Correction of Murine Rag2 Severe Combined Immunodeficiency by Lentiviral Gene Therapy Using a Codon-optimized RAG2 Therapeutic Transgene (Articolo in rivista)

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  • Correction of Murine Rag2 Severe Combined Immunodeficiency by Lentiviral Gene Therapy Using a Codon-optimized RAG2 Therapeutic Transgene (Articolo in rivista) (literal)
Anno
  • 2012-01-01T00:00:00+01:00 (literal)
Alternative label
  • Niek P van Til1, Helen de Boer1, Nomusa Mashamba1, Agnieszka Wabik1, Marshall Huston1, Trudi P Visser1, Elena Fontana2, Pietro Luigi Poliani2, Barbara Cassani3, Fang Zhang4, Adrian J Thrasher4,5, Anna Villa6,7 and Gerard Wagemaker1 (2012)
    Correction of Murine Rag2 Severe Combined Immunodeficiency by Lentiviral Gene Therapy Using a Codon-optimized RAG2 Therapeutic Transgene
    in Molecular therapy (Print)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Niek P van Til1, Helen de Boer1, Nomusa Mashamba1, Agnieszka Wabik1, Marshall Huston1, Trudi P Visser1, Elena Fontana2, Pietro Luigi Poliani2, Barbara Cassani3, Fang Zhang4, Adrian J Thrasher4,5, Anna Villa6,7 and Gerard Wagemaker1 (literal)
Pagina inizio
  • 1968 (literal)
Pagina fine
  • 1980 (literal)
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  • 20 (literal)
Rivista
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  • 10 (literal)
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  • 1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands 2Department of Pathology, University of Brescia, Brescia, Italy 3Fondazione Humanitas per la Ricerca, Milano, Italy 4Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, University College London, London, UK 5Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, UK 6CNR-IRGB, Milano, Italy 7Telethon Institute for Gene Therapy-HSR, Milano, Italy (literal)
Titolo
  • Correction of Murine Rag2 Severe Combined Immunodeficiency by Lentiviral Gene Therapy Using a Codon-optimized RAG2 Therapeutic Transgene (literal)
Abstract
  • Recombination activating gene 2 (RAG2) deficiency results in severe combined immunodeficiency (SCID) with complete lack of T and B lymphocytes. Initial gammaretroviral gene therapy trials for other types of SCID proved effective, but also revealed the necessity of safe vector design. We report the development of lentiviral vectors with the spleen focus forming virus (SF) promoter driving codon-optimized human RAG2 (RAG2co), which improved phenotype amelioration compared to native RAG2 in Rag2-/- mice. With the RAG2co therapeutic transgene, T-cell receptor (TCR) and immunoglobulin repertoire, T-cell mitogen responses, plasma immunoglobulin levels and T-cell dependent and independent specific antibody responses were restored. However, the thymus double positive T-cell population remained subnormal, possibly due to the SF virus derived element being sensitive to methylation/silencing in the thymus, which was prevented by replacing the SF promoter by the previously reported silencing resistant element (ubiquitous chromatin opening element (UCOE)), and also improved B-cell reconstitution to eventually near normal levels. Weak cellular promoters were effective in T-cell reconstitution, but deficient in B-cell reconstitution. We conclude that immune functions are corrected in Rag2-/- mice by genetic modification of stem cells using the UCOE driven codon-optimized RAG2, providing a valid optional vector for clinical implementation. (literal)
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