Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.
Blood. 2017 Dec 12;:
Authors: 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, Casaova JL, Bustamante J, Schambach A, Kalinke U, Lachmann N
Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare primary immunodeficiency, characterized by severe infections caused by weakly virulent mycobacteria. Bi-allelic null mutations in genes encoding interferon gamma (IFNγ) receptor 1 or -2 (IFNGR1, IFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant IFNγ therapy is inefficient and hematopoietic stem cell transplantation (HSCT) has a poor prognosis. Thus, we developed a HSC gene therapy approach using lentiviral vectors expressing Ifnγr1 either constitutively or myeloid-specifically. Transduction of mouse Ifnγr1-/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFNγ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored anti-mycobacterial activity against Mycobacterium avium and Mycobacterium bovis Bacillus-Calmette-Guérin (BCG) in vitro Transplantation of genetically corrected HSC into Ifnγr1-/- mice prior 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 of transplanted animals. 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 the corresponding human patients.
PMID: 29233822 [PubMed – as supplied by publisher]
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