Novel protocols of inhaled GM-CSF therapy for patients with pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare lung disease in which build-up of surfactant-derived lipo-proteinaceous material can cause respiratory failure. Effective treatment is paramount to saving lives and existing options include partial or whole lung lavage, however, as there are limitations to this the development of new treatment options is needed. Dr Ryushi Tazawa of Tokyo Medical and Dental University (TMDU) is a member of Japanese PAP multi-disciplinary research team which has been working on the potential to treat PAP through the inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF), an essential agent for maintaining biological functions of alveolar macrophages to clean up alveoli. Originally, Dr Koh Nakata and his colleagues found in 1999 that most patients with PAP have the autoantibody against GM-CSF. The anti-GM-CSF autoantibody blocks GM-CSF and deteriorates alveolar macrophages and alveolar cleanliness. GM-CSF inhalation would represent a simple treatment that can be prescribed on an outpatient basis and inhaled at home. It is believed that inhaled CM-CSF could help restore functions of impaired alveolar macrophages and renew alveolar macrophages. Following a pilot study published in 2005 and a phase II study in 2010, Dr Koh Nakata secured the budget for regulatory approval of GM-CSF inhalation therapy for autoimmune PAP (aPAP) and a clinical trial for the treatment in 2016. The Pulmonary Alveolar Proteinosis GM-CSF Inhalation Efficacy (PAGE) trial with twelve institutions nationwide successfully demonstrated the safety and efficacy of GM-CSF inhalation for aPAP. Based on PAGE trial data, Japanese pharmaceutical authority approved GM-CSF inhalation as a therapy for aPAP in 2024. The research team is currently interested in optimising the inhalation modes using mathematical models and a combination therapy of whole lung lavage and inhalation methods for severe cases.