Effective hematopoietic stem cell-based gene therapy in a murine model of hereditary pulmonary alveolar proteinosis
Miriam Hetzel,
Elena Lopez-Rodriguez,
Adele Mucci,
Ariane Hai Ha Nguyen,
Takuji Suzuki,
Kenjiro Shima,
Theresa Buchegger,
Sabine Dettmer,
Thomas Rodt,
Jens P. Bankstahl,
Punam Malik,
Lars Knudsen,
Axel Schambach,
Gesine Hansen,
Bruce C. Trapnell,
Nico Lachmann,
Thomas Moritz
Affiliations
Miriam Hetzel
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
Elena Lopez-Rodriguez
Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
Adele Mucci
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
Ariane Hai Ha Nguyen
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
Takuji Suzuki
Translational Pulmonary Science Center, Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Pulmonary Medicine, Jichi Medical University, Shimotsukeshi, Tochigi, Japan
Kenjiro Shima
Translational Pulmonary Science Center, Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Theresa Buchegger
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
Sabine Dettmer
Department of Radiology, Hannover Medical School, Hannover, Germany
Thomas Rodt
Department of Radiology, Hannover Medical School, Hannover, Germany
Jens P. Bankstahl
Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
Punam Malik
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Disease Institute (CBDI), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Lars Knudsen
Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
Axel Schambach
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany;Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Gesine Hansen
Department of Pediatrics, Allergology, and Neonatology, Hannover Medical School, Hannover, Germany
Bruce C. Trapnell
Translational Pulmonary Science Center, Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Pulmonary Medicine, Children’s Hospital Medical Center, Cincinnati, OH, USA
Nico Lachmann
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
Thomas Moritz
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
Hereditary pulmonary alveolar proteinosis due to GM-CSF receptor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein secondary 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, including bronchoalveolar fluid protein, cholesterol and cytokine levels, pulmonary 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 transplantation. Based on these data, we suggest hematopoietic stem cell-based gene therapy as an effective and cause-directed treatment approach for herPAP.
