Hereditary pulmonary alveolar proteinosis (hPAP) is a rare lung disease characterized by the progressive accumulation of pulmonary surfactant in alveoli resulting in progressive hypoxemic respiratory failure, and in some patients, secondary infections and/or pulmonary fibrosis. While hPAP affects men, women, and children, most patients present as children. The lung structure appears well-preserved in many cases with pathogenesis being driven by the consequences of the filling of alveoli with surfactant sediment; however, some patients develop respiratory failure caused by pulmonary fibrosis requiring therapeutic lung transplantation.~Hereditary PAP is caused by homozygous or compound heterozygous mutations in the genes (CSF2RA or CSF2RB) encoding the GM-CSF receptor alpha or beta chains, respectively. Mutations in these genes disrupt GM-CSF receptor function, blocking GM-CSF signaling and impairing the removal of excess surfactant from alveoli by alveolar macrophages (AMs).~This study is an open-label, non-randomized, single center clinical treatment study to evaluate the feasibility of manufacturing CSF2RA gene-corrected macrophages, as well as the safety, tolerability, efficacy, and durability of CSF2RA gene correction/pulmonary macrophage transplantation (PMT) therapy in three patients with hPAP caused by recessive homozygous or compound heterozygous CSF2RA mutations. In addition to safety and tolerability, the clinical trial will evaluate outcome measures related to clinical efficacy and biologic signature of CSF2RA gene-correction/PMT therapy, as well as pharmacokinetics, pharmacodynamics, and the mechanism of action.~The clinical trial design includes a 2-month observation period, a Baseline visit, 5-month treatment period, and Short-, Medium-, and Long-Term follow-up periods of 1, 4, and 10 years, respectively. Each patient will serve as their own self-control and receive a split-dose comprising three administrations of autologous, bone marrow cluster of differentiation 34+ (CD34+) cell-derived, lentiviral CSF2RA gene-corrected macrophages at a minimum of 2-month intervals, delivered by direct bronchoscopic instillation of cells into individual lung segments (5.8x105 cells/segment); an increasing number of cells at each administration will be achieved by sequentially increasing the number of segments treated. Current standard medical care (whole lung lavage and supplemental oxygen) will be continuously available to all enrolled patients.~Assessments will include safety (adverse events and serious adverse events), tolerability (short-term, treatment-emergent pulmonary symptoms), efficacy (beneficial effects on clinical, physiological, and radiological manifestations of hPAP), durability (persistence of beneficial effects), and mechanism of action (persistence, CSF2RA-expression, and function of alveolar macrophages (AMs)).~Expected results will inform the feasibility, safety, tolerability, efficacy, durability, and mechanism of action of gene transfer/PMT as therapy of hPAP. These results will impact the field because it departs markedly from the current inefficient, highly invasive method of physically removing surfactant by whole lung lavage (WLL) and instead uses a novel approach to restore AM function. This study is expected to establish the feasibility of a novel, specific therapy for children with hPAP and a new type of cell transplantation therapy (PMT) that may be useful for other diseases.
The major goal of this study is to evaluate a new type of cell transplantation therapy for individuals with hereditary PAP, study a new treatment that may be useful for treatment of other diseases, and research mechanisms that drive the development and function of lung macrophages.