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: 10700810
• 负责人: Brian Akerley
• 金额: $ 28.62万
• 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/10700810
• 关键词: Acceleration; Acute Lung Injury; 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; Distal; Dose; Double-Stranded RNA; Drug Kinetics; Drug toxicity; Elderly; Embryonic Development; Epithelial Cells; Epithelium; 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; Proliferating; Pulmonary Inflammation; 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; Tissue Differentiation; Tissues; Translating; Treatment Efficacy; United States; Viral Pneumonia; airway epithelium; airway inflammation; alveolar epithelium; 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; microRNA delivery; 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 的新型疗法来治疗细菌性肺炎中的急性肺损伤 细菌性肺炎是儿童和老年人严重和致命感染的主要原因。 在世界范围内，即使采用抗生素干预，许多患者仍然迅速进展为急性呼吸窘迫。 需要住院、重症监护和机械通气的综合征（ARDS） ARDS 的死亡率。 患者人数很高，许多幸存者仍面临着从各种长期并发症中恢复的漫长道路 ARDS 的肺功能障碍严重依赖于受损气道上皮的再生。 细胞，上皮损伤修复失败会损害肺功能，叶子和气道容易复发 目前尚无 FDA 批准的治疗方法来刺激感染和气道炎症。 肺组织修复肺损伤，这将为我们的肺炎/ARDS患者带来巨大的好处。 使用肺炎链球菌（Sp）引起的肺炎小鼠模型进行初步研究，我们 观察到急性肺损伤，伴有气道上皮细胞（AEC）的大量破坏和广泛的损伤 到实质的远端气道，类似于人类 ARDS 患者的病理描述。 发现 Sp 感染会诱导肺部表达一个特定的 miRNA 家族，该家族发挥着 为了测试该 miRNA 在胚胎发生过程中呼吸道上皮细胞生成中的作用。 为了修复肺损伤，我们用装载有“miRNA-mimic”的脂质体治疗了 Sp 感染的小鼠，脂质体是一种双 我们发现了一种旨在模拟和增强体内内源性 miRNA 功能的链状 RNA 分子。 给 Sp 感染的小鼠施用 miRNA 模拟物可促进气道上皮再生，从而导致 改善肺功能，增强宿主恢复和存活率，将这些发现转化为临床。 应用中，我们建议进一步改进这项技术，将 miRNA 模拟物靶向递送至发炎部位 肺，以提高疗效，尽量减少脱靶效应，并减少潜在的药物毒性。为此，我们将。 开发装载有 miRNA 模拟物的肺泡靶向脂质体 (ATL)，并评估肺蓄积和 我们还将比较静脉注射后与非靶向剂量的治疗效果。 评估 Sp 感染小鼠和 ex 的药代动力学/生物分布/药效学和安全性概况 这一阶段 STTR 项目的结果将为未来的研究奠定基础，以开发第一个 - 治疗肺炎/ARDS的再生医学类药物。