CSF2RA mutations cause hereditary pulmonary alveolar proteinosis (hPAP), a disorder of alveolar macrophage dysfunction, surfactant accumulation, and hypoxemic respiratory failure, and, in some patients, serious infections or pulmonary fibrosis - without an approved disease-specific therapy. After reporting hPAP in 2008, we developed diagnostics, identified a patient cohort, and defined its pathogenesis, presentation, and natural history. We discovered that lentiviral-mediated CSF2RA gene transfer restored GM-CSF signaling in hPAP patient macrophages. We developed and validated Csf2ra^KO mice as a model of hPAP and found pulmonary macrophage transplantation (PMT) corrected hPAP and normalized disease-related biomarkers. After reaching an agreement with the US FDA, a formal toxicology study demonstrated that PMT was safe, defined the cell dose-clinical benefit response relationship, and established a no adverse effects level (NOAEL), minimum effective dose, and maximum safe dose. In addition, we developed novel methods for manufacturing and certificating clinical grade, autologous CD34+ cell-derived, lentiviral vector-mediated CSF2RA gene-corrected macrophages under good manufacturing practice (GMP)-compliant conditions in our institutional GMP manufacturing facility. A macrophage cell product-delivery device compatibility study established the accuracy, viability, potency, composition, and sterility of delivering gene-corrected macrophages using a video-bronchoscope. Our investigational new drug application (IND 28593) and human clinical trial were approved by the FDA and our institutional review board and the clinical trial is scheduled to begin in 2023.