Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity
| Autor: | Frédéric Rieux-Laucat, Frank Yates, Marie-Lise Gougeon, Chantal Lagresle-Peyrou, Brigitte Lemercier, Jean-Pierre de Villartay, Olivier Danos, Michèle Malassis-Séris, Allen Liu, Marina Cavazzana-Calvo, Alexandrine Garrigue, Estelle Morillon, Alain Fischer, Daniel Stockholm, Christophe Hue, Philippe Hajdari |
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| Rok vydání: | 2005 |
| Předmět: |
T-Lymphocytes
medicine.medical_treatment Genetic enhancement Transgene Immunology Gene Dosage Hematopoietic stem cell transplantation Biology Biochemistry Gene dosage Recombination-activating gene Mice medicine Animals Regeneration Progenitor cell Homeodomain Proteins Mice Knockout B-Lymphocytes Severe combined immunodeficiency Genetic transfer Genetic Therapy Cell Biology Hematology medicine.disease Lymphoproliferative Disorders Retroviridae Immune System Severe Combined Immunodeficiency |
| Zdroj: | Blood. 107:63-72 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2005-05-2032 |
| Popis: | Severe combined immunodeficiency (SCID) caused by mutations in RAG1 or RAG2 genes is characterized by a complete block in T- and B-cell development. The only curative treatment is allogeneic hematopoietic stem cell transplantation, which gives a high survival rate (90%) when an HLA-genoidentical donor exists but unsatisfactory results when only partially compatible donors are available. We have thus been interested in the development of a potential alternative treatment by using retroviral gene transfer of a normal copy of RAG1 cDNA. We show here that this approach applied to RAG-1-deficient mice restores normal B- and T-cell function even in the presence of a reduced number of mature B cells. The reconstitution is stable over time, attesting to a selective advantage of transduced progenitors. Notably, a high transgene copy number was detected in all lymphoid organs, and this was associated with a risk of lymphoproliferation as observed in one mouse. Altogether, these results demonstrate that correction of RAG-1 deficiency can be achieved by gene therapy in immunodeficient mice but that human application would require the use of self-inactivated vector to decrease the risk of lymphoproliferative diseases. |
| Databáze: | OpenAIRE |
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