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Therapeutics for Rare and Neglected Diseases

Inhaled GM-CSF Therapy of Autoimmune Pulmonary Alveolar Proteinosis

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease marked by an accumulation of surfactant (proteins and lipids) in the narrow gas exchange pockets of the lung, leading to respiratory failure. Patients generate antibodies against a normal protein, Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), neutralizing its ability to signal to important immune cells (macrophages), whose function is critical for the proper clearance of accumulated surfactant. Current therapy requires lifelong, periodic washing of the lungs (whole lung lavage, or WLL) under general anesthesia, a risky and invasive procedure that is particularly problematic in children. The purpose of this project is to develop an inhaler-based formulation of the GM-CSF protein to stimulate PAP patients’ own immune cells to properly clear the lungs and thus avoid WLL.

Scientific Synopsis

In autoimmune PAP, patients generate antibodies against the GM-CSF protein normally found in circulation. GM-CSF plays an important role in the development and activation of macrophages. In the lungs, surfactant proteins and lipids facilitate gas exchange in the alveoli. Alveolar macrophages are responsible for maintaining surfactant homeostasis. If circulating autoantibodies prevent functional GM-CSF from reaching the alveoli, alveolar macrophages fail to clear accumulated surfactant. If not properly cleared, excess surfactant accumulation can lead to shortness of breath, decreased oxygenation, and increased risk of lung infections. The goal of this project is to develop inhaled recombinant human GM-CSF as therapy for autoimmune PAP and directly deliver GM-CSF to the lungs. As GM-CSF is currently used as an intravenous treatment for other conditions, the Food and Drug Administration (FDA) has required the completion of a formal toxicology study to ensure safety via the inhalation route before proceeding to further clinical trials in humans for PAP.

Lead Collaborator

Cincinnati Children’s Hospital Medical Center
Bruce Trapnell, M.D.

Public Health Impact

Current WLL treatment for PAP requires general anesthesia and hospitalization. It is a risky and invasive procedure, particularly for children with the disease. No other therapeutic treatments are available for this rare disease. Inhaled GM-CSF would be a major improvement over standard care.


A comprehensive project plan was developed by TRND researchers and the lead collaborators at Cincinnati Children’s Hospital. The team subsequently entered into collaboration with Genzyme Corp., which provided essential research materials to the partnership. TRND scientists supported extensive preliminary toxicology and dosing studies in primates, which were necessary to demonstrate the safety of using inhaled GM-CSF. TRND supported formal toxicology studies that enabled the lead collaborator to successfully open an Investigational New Drug (IND) application with the FDA. The lead collaborator subsequently secured additional resources through the NCATS Division of Clinical Innovation, Clinical and Translational Science Awards (CTSA) Program to support a Phase 1 clinical evaluation of inhaled GM-CSF in autoimmune PAP patients, utilizing existing infrastructure provided by the Rare Lung Diseases Consortium.

Last updated: 12-24-2016
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