Hematopoietic Stem Cell Gene Therapy For Ifn Gamma R1 Deficiency Protects Mice From Mycobacterial Infections

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 gamma (IFN-gamma) 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 Ifn gamma r1 either constitutively or myeloid specifically. Transduction of mouse Ifn gamma r1(-/-) HSCs led to stable IFN gamma R1 expression on macrophages, which rescued their cellular responses to IFN-gamma. 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-Guerin (BCG) in vitro. Transplantation of genetically corrected HSCs into Ifn gamma r1(-/-) 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 IFN gamma R1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients.