Targeted delivery of novel miRNA-based therapeutics for pneumonia-induced acute lung injury

基于 miRNA 的新型疗法的靶向递送治疗肺炎引起的急性肺损伤

• 批准号: 10395376
• 负责人: Brian Akerley
• 金额: $ 29.69万
• 依托单位: ADVAC THERAPEUTIC, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395376
• 关键词: Acute Lung Injury; Acute Pneumonia; Acute Respiratory Distress Syndrome; Address; Alveolar; Alveolus; Antibiotic Therapy; Antibiotics; Antibodies; Bacterial Pneumonia; Biodistribution; Blood; Blood Circulation; COVID-19 patient; Cells; Child; Chronic lung disease; Clinical Trials; Complication; Data; Defect; Diabetes Mellitus; Differentiation and Growth; Distal; Dose; Double-Stranded RNA; Drug Kinetics; Drug toxicity; Elderly; Embryonic Development; Epithelial; Epithelial Cells; FDA approved; Failure; Family; Formulation; Foundations; Functional disorder; Future; Generations; Goals; Growth; Hepatitis; Hospitalization; Human; Immune response; Impairment; Infection; Injury; Intensive Care; Intercellular adhesion molecule 1; Intervention; Investigation; Investigational Drugs; Kinetics; Link; Liposomes; Lung; Lung diseases; Lung infections; Mechanical ventilation; MicroRNAs; Modeling; Mus; Natural regeneration; Organ; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Play; Pneumococcal Infections; Pneumonia; Process; Quality Control; Recovery; Recovery of Function; Recurrence; Regenerative Medicine; Regimen; Respiratory Tract Infections; Role; Safety; Shortness of Breath; Signal Pathway; Small Business Technology Transfer Research; Streptococcus pneumoniae; Structure of parenchyma of lung; Supportive care; Survivors; Symptoms; Technology; Testing; Time; Tissues; Translating; Treatment Efficacy; United States; Viral Pneumonia; airway epithelium; airway inflammation; alveolar epithelium; base; cancer therapy; clinical application; cost estimate; epithelial repair; epithelial stem cell; epithelium regeneration; experience; fetal; frontier; improved; in vivo; influenza infection; intravenous administration; lung development; lung injury; lung repair; member; mortality; mouse model; nanoparticle delivery; novel; novel therapeutic intervention; pharmacodynamic biomarker; pneumonia model; pneumonia treatment; pre-clinical; preclinical study; pulmonary function; recurrent infection; regenerative; regenerative therapy; repaired; respiratory; safety assessment; targeted delivery; testing uptake; therapeutic miRNA; tissue regeneration; tissue repair

SUMMARY We propose to develop a novel miRNA-based therapeutic to treat acute lung injury in a bacterial pneumonia model. Bacterial pneumonia is a leading cause of serious and lethal infections in children and the elderly worldwide. Even with antibiotic intervention, many patients still rapidly progress to acute respiratory distress syndrome (ARDS) requiring hospitalization, intensive care, and mechanical ventilation. Mortality rate in ARDS patients is high, with many survivors still facing a long road to recovery from various long-term complications of lung dysfunction. Recovery from ARDS is critically dependent on regeneration of the damaged airway epithelial cells, and failure to repair epithelial damage impairs lung function and leaves airways vulnerable to recurrent infection and airway inflammation. There are currently no FDA approved therapies to stimulate regrowth of lung tissue to repair lung injury, which would provide great benefits to pneumonia/ARDS patients. In our preliminary studies using a mouse model of pneumonia caused by Streptococcus pneumoniae (Sp), we observed acute lung injury with substantial destruction of airway epithelial cells (AECs) and extensive damage to the distal airway of the parenchyma, similar to pathology described in human patients with ARDS. We discovered that Sp-infection induces lung expression in the lung of a specific family of miRNA that plays a critical role in the generation of respiratory epithelia during embryogenesis. To test the role of this miRNA in repairing lung injury, we treated Sp-infected mice with liposomes loaded with “miRNA-mimic”, a double- stranded RNA molecule intended to mimic and augment the function of endogenous miRNA in vivo. We found that administration of miRNA-mimic to Sp-infected mice promoted airway epithelial regeneration, resulting in improved lung function, enhanced host recovery and survival. To translate these findings into clinical application, we propose to further improve this technology with targeted delivery of miRNA-mimic to inflamed lungs, to increase efficacy, minimize off-target effects, and reduce potential drug toxicity. To this end, we will develop alveolar-targeted liposomes (ATLs) loaded with miRNA-mimic and assess lung accumulation and therapeutic efficacy after intravenous administration compared to the non-targeted counterparts. We will also evaluate pharmacokinetics/bio-distribution/pharmacodynamics and safety profiles in Sp-infected mice and ex vivo human lung. The results of this phase I STTR project will set the stage for future studies to develop a first- in-class drug of regenerative medicine for treating pneumonia/ARDS.

概括 我们建议开发一种基于miRNA的新型疗法，以治疗肺炎细菌中的急性肺损伤 模型。细菌性肺炎是儿童严重和致命感染的主要原因 全世界。即使采用抗生素干预，许多患者仍然迅速发展为急性呼吸窘迫 需要住院，重症监护和机械通气的综合征（ARDS）。阿尔德的死亡率 患者很高，许多表面仍然面临着从各种长期并发症中恢复的漫长道路 肺功能障碍。从ARDS中恢复至关重要取决于受损气道上皮的再生 细胞，无法修复上皮损伤会损害肺功能，并使气道很容易发生 感染和气道注射。目前尚无FDA批准的疗法来刺激原因 肺组织可修复肺损伤，这将为肺炎/ARDS患者带来巨大益处。在我们的 初步研究使用肺炎链球菌引起的肺炎小鼠模型（SP），我们 观察到急性肺损伤，气道上皮细胞（AEC）严重破坏和广泛的损害 到副群的远端气道，类似于人类ARDS患者中描述的病理学。我们 发现SP感染在特定的miRNA家族的肺中诱导肺表达 在胚胎发生过程中的呼吸性上皮生成中的关键作用。测试该miRNA在 修复肺损伤，我们用带有“ miRNA-MIMIC”的脂质体处理了SP感染的小鼠，这是双重的 滞留的RNA分子旨在模仿和增强体内内源miRNA的功能。我们发现 给予miRNA对SP感染的小鼠的给药促进了气道上皮再生，导致 改善的肺功能，增强的宿主恢复和生存。将这些发现转化为临床 应用，我们建议通过针对MiRNA-MIMIC的靶向输送到发炎，以进一步改进这项技术 肺部提高有效性，最大程度地减少脱靶作用，并降低潜在的药物毒性。为此，我们将 开发靶向肺泡靶向脂质体（ATL），该脂质体（ATLS）充满miRNA-MIMIC和评估肺积累， 与未靶向的对应物相比，静脉内给药后的治疗效率。我们也会 评估SP感染的小鼠和EX的药代动力学/生物分布/药效学和安全概况 体内人肺。此I阶段ISTTR项目的结果将为未来的研究奠定阶段，以开发第一台研究 用于治疗肺炎/ARDS的再生医学的班级药物。