Amelioration of lung function and pulmonary tissue regeneration after treatment with AAT-expressing human mscs in a murine model of elastase-induced emphysema

      Chronic obstructive pulmonary disease (COPD) is a devastating lung disease characterized by progressive airflow limitation, chronic bronchitis, emphysema, and small airway remodeling. It is currently the third leading cause of death worldwide. There is no cure for COPD to date, thus innovative alternative treatments are desperately needed. Although the molecular mechanisms leading to COPD development are still incompletely understood, chronic inflammation of the lung parenchyma and a protease-antiprotease imbalance are hypothesized to be crucially involved in COPD pathogenesis. We developed a novel cell therapy product composed of bone marrow-derived mesenchymal stem/stromal cells (MSCs) which are genetically modified to stably express the protease inhibitor alpha-1 antitrypsin (AAT). Using this approach, it is possible to combine the potent immunomodulatory and cytoprotective properties of MSCs with the immunoregulatory and protease inhibition functions of AAT. After generation of an optimized AAT expression cassette, in vitro functionality of transgenically expressed AAT was confirmed by a neutrophil elastase inhibition assay. Next, a process for large scale transduction and expansion of gene-modified MSCs was established. To evaluate the therapeutic benefit of AAT-MSCs in vivo, a mouse model of elastase-induced emphysema was performed. Treatment of the mice with AAT-MSCs resulted in significant improvement of pulmonary function parameters, while only a slight functional amelioration was observed after treatment with non-modified MSCs. Application of AAT protein isolated from human plasma alone did not improve lung functions. Histopathologic examination of AAT-MSC-treated mice revealed a significant decrease of airspace enlargement, indicating regeneration of pulmonary tissue. Again, we did not observe an effect on pulmonary tissue after treatment with non-modified MSCs or AAT protein, suggesting a synergistic effect of AAT and MSCs. In conclusion, the present study provides the first in vivo proof of concept for the treatment of emphysematous COPD with AAT-MSCs.
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