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

Miriam Hetzel, Adele Mucci, Patrick Blank, Ariane Hai Ha Nguyen, Jan Schiller, Olga Halle, Mark-Philipp Kühnel, Sandra Billig, Robert Meineke, Daniel Brand, Vanessa Herder, Wolfgang Baumgärtner, Franz-Christoph Bange, Ralph Goethe, Danny Jonigk, Reinhold Förster, Bernhard Gentner, Jean-Laurent Casaova, Jacinta Bustamante, Axel Schambach, Ulrich Kalinke and Nico Lachmann

Key points

  • Hematopoietic cell and gene therapy can prevent in vivo infections by Mycobacteria spp. using different SIN lentiviral vectors

  • Cellular repair of macrophages in vivo highlights phagocytes as key players in the disease progression of MSMD


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.

  • Submitted October 24, 2017.
  • Accepted December 1, 2017.