Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections

M Hetzel, A Mucci, P Blank, AHH Nguyen, J Schiller, O Halle, MP Kühnel, S Billig, R Meineke, D Brand, V Herder, W Baumgärtner, FC Bange, R Goethe, D Jonigk, R Förster, B Gentner, JL Casanova, J Bustamante, A SchambachU Kalinke, N Lachmann

Research output: Contribution to journalArticlepeer-review


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 (IFNGR1 or IFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant interferon g (IFN-g) 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 express Ifngr1 either constitutively or myeloid specifically. Transduction of mouse Ifngr12/2 HSCs led to stable IFNgR1 expression on macrophages, which rescued their cellular responses to IFN-g. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity against Mycobacterium avium and Mycobacterium bovis Bacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs into Ifngr12/2 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 IFNgR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients. © 2018 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)533-545
Number of pages13
Issue number5
Publication statusPublished - 2018


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