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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2011-9-7
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pubmed:abstractText |
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? 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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1476-5551
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pubmed:author |
pubmed-author:BaertM R MMR,
pubmed-author:BaurHH,
pubmed-author:BrediusR G MRG,
pubmed-author:Cavazzana-CalvoMM,
pubmed-author:DriessenG J AGJ,
pubmed-author:Hacein-Bey-AbinaSS,
pubmed-author:HoebenR CRC,
pubmed-author:Lagresle-PeyrouCC,
pubmed-author:LankesterA CAC,
pubmed-author:Pike-OverzetKK,
pubmed-author:RodijkMM,
pubmed-author:SchambachAA,
pubmed-author:StaalF J TFJ,
pubmed-author:ThrasherA JAJ,
pubmed-author:ZECDD,
pubmed-author:ZhangFF,
pubmed-author:van DongenJ J MJJ
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pubmed:issnType |
Electronic
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pubmed:volume |
25
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1471-83
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pubmed:meshHeading |
pubmed-meshheading:21617701-Animals,
pubmed-meshheading:21617701-B-Lymphocytes,
pubmed-meshheading:21617701-Blotting, Western,
pubmed-meshheading:21617701-Bone Marrow,
pubmed-meshheading:21617701-Bone Marrow Transplantation,
pubmed-meshheading:21617701-Cell Proliferation,
pubmed-meshheading:21617701-Cytokines,
pubmed-meshheading:21617701-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:21617701-Flow Cytometry,
pubmed-meshheading:21617701-Gene Rearrangement,
pubmed-meshheading:21617701-Gene Therapy,
pubmed-meshheading:21617701-Gene Transfer Techniques,
pubmed-meshheading:21617701-Genetic Vectors,
pubmed-meshheading:21617701-Homeodomain Proteins,
pubmed-meshheading:21617701-Humans,
pubmed-meshheading:21617701-Immunoglobulin G,
pubmed-meshheading:21617701-Lentivirus,
pubmed-meshheading:21617701-Mice,
pubmed-meshheading:21617701-Mice, Inbred C57BL,
pubmed-meshheading:21617701-Mice, Knockout,
pubmed-meshheading:21617701-RNA, Messenger,
pubmed-meshheading:21617701-Receptors, Antigen, T-Cell,
pubmed-meshheading:21617701-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:21617701-Severe Combined Immunodeficiency,
pubmed-meshheading:21617701-Spleen,
pubmed-meshheading:21617701-T-Lymphocytes,
pubmed-meshheading:21617701-Transgenes
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pubmed:year |
2011
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pubmed:articleTitle |
Correction of murine Rag1 deficiency by self-inactivating lentiviral vector-mediated gene transfer.
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pubmed:affiliation |
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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