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- Title
Correction of murine Rag1 deficiency by self-inactivating lentiviral vector-mediated gene transfer.
- Authors
Pike-Overzet, K.; Rodijk, M.; Ng, Y.-Y.; Baert, M. R. M.; Lagresle-Peyrou, C.; Schambach, A.; Zhang, F.; Hoeben, R. C.; Hacein-Bey-Abina, S.; Lankester, A. C.; Bredius, R. G. M.; Driessen, G. J. A.; Thrasher, A. J.; Baum, C.; Cavazzana-Calvo, M.; van Dongen, J. J. M.; Staal, F. J. T.
- Abstract
Severe combined immunodeficiency (SCID) patients with an inactivating mutation in recombination activation gene 1 (RAG1) lack B and T cells due to the inability to rearrange immunoglobulin (Ig) and T-cell receptor (TCR) genes. Gene therapy is a valid treatment option for RAG-SCID patients, especially for patients lacking a suitable bone marrow donor, but developing such therapy has proven challenging. As a preclinical model for RAG-SCID, we used Rag1-/- mice and lentiviral self-inactivating (SIN) vectors harboring different internal elements to deliver native or codon-optimized human RAG1 sequences. Treatment resulted in the appearance of B and T cells in peripheral blood and developing B and T cells were detected in central lymphoid organs. Serum Ig levels and Ig and TCR Vβ gene segment usage was comparable to wild-type (WT) controls, indicating that RAG-mediated rearrangement took place. Remarkably, relatively low frequencies of B cells produced WT levels of serum immunoglobulins. Upon stimulation of the TCR, corrected spleen cells proliferated and produced cytokines. In vivo challenge resulted in production of antigen-specific antibodies. No leukemia development as consequence of insertional mutagenesis was observed. The functional reconstitution of the B- as well as the T-cell compartment provides proof-of-principle for therapeutic RAG1 gene transfer in Rag1-/- mice using lentiviral SIN vectors.
- Subjects
SEVERE combined immunodeficiency; CYTOKINES; MUTAGENESIS; GENETIC transformation; GENE therapy; T cell receptors; BONE marrow transplantation; B cells; T cells; ANIMAL experimentation; BONE marrow; CELL physiology; CELL receptors; COMPARATIVE studies; ENZYME-linked immunosorbent assay; FLOW cytometry; GENES; GENETIC techniques; IMMUNOGLOBULINS; RESEARCH methodology; MEDICAL cooperation; MICE; POLYMERASE chain reaction; PROTEINS; RESEARCH; RESEARCH funding; RETROVIRUSES; RNA; SPLEEN; WESTERN immunoblotting; EVALUATION research; REVERSE transcriptase polymerase chain reaction; THERAPEUTICS; PHYSIOLOGY
- Publication
Leukemia (08876924), 2011, Vol 25, Issue 9, p1471
- ISSN
0887-6924
- Publication type
journal article
- DOI
10.1038/leu.2011.106