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 journalArticle

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 (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
JournalBlood
Volume131
Issue number5
DOIs
Publication statusPublished - 2018

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Gene therapy
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Stem cells
Genetic Therapy
Interferons
Macrophages
Spleen
Infection
Mycobacterium avium
Hematopoietic Stem Cell Transplantation
Mycobacterium
Mycobacterium bovis
Transplants
Lung Diseases
Gene encoding
T-cells
Transplantation
T-Lymphocytes
Phenotype

Cite this

Hetzel, M., Mucci, A., Blank, P., Nguyen, AHH., Schiller, J., Halle, O., ... Lachmann, N. (2018). Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. Blood, 131(5), 533-545. https://doi.org/10.1182/blood-2017-10-812859

Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. / Hetzel, M; Mucci, A; Blank, P; Nguyen, AHH; Schiller, J; Halle, O; Kühnel, MP; Billig, S; Meineke, R; Brand, D; Herder, V; Baumgärtner, W; Bange, FC; Goethe, R; Jonigk, D; Förster, R; Gentner, B; Casanova, JL; Bustamante, J; Schambach, A; Kalinke, U; Lachmann, N.

In: Blood, Vol. 131, No. 5, 2018, p. 533-545.

Research output: Contribution to journalArticle

Hetzel, M, Mucci, A, Blank, P, Nguyen, AHH, Schiller, J, Halle, O, Kühnel, MP, Billig, S, Meineke, R, Brand, D, Herder, V, Baumgärtner, W, Bange, FC, Goethe, R, Jonigk, D, Förster, R, Gentner, B, Casanova, JL, Bustamante, J, Schambach, A, Kalinke, U & Lachmann, N 2018, 'Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections', Blood, vol. 131, no. 5, pp. 533-545. https://doi.org/10.1182/blood-2017-10-812859
Hetzel, M ; Mucci, A ; Blank, P ; Nguyen, AHH ; Schiller, J ; Halle, O ; Kühnel, MP ; Billig, S ; Meineke, R ; Brand, D ; Herder, V ; Baumgärtner, W ; Bange, FC ; Goethe, R ; Jonigk, D ; Förster, R ; Gentner, B ; Casanova, JL ; Bustamante, J ; Schambach, A ; Kalinke, U ; Lachmann, N. / Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. In: Blood. 2018 ; Vol. 131, No. 5. pp. 533-545.
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AU - Blank, P

AU - Nguyen, AHH

AU - Schiller, J

AU - Halle, O

AU - Kühnel, MP

AU - Billig, S

AU - Meineke, R

AU - Brand, D

AU - Herder, V

AU - Baumgärtner, W

AU - Bange, FC

AU - Goethe, R

AU - Jonigk, D

AU - Förster, R

AU - Gentner, B

AU - Casanova, JL

AU - Bustamante, J

AU - Schambach, A

AU - Kalinke, U

AU - Lachmann, N

PY - 2018

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N2 - 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.

AB - 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.

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