Researchers from Boston University School of Medicine (BUSM) have developed a technique to deliver therapeutic genes in vivo to mice with emphysema. Following a single in vivo lentiviral transduction, genetically tagged alveolar macrophages (AMs) persisted in lung alveoli and expressed transferred genes for the lifetime (two years) of the adult mouse, the team reports.
Their technique is detailed in The Journal of Clinical Investigation in an article titled “Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages.”
Gene transfer into specific cell lineages in vivo has been limited in many cell types by inefficient gene delivery as well as the limited life-span of differentiated cell types. The BUSM group decided to study alpha-1 antitrypsin deficiency, which is the most common inherited form of emphysema seen in young people due to a mutation in the alpha-1 antitrypsin gene.
They were able to deliver genes selectively to as much as 70% of a mouse lung's AMs, a cell type that contributes to emphysema. “We applied this novel approach to achieve sustained in vivo expression of normal human alpha-1 antitrypsin (hAAT) protein at levels able to ameliorate emphysema in mice,” says senior author, Darrell Kotton, M.D., an associate professor of medicine and pathology and co-director, Center for Regenerative Medicine at BUSM.
“The lung macrophages carrying the therapeutic gene survived in the lungs’ air sacks for the two-year lifetime of the treated mice following a single intratracheal injection of the lentiviral vector we had engineered,” Dr. Kotton continues. A prolonged macrophage lifespan rather than precursor cell proliferation accounted for the surprisingly sustained presence of transduced AMs, the scientists explain. They were thus able to utilize this long-lived population to achieve localized secretion of therapeutic levels of hAAT protein in lung epithelial lining fluid.
“The progression of emphysema in mice exposed to elastase was significantly improved by the gene therapy as evidenced by improvements in lung compliance and alveolar size,” adds Andrew Wilson, M.D., lead author of the study and an assistant professor of medicine at BUSM. After 24 weeks of sustained gene expression, no humoral or cellular immune responses to the human hAAT protein were detected.
“Our results challenge the dogma that lung macrophages are short-lived and suggest these differentiated cells as a target cell that may be considered for in vivo gene therapy applications including the sustained correction of hAAT deficiency,” Dr. Wilson concludes.