Lipid nanoparticle GM-CSF replacement for autoimmune pulmonary alveolar proteinosis
Abstract
Granulocyte–macrophage colony-stimulating factor (GM-CSF) deficiency drives autoimmune pulmonary alveolar proteinosis (aPAP), a disease characterized by impaired macrophage-mediated clearance of pulmonary surfactants. Clinical data suggest that inhaled recombinant GM-CSF reduces symptoms in aPAP patients, providing a rationale for mRNA-based GM-CSF replacement therapies. However, these require effective mRNA delivery after nebulization. Here, we report the iterative in vivo design of a lipid nanoparticle, named nebulized lung delivery 2 (NLD2), that efficiently delivers mRNA after nebulization. NLD2 carrying GM-CSF mRNA transfected alveolar macrophages in vivo, leading to interleukin-10 pathway activation and subsequent surfactant lipoprotein clearance. In a preclinical disease model of aPAP, GM-CSF mRNA delivery reduced surfactant protein thickness more than recombinant GM-CSF. These data support continued exploration of nebulized lipid nanoparticle therapies for aPAP.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Liming Lian
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Bora Jang
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Sebastian G. Huayamares
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology
Avraham Shakked
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Kara Gentry
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Ryan Zenhausern
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Afsane Radmand
Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology
Elisa Schrader Echeverri
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology
Vaunita C. Parihar
Cancer Tissue Pathology Shared Resource, Winship Cancer Institute, Emory University School of Medicine
Ricardo C. Guerrero-Ferreira
Robert P. Apkarian Integrated Electron Microscopy Core, Emory University School of Medicine
Randi Calkins
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology
Daryll Vanover
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology
Philip J. Santangelo
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology
Hyejin Kim
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
James E. Dahlman
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine