| First Author | Hetzel M | Year | 2018 |
| Journal | Blood | Volume | 131 |
| Issue | 5 | Pages | 533-545 |
| PubMed ID | 29233822 | Mgi Jnum | J:257495 |
| Mgi Id | MGI:6119961 | Doi | 10.1182/blood-2017-10-812859 |
| Citation | Hetzel M, et al. (2018) Hematopoietic stem cell gene therapy for IFNgammaR1 deficiency protects mice from mycobacterial infections. Blood 131(5):533-545 |
| abstractText | 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 Ifngammar1 either constitutively or myeloid specifically. Transduction of mouse Ifngammar1(-/-) HSCs led to stable IFNgammaR1 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 Ifngammar1(-/-) 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 IFNgammaR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients. |
