该脚架包括创建一个裸 小鼠肺支架（NMLS）通过脱细胞化，然后与NML进行覆盖 所需的人类细胞，例如HMSC和上皮细胞，然后感染脚手架中的细胞 使用RSV。 iv）通过组合创建了强大的免疫功能低下的鼠标模型 通过高度粘膜菌株RSV-L19F感染的环磷酰胺治疗。这些 发展导致了一个假设，即结合了HR2D的RSV靶向PMN（RTPMN） 针对RSV-NS1和/或RSV-P基因的抗融合肽和质粒编码的siRNA可以 提供安全，有效且廉价的抗RSV预防和/或治疗。三个具体目标 （SAS）将检验这些假设。 在SA＃1中，多功能和智能RTPMN将与编码质粒合成 核心和抗融合HR2D肽的RSV-NS1和RSV-P基因的siRNA 并在体外表征。在SA＃2中，将检查RTPMN的生物分布，Pharm-T​​ox 和PK/PD属性。 SA＃3将检查RTPMN-的预防和治疗潜力 HR2D-PSINS1-P在体外3D肺支架中针对RSV感染和免疫功能低下 小鼠研究作用机理。 这些高度创新的多学科翻译研究的结果有望 增加对人源化小鼠肺模型中RSV病理的理解和模型 使用成年免疫功能低下的小鼠。成功完成了抗临床前制定的抗 基于RSV PMN的预防药物和治疗学有望为辅助研究铺平道路 和临床试验。