Hetzel, M. et al. (2018) Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. Blood, 131(5), pp. 533-545. (doi: 10.1182/blood-2017-10-812859) (PMID:29233822)
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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 (IFNGR1 or IFNGR2) 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 express Ifnγr1 either constitutively or myeloid specifically. Transduction of mouse Ifnγr1−/− 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 against Mycobacterium avium and Mycobacterium bovis Bacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs into Ifnγr1−/− 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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Herder, Dr Vanessa |
Authors: | Hetzel, M., Mucci, A., Blank, P., Nguyen, A. H. H., Schiller, J., Halle, O., Kühnel, M.-P., Billig, S., Meineke, R., Brand, D., Herder, V., Baumgärtner, W., Bange, F.-C., Goethe, R., Jonigk, D., Förster, R., Gentner, B., Casanova, J.-L., Bustamante, J., Schambach, A., Kalinke, U., and Lachmann, N. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
Journal Name: | Blood |
Publisher: | American Society of Hematology |
ISSN: | 0006-4971 |
ISSN (Online): | 1528-0020 |
Published Online: | 13 December 2017 |
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