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The Department of Genetic Medicine at Weill Cornell leads a dynamic and innovative translational research program, advancing diverse fields such as Genetic Therapy and Personalized Medicine.
Trans-splicing repair of CD40 ligand deficiency results in naturally regulated correction of a mouse model of hyper-IgM X-linked immunodeficiency.
| Publication Type | Academic Article |
| Authors | Tahara M, Pergolizzi R, Kobayashi H, Krause A, Luettich K, Lesser M, Crystal R |
| Journal | Nat Med |
| Volume | 10 |
| Issue | 8 |
| Pagination | 835-41 |
| Date Published | 07/25/2004 |
| ISSN | 1078-8956 |
| Keywords | CD40 Ligand, Gene Expression Regulation, Genetic Diseases, X-Linked, Genetic Engineering, Hypergammaglobulinemia, Immunoglobulin M, RNA, Messenger |
| Abstract | X-linked immunodeficiency with hyper-IgM (HIGM1), characterized by failure of immunoglobulin isotype switching, is caused by mutations of the CD40 ligand (CD40L), which is normally expressed on activated CD4(+) T cells. As constitutive expression of CD40L induces lymphomas, we corrected the mutation while preserving the natural regulation of CD40L using pre-mRNA trans-splicing. Bone marrow from mice lacking CD40L was modified with a lentivirus trans-splicer encoding the normal CD40L exons 2-5 and was administered to syngenic CD40L-knockout mice. Recipient mice had corrected CD40L mRNA, antigen-specific IgG1 responses to keyhole limpet hemocyanin immunization, regulated CD4(+) T-cell CD40L expression after CD3 stimulation in primary and secondary transplanted mice, attenuation of Pneumocystis carinii pneumonia, and no evidence of lymphoproliferative disease over 1 year. Thus, HIGM1 can be corrected by CD40L trans-splicing, leading to functional correction of the genetic defect without the adverse consequences of unregulated expression of the CD40L gene. |
| DOI | 10.1038/nm1086 |
| PubMed ID | 15273748 |