期刊
LEUKEMIA
卷 25, 期 9, 页码 1471-1483出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2011.106
关键词
gene therapy; T lymphocyte; SCID
资金
- European Union [QLK3-CT-2001-0427, LSHB-CT-2004-005242]
- Netherlands Organization for Health Research and Development [43100016, 91610083]
- Kika (Children Cancer Free) [09/036]
- REBIRTH Excellence Cluster [Exc62/1]
- Great Ormond Street Hospital Childrens Charity [V1223] Funding Source: researchfish
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 V beta gene segment usage was comparable to wildtype (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. Leukemia (2011) 25, 1471-1483; doi: 10.1038/leu.2011.106; published online 27 May 2011
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