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Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning

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...

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Hauptverfasser: Huston, Marshall W. (VerfasserIn) , van Til, Niek P (VerfasserIn) , Visser, Trudi P (VerfasserIn) , Arshad, Shazia (VerfasserIn) , Brugman, Martijn H (VerfasserIn) , Cattoglio, Claudia (VerfasserIn) , Nowrouzi, Ali (VerfasserIn) , Li, Yuedan (VerfasserIn) , Schambach, Axel (VerfasserIn) , Schmidt, Manfred (VerfasserIn) , Baum, Christopher (VerfasserIn) , Kalle, Christof von (VerfasserIn) , Mavilio, Fulvio (VerfasserIn) , Zhang, Fang (VerfasserIn) , Blundell, Mike P (VerfasserIn) , Thrasher, Adrian J (VerfasserIn) , Verstegen, Monique MA (VerfasserIn) , Wagemaker, Gerard (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2011
In: Molecular therapy
Year: 2011, Jahrgang: 19, Heft: 10, Pages: 1867-1877
ISSN:1525-0024
DOI:10.1038/mt.2011.127
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/mt.2011.127
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1525001616327794
Volltext
Verfasserangaben: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 M.A. Verstegen and Gerard Wagemaker
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Zusammenfassung: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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Beschreibung:Online Resource
ISSN:1525-0024
DOI:10.1038/mt.2011.127

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