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Bone Marrow Failure
Effective hematopoietic stem cell-based gene therapy in a murine model of hereditary pulmonary alveolar proteinosis
Miriam Hetzel,1 Elena Lopez-Rodriguez,2 Adele Mucci,1 Ariane Hai Ha Nguyen,1 Takuji Suzuki,3,4 Kenjiro Shima,3 Theresa Buchegger,1 Sabine Dettmer,5 Thomas Rodt,5 Jens P. Bankstahl,6 Punam Malik,7 Lars Knudsen,2 Axel Schambach,1,8 Gesine Hansen,9 Bruce C. Trapnell,3,10 Nico Lachmann1*
and Thomas Moritz1*
1Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany; 2Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; 3Translational Pulmonary Science Center, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; 4Division of Pulmonary Medicine, Jichi Medical University, Shimotsukeshi, Tochigi, Japan; 5Department of Radiology, Hannover Medical School, Hannover, Germany; 6Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany; 7Division of Experimental Hematology and Cancer Biology, Cancer and Blood Disease Institute (CBDI), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; 8Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; 9Department of Pediatrics, Allergology, and Neonatology, Hannover Medical School, Hannover, Germany and 10Division of Pulmonary Medicine, Children's Hospital Medical Center, Cincinnati, OH, USA
*NL and TM contributed equally to this work.
ABSTRACT
Hereditary pulmonary alveolar proteinosis due to GM-CSF recep- tor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein second- ary to defective alveolar macrophage function. As current therapeutic options are primarily symptomatic, we have explored the potential of hematopoietic stem cell-based gene therapy. Using Csf2rb-/- mice, a model closely reflecting the human herPAP disease phenotype, we here demonstrate robust pulmonary engraftment of an alveolar macrophage population following intravenous transplantation of lentivirally corrected hematopoietic stem and progenitor cells. Engraftment was associated with marked improvement of critical herPAP disease parameters, includ- ing bronchoalveolar fluid protein, cholesterol and cytokine levels, pul- monary density on computed tomography scans, pulmonary deposition of Periodic Acid-Schiff+ material as well as respiratory mechanics. These effects were stable for at least nine months. With respect to engraftment and alveolar macrophage differentiation kinetics, we demonstrate the rapid development of CD11c+/SiglecF+ cells in the lungs from a CD11c–/SiglecF+ progenitor population within four weeks after trans- plantation. Based on these data, we suggest hematopoietic stem cell- based gene therapy as an effective and cause-directed treatment approach for herPAP.
Introduction
Hereditary pulmonary alveolar proteinosis (herPAP) represents an extremely rare life-threatening genetic disorder associated with malfunction of alveolar macrophages (AM).1 HerPAP is caused by mutations in genes encoding the granu- locyte/macrophage-colony-stimulating factor receptor (GM-CSFR), a high-affinity receptor complex composed of a cytokine-specific α (GM-CSFRα, CSF2RA) and a signal-transducing common β (GM-CSFRβ, CSF2RB) chain shared with the IL-3
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):1147-1157
Correspondence:
THOMAS MORITZ
moritz.thomas@mh-hannover.de
Received: December 17, 2018. Accepted: July 5, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2018.214866
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/1147
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