Hereditary pulmonary alveolar proteinosis (PAP) is a genetic lung disease characterized by surfactant accumulation and respiratory failure arising from disruption of GM-CSF signaling. While mutations in either CSF2RA or CSF2RB (encoding GM-CSF receptor α or β chains， respectively) can cause PAP， α chain mutations are responsible in most patients. Pulmonary macrophage transplantation (PMT) is a promising new cell therapy in development; however， no studies have evaluated this approach for hereditary PAP (hPAP) caused by Csf2ra mutations. Here， we report on the preclinical safety， tolerability， and efficacy of lentiviral-vector (LV)-mediated Csf2ra expression in macrophages and PMT of gene-correcte... More
Hereditary pulmonary alveolar proteinosis (PAP) is a genetic lung disease characterized by surfactant accumulation and respiratory failure arising from disruption of GM-CSF signaling. While mutations in either CSF2RA or CSF2RB (encoding GM-CSF receptor α or β chains， respectively) can cause PAP， α chain mutations are responsible in most patients. Pulmonary macrophage transplantation (PMT) is a promising new cell therapy in development; however， no studies have evaluated this approach for hereditary PAP (hPAP) caused by Csf2ra mutations. Here， we report on the preclinical safety， tolerability， and efficacy of lentiviral-vector (LV)-mediated Csf2ra expression in macrophages and PMT of gene-corrected macrophages (gene-PMT therapy) in Csf2ra gene-ablated (Csf2ra) mice. Gene-PMT therapy resulted in a stable transgene integration and correction of GM-CSF signaling and functions in Csf2ra macrophages in vitro and in vivo and resulted in engraftment and long-term persistence of gene-corrected macrophages in alveoli; restoration of pulmonary surfactant homeostasis; correction of PAP-specific cytologic， histologic， and biomarker abnormalities; and reduced inflammation associated with disease progression in untreated mice. No adverse consequences of gene-PMT therapy in Csf2ra mice were observed. Results demonstrate that gene-PMT therapy of hPAP in Csf2ra mice was highly efficacious， durable， safe， and well tolerated.
