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 Blood, 1 January 2006, Vol. 107, No. 1, pp. 63-72.
Prepublished online as a Blood First Edition Paper on September 20, 2005; DOI 10.1182/blood-2005-05-2032.

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GENE THERAPY

Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity

Chantal Lagresle-Peyrou, Frank Yates, Michèle Malassis-Séris, Christophe Hue, Estelle Morillon, Alexandrine Garrigue, Allen Liu, Philippe Hajdari, Daniel Stockholm, Olivier Danos, Brigitte Lemercier, Marie-Lise Gougeon, Frederic Rieux-Laucat, Jean-Pierre de Villartay, Alain Fischer, and Marina Cavazzana-Calvo

From the Université Paris-Descartes, Faculté demédecine, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 429, site Necker-Enfants Malades, France; Department of Biotherapy,Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker-Enfants Malades, Paris, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche (UMR) 8115, Généthon, Evry, France; Immunité anti-virale, biothérapie et vaccins, Inserm U668, Institut Pasteur, Paris, France; AP-HP, France; and Unité d'Immunologie et d'Hématologie Pédiatriques, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.

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.


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