Correction of Murine SCID-X1 by Lentiviral Gene Therapy Using a Codon-optimized IL2RG Gene and Minimal Pretransplant Conditioning |
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| Authors: | Marshall W Huston Niek P van Til Trudi P Visser Shazia Arshad Martijn H Brugman Claudia Cattoglio Ali Nowrouzi Yuedan Li Axel Schambach Manfred Schmidt Christopher Baum Christof von Kalle Fulvio Mavilio Fang Zhang Mike P Blundell Adrian J Thrasher Monique MA Verstegen Gerard Wagemaker |
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| Affiliation: | 1. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;2. Department of Experimental Hematology, Hannover Medical School, Hannover, Germany;3. Istituto Scientifico H. San Raffaele, Milan, Italy;4. Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany;5. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy;6. Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, University College London, London, UK;7. Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, UK |
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| Abstract: | Clinical trials have demonstrated the potential of ex vivo hematopoietic stem cell gene therapy to treat X-linked severe combined immunodeficiency (SCID-X1) using γ-retroviral vectors, leading to immune system functionality in the majority of treated patients without pretransplant conditioning. The success was tempered by insertional oncogenesis in a proportion of the patients. To reduce the genotoxicity risk, a self-inactivating (SIN) lentiviral vector (LV) with improved expression of a codon optimized human interleukin-2 receptor γ gene (IL2RG) cDNA (coγc), regulated by its 1.1 kb promoter region (γcPr), was compared in efficacy to the viral spleen focus forming virus (SF) and the cellular phosphoglycerate kinase (PGK) promoters. Pretransplant conditioning of Il2rg−/− mice resulted in long-term reconstitution of T and B lymphocytes, normalized natural antibody titers, humoral immune responses, ConA/IL-2 stimulated spleen cell proliferation, and polyclonal T-cell receptor gene rearrangements with a clear integration preference of the SF vector for proto-oncogenes, contrary to the PGK and γcPr vectors. We conclude that SIN lentiviral gene therapy using coγc driven by the γcPr or PGK promoter corrects the SCID phenotype, potentially with an improved safety profile, and that low-dose conditioning proved essential for immune competence, allowing for a reduced threshold of cell numbers required. |
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