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Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.
Hetzel, Miriam Mucci, Adele Blank, Patrick Nguyen, Ariane Hai Ha Schiller, Jan Halle, Olga Kühnel, Mark-Philipp Billig, Sandra Meineke, Robert Brand, Daniel
Hetzel, Miriam
Mucci, Adele
Blank, Patrick
Nguyen, Ariane Hai Ha
Schiller, Jan
Halle, Olga
Kühnel, Mark-Philipp
Billig, Sandra
Meineke, Robert
Brand, Daniel
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2018-02-01
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Abstract
Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 (IFNGR1orIFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-γ) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that expressIfnγr1either constitutively or myeloid specifically. Transduction of mouseIfnγr1 -/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFN-γ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity againstMycobacterium aviumandMycobacterium bovisBacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs intoIfnγr1-/-mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients.
Citation
Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. 2018, 131 (5):533-545 Blood
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en
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1528-0020