Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity.
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.
Lagresle-Peyrou
Chantal
C
Université Paris-Descartes, Faculté de médecine, Inserm Unit 429, site Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex15, France. lagresle@necker.fr
Yates
Frank
F
Malassis-Séris
Michèle
M
Hue
Christophe
C
Morillon
Estelle
E
Garrigue
Alexandrine
A
Liu
Allen
A
Hajdari
Philippe
P
Stockholm
Daniel
D
Danos
Olivier
O
Lemercier
Brigitte
B
Gougeon
Marie-Lise
ML
Rieux-Laucat
Frederic
F
de Villartay
Jean-Pierre
JP
Fischer
Alain
A
Cavazzana-Calvo
Marina
M
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
D018398:Homeodomain Proteins; C064658:RAG-1 protein