Acute lung injury (ALI), Acute Respiratory Distress Syndrome (ARDS), and Neonatal Respiratory Distress Syndrome (NRDS) are common, devastating clinical syndromes that affect large numbers of adult and neonatal patients (200,000 cases in the US per year) and have approximately 25% mortality with the current standard of care. We have developed a highly effective treatment for this disease in pig models that uses the ubiquitous overexpression of the Na+, K+-ATPase and epithelial sodium channel ENaC to increase alveolar fluid clearance from the previously injured lung. Our experiments show that this treatment not only improves edema resolution (and lung function and survival), but also improves alveolar epithelial/endothelial barrier function by upregulating tight junction complexes in both animal models. Highly efficient and safe gene delivery is carried out using electroporation, the application of brief synchronized square wave electric pulses across the chest. The procedure causes no trauma, no inflammation, no lung injury, no cardiac dysfunction, and uses less than 0.1 J/kg of energy. We also have developed a chronic (48 h) sepsis + gut ischemia/reperfusion pig model that accurately parallels the pathologic progression from injury to systemic inflammatory response syndrome (SIRS), to septic shock and finally to ARDS seen in human patients. Following injury, the animals are maintained, anesthetized, according to the clinical standard of care ARDSnet treatment paradigm, making comparisons to existing human clinical trial data more relevant and clear. Four hours after injury, empty control or Na+, K+-ATPase- and ENaC-expressing plasmids were electroporated into the lungs of these animals. While pigs receiving empty plasmids died from lung failure, kidney failure, and hemodynamic collapse between 24 and 40 hours after injury, animals receiving Na+,K+-ATPase- and ENaC-expressing plasmids showed greatly improved lung function, improved kidney function, less injured lungs upon gross and microscopic histological analysis, less pulmonary edema, and 60% survival (p<0.01). More impressively, an animal that received treatment plasmids when blood oxygenation dropped to the clinically defined values for ARDS of PaO2/FiO2?300 (26 hours after injury) also showed improved lung function, survival to 48 hrs. and less injured lungs by histology. The experiments in this proposal will address questions and collect critical preclinical data needed to proceed to an IND filing with the FDA and move this treatment platform and this specific therapy forward to clinical trials.
Our Aims are to (1) Test whether gene transfer of Na+, K+-ATPase alone can lessen injury and improve outcome in our pig ARDS model compared to co-transfer of Na+, K+-ATPase and ENaC genes, (2) Determine the golden hour or window of electroporation-mediated Na+, K+-ATPase/ENaC gene therapy treatment following injury, and (3) Determine how long the electroporation-mediated treatment provides survival and clinical benefit.
Acute lung injury, Acute Respiratory Distress Syndrome (ARDS), and Neonatal Respiratory Distress Syndrome are common, devastating clinical syndromes that affect an estimated 200,000 adult and neonatal patients each year in the US and have up to 40% mortality with the current standard of care. We have developed a nonviral gene therapy approach using electric fields that can effectively treat existing ARDS in a spetic pig model of acute lung injury. The work proposed in this study will extend these findings to determine the optimal time for treatment following injury, the duration of treatment efficacy, and will optimize the treatment plan. At the end of the study, we will have demonstrated efficacy of this novel approach to treat lung injury in an established pre-clinical model for the ultimate treatment of patients in the near future.
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