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

Blood. 2018 Feb 1;131(5):533-545. doi: 10.1182/blood-2017-10-812859. Epub 2017 Dec 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Genetic Therapy*
  • Hematopoietic Stem Cell Transplantation* / methods
  • Hematopoietic Stem Cells / metabolism*
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium Infections / prevention & control*
  • Mycobacterium avium
  • Protective Agents* / metabolism
  • Protective Agents* / therapeutic use
  • RAW 264.7 Cells
  • Receptors, Interferon / genetics*

Substances

  • Protective Agents
  • Receptors, Interferon
  • interferon gamma receptor