Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages

摘要: Directed gene transfer into specific cell lineages in vivo is an attractive approach for both modulating expression and correcting inherited mutations such as emphysema caused by human α1 antitrypsin (hAAT) deficiency. However, somatic tissues are mainly comprised of heterogeneous, differentiated that can be short lived difficult to specifically transfect. Here, we describe intratracheally instilled lentiviral system able deliver genes selectively many 70% alveolar macrophages (AMs) the mouse lung. Following a single transduction, genetically tagged AMs persisted lung alveoli expressed transferred lifetime adult mouse. A prolonged macrophage lifespan, rather than precursor proliferation, accounted surprisingly sustained presence transduced AMs. We utilized this long-lived population achieve localized secretion therapeutic levels hAAT protein epithelial lining fluid. In established model emphysema, lentivirally delivered ameliorated progression evidenced attenuation increased compliance size. After 24 weeks expression, no humoral or cellular immune responses were detected. Our results challenge dogma suggest these cells may possible target therapy applications, including correction