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

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 (<i>IFNGR1</i> or <i>IFNGR2</i>) 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 <i>Ifnγr1</i> either constitutively or myeloid specifically. Transduction of mouse <i>Ifnγr1</i>^<i>-/-</i> 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 <i>Mycobacterium avium</i> and <i>Mycobacterium bovis</i> Bacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs into <i>Ifnγr1</i>^-/- 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.