title: Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity.
abstract: 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.
authors.affiliation: Université Paris-Descartes, Faculté de médecine, Inserm Unit 429, site Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex15, France. lagresle@necker.fr
authors.forename: Chantal
authors.initials: C
authors.lastname: Lagresle-Peyrou
authors.forename: Frank
authors.initials: F
authors.lastname: Yates
authors.forename: Michèle
authors.initials: M
authors.lastname: Malassis-Séris
authors.forename: Christophe
authors.initials: C
authors.lastname: Hue
authors.forename: Estelle
authors.initials: E
authors.lastname: Morillon
authors.forename: Alexandrine
authors.initials: A
authors.lastname: Garrigue
authors.forename: Allen
authors.initials: A
authors.lastname: Liu
authors.forename: Philippe
authors.initials: P
authors.lastname: Hajdari
authors.forename: Daniel
authors.initials: D
authors.lastname: Stockholm
authors.forename: Olivier
authors.initials: O
authors.lastname: Danos
authors.forename: Brigitte
authors.initials: B
authors.lastname: Lemercier
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Gougeon
authors.forename: Frederic
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D018628:Gene Dosage; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D018398:Homeodomain Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics; D007107:Immune System / Q000187:drug effects* / Q000502:physiology; D008232:Lymphoproliferative Disorders / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D012038:Regeneration / Q000187:drug effects*; D012190:Retroviridae / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000628:therapy*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein