| Autor: |
Pike-Overzet K; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands., Rodijk M, Ng YY, Baert MR, Lagresle-Peyrou C, Schambach A, Zhang F, Hoeben RC, Hacein-Bey-Abina S, Lankester AC, Bredius RG, Driessen GJ, Thrasher AJ, Baum C, Cavazzana-Calvo M, van Dongen JJ, Staal FJ |
| Jazyk: |
angličtina |
| Zdroj: |
Leukemia [Leukemia] 2011 Sep; Vol. 25 (9), pp. 1471-83. Date of Electronic Publication: 2011 May 27. |
| DOI: |
10.1038/leu.2011.106 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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