학술논문
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID
Document Type
article
Author
Laura Garcia-Perez; Marja van Eggermond; Lieke van Roon; Sandra A. Vloemans; Martijn Cordes; Axel Schambach; Michael Rothe; Dagmar Berghuis; Chantal Lagresle-Peyrou; Marina Cavazzana; Fang Zhang; Adrian J. Thrasher; Daniela Salvatori; Pauline Meij; Anna Villa; Jacques J.M. Van Dongen; Jaap-Jan Zwaginga; Mirjam van der Burg; H. Bobby Gaspar; Arjan Lankester; Frank J.T. Staal; Karin Pike-Overzet
Source
Molecular Therapy: Methods & Clinical Development, Vol 17, Iss , Pp 666-682 (2020)
Subject
Language
English
ISSN
2329-0501
Abstract
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.