Inhaled GM-CSF Therapy of Autoimmune Pulmonary Alveolar Proteinosis

National Center For Advancing Translational Sciences

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Abstract

Pulmonary alveolar proteinosis (PAP) is a rare disease marked by accumulation of proteins and lipids in the narrow gas exchange pockets of the lung, leading to respiratory failure. PAP is an autoimmune disorder in which patients generate antibodies against a normal protein found in the circulation (GM-CSF), which is a critical modulator of macrophage development. When circulating macrophages are impaired, they are unable to reach the lungs and clear the accumulated proteins and lipids. The goal of this project is to develop inhaled GM-CSF as therapy for PAP. As GM-CSF is currently used as an intravenous treatment for other conditions, the Food and Drug Administration has required the completion of a formal toxicology study to ensure safety before proceeding to further clinical trials in humans for PAP. The lead collaborators at Cincinnati Childrens Hospital previously demonstrated the efficacy of using inhaled GM-CSF to stimulate the alveolar macrophages in aPAP patients. The TRND-Cincinnati team subsequently entered into collaboration with Genzyme Corporation (now Sanofi Genzyme) to provide the rhGM-CSF drug, Leukine(Sargramostim). TRND scientists supported extensive preliminary primate toxicology and dosing studies necessary to demonstrate the safety of using inhaled GM-CSF, as well as formal Good Laboratory Practice (GLP) toxicology studies. With these data, the team received concurrence from the FDA to initiate a limited Phase 1 pharmacokinetic and pharmacodynamic study in aPAP patients, which is ongoing.