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

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

Author information

1
Institute of Experimental Hematology and.
2
Research Group Reprogramming and Gene Therapy, REBIRTH Cluster-of Excellence, Hannover Medical School, Hannover, Germany.
3
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
4
Young Research Group Translational Hematology of Congenital Diseases, REBIRTH Cluster-of Excellence.
5
Institute of Immunology.
6
Institute for Pathology, and.
7
Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
8
Department of Pathology and.
9
Institute for Microbiology, Department of Infectious Diseases, University of Veterinary Medicine Hannover, Hannover, Germany.
10
San Raffaele Telethon Institute for Gene Therapy, Scientific Institute Hospital San Raffaele, Milan, Italy.
11
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
12
Paris Descartes University, Imagine Institute, Paris, France.
13
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
14
Howard Hughes Medical Institute, New York, NY.
15
Pediatric Hematology-Immunology Unit and.
16
Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France; and.
17
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.

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.

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