Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID

Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We d...

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Veröffentlicht in:Molecular therapy. Methods & clinical development 2020-06, Vol.17, p.666-682
Hauptverfasser: Garcia-Perez, Laura, van Eggermond, Marja, van Roon, Lieke, Vloemans, Sandra A., Cordes, Martijn, Schambach, Axel, Rothe, Michael, Berghuis, Dagmar, Lagresle-Peyrou, Chantal, Cavazzana, Marina, Zhang, Fang, Thrasher, Adrian J., Salvatori, Daniela, Meij, Pauline, Villa, Anna, Van Dongen, Jacques J.M., Zwaginga, Jaap-Jan, van der Burg, Mirjam, Gaspar, H. Bobby, Lankester, Arjan, Staal, Frank J.T., Pike-Overzet, Karin
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Sprache:eng
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Zusammenfassung:Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1−/− mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID. [Display omitted] A self-inactivating lentiviral vector was developed that functionally corrected Rag1 deficiency in a murine disease model and in RAG1-SCID patient cells. After X-linked and ADA SCID, RAG1-SCID is the third most frequent form of SCID, for which gene therapy may now become available.
ISSN:2329-0501
2329-0501
DOI:10.1016/j.omtm.2020.03.016