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.
Public Health Relevance Statement: Narrative Acute respiratory distress syndrome (ARDS) is a rapidly progressing lung disease with a very high mortality rate. Many patients who recover from ARDS will still experience various long-term complications of lung dysfunction, such as shortness of breath. The single most frequent cause of ARDS is pulmonary infections including bacterial here are relatively few treatments available for ARDS, with supportive care via mechanical ventilation as the mainstay of management. In this study, we will develop a novel miRNA-based therapeutic that will stimulate regeneration of lung cells and enhance repair of lung injury for treatment of ARDS induced by pneumonia. and viral pneumonia. ARDS has been the most serious complication in COVID-19 patients. Currently, t
Project Terms: Elderly; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antibodies; Bacterial Pneumonia; bacteria pneumonia; Blood; Blood Reticuloendothelial System; Blood Circulation; Bloodstream; Circulation; Cells; Cell Body; Child; 0-11 years old; Child Youth; Children (0-21); youngster; Clinical Trials; Complication; Diabetes Mellitus; diabetes; intravenous administration; Drug toxicity; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Embryonic Development; Embryo Development; Embryogenesis; Epithelial Cells; Family; Foundations; Future; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Hepatitis; Hospitalization; Hospital Admission; Human; Modern Man; Infection; Kinetics; Liposomes; Liposomal; Lung; Lung Respiratory System; pulmonary; Lung diseases; Pulmonary Diseases; Pulmonary Disorder; disease of the lung; disorder of the lung; lung disorder; mortality; Mus; Mice; Mice Mammals; Murine; Pathology; Patients; Pharmacokinetics; Drug Kinetics; Play; Streptococcus pneumoniae Infections; pneumococcal disease; pneumococcus infection; Pneumococcal Infections; Pneumonia; Viral Pneumonia; Quality Control; Recurrent; Recurrence; Regeneration; regenerate; Natural regeneration; ARDS; Acute Respiratory Distress; Adult ARDS; Adult RDS; Adult Respiratory Distress Syndrome; Da Nang Lung; Shock Lung; Stiff lung; wet lung; Acute Respiratory Distress Syndrome; Airway infections; Respiratory Infections; Respiratory Tract Infections; dsRNA; Double-Stranded RNA; social role; Role; Safety; Signal Pathway; D pneumoniae; D. pneumoniae; Diplococcus pneumoniae; Pneumococcus; S pneumoniae; S. pneumoniae; Streptococcus pneumoniae; Technology; Testing; Time; Tissues; Body Tissues; Translating; United States; Intercellular adhesion molecule 1; CD54 Antigens; ICAM-1; Generations; Intensive Care; Injury; injuries; base; Organ; improved; Mechanical ventilation; mechanical respiratory assist; mechanically ventilated; Distal; repaired; repair; Phase; Survivors; Link; Epithelial; Lung Alveolar Epithelia; alveolar epithelium; Failure; lung function; pulmonary function; Recovery; Acute Pulmonary Injury; Acute Lung Injury; Lung damage; pulmonary damage; pulmonary injury; pulmonary tissue damage; pulmonary tissue injury; lung injury; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Immunological response; host response; immune system response; immunoresponse; Immune response; Antibiotic Treatment; bacterial disease treatment; bacterial infectious disease treatment; Antibiotic Therapy; Supportive Therapy; Supportive care; Shortness of Breath; Investigation; respiratory; fetal; experience; functional recovery; Recovery of Function; novel; member; Acute Pneumonia; chronic pulmonary disease; Chronic lung disease; Lung Parenchyma; Lung Tissue; Structure of parenchyma of lung; Pharmacodynamics; Modeling; Intervention Strategies; interventional strategy; Intervention; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; MicroRNAs; Micro RNA; miRNA; miRNAs; lung development; Regenerative Medicine; Alveolar; Address; Dose; Defect; Symptoms; Data; Differentiation and Growth; in vivo; Alveolus; Bronchial Alveolus; Small Business Technology Transfer Research; STTR; Process; tissue regeneration; regenerate new tissue; regenerate tissue; regenerating damaged tissue; regenerating tissue; tissue regrowth; tissue renewal; tissue specific regeneration; pre-clinical; preclinical; preclinical study; pre-clinical study; airway inflammation; airway epithelium inflammation; respiratory inflammation; respiratory tract inflammation; Biodistribution; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; targeted delivery; site targeted delivery; frontier; Impairment; airway epithelium; Respiratory Epithelium; Structure of respiratory epithelium; clinical application; clinical applicability; mouse model; murine model; regenerative therapy; regeneration based therapy; regeneration therapy; regenerative therapeutics; novel therapeutic intervention; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; FDA approved; regenerative; Regimen; lung repair; lung tissue repair; pulmonary repair; tissue repair; therapeutic miRNA; miR therapy; miR-based therapeutic; miR-based therapy; miRNA therapy; miRNA-based therapeutic; miRNA-based therapy; microRNA-based therapy; therapeutic miRs; therapeutic microRNA; Formulation; pharmacodynamic biomarker; pharmacodynamic marker; Lung infections; pulmonary infections; pneumonia model; pneumonia models; nanoparticle delivery; nano particle delivery; nanoparticle delivered; safety assessment; recurrent infection; infection recurrence; cost estimate; cost estimation; epithelial stem cell; epithelial progenitor cell; epithelium regeneration; regenerate epithelium; influenza infection; flu infection; flu virus infection; infected with flu; infected with flu virus; infected with influenza; infected with influenza virus; influenza virus infection; COVID-19 patient; COVID infected patient; COVID patient; COVID positive patient; COVID-19 infected patient; COVID-19 positive patient; COVID19 patient; COVID19 positive patient; SARS-CoV-2 infected patient; SARS-CoV-2 patient; SARS-CoV-2 positive patient; coronavirus disease 2019 infected patient; coronavirus disease 2019 patient; coronavirus disease 2019 positive patient; coronavirus disease infected patient; coronavirus disease patient; coronavirus disease positive patient; coronavirus disease-19 patient; coronavirus patient; patient infected with COVID; patient infected with COVID-19; patient infected with SARS-CoV-2; patient infected with coronavirus disease; patient infected with coronavirus disease 2019; patient infected with severe acute respiratory syndrome coronavirus 2; patient with COVID; patient with COVID-19; patient with COVID19; patient with SARS-CoV-2; patient with coronavirus disease; patient with coronavirus disease 2019; patient with severe acute respiratory distress syndrome coronavirus 2; severe acute respiratory syndrome coronavirus 2 infected patient; severe acute respiratory syndrome coronavirus 2 patient; severe acute respiratory syndrome coronavirus 2 positive patient; testing uptake; pneumonia treatment; pneumonia therapy; treat pneumonia; epithelial repair
