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Previous Volume 346:1185-1193 April 18, 2002 Number 16 Next

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ABSTRACT

Background X-linked severe combined immunodeficiency due to a mutation in the gene encoding the common (c) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the c gene can restore the immune system in patients with severe combined immunodeficiency.

Methods CD34+ bone marrow cells from five boys with X-linked severe combined immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the c transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer.

Results No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro proliferative responses of T cells to several antigens after immunization were nearly normal up to two years after treatment. Thymopoiesis was documented by the presence of naive T cells and T-cell antigen-receptor episomes and the development of a normal-sized thymus gland. The frequency of transduced B cells was low, but serum immunoglobulin levels and antibody production after immunization were sufficient to avoid the need for intravenous immunoglobulin. Correction of the immunodeficiency eradicated established infections and allowed patients to have a normal life.

Conclusions Ex vivo gene therapy with c can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency.

Source Information

From the Laboratoire INSERM (S.H.-B.-A., F.D., C.H., J.-P.V., A.F., M.C.-C.), the Laboratoire de Thérapie Cellulaire et Génique (S.H.-B.-A., F.C., C.H., M.C.-C.), the Laboratoire d'Immunologie Pédiatrique (F.D.), and Unité d'Immunologie et d'Hématologie Pédiatriques (S.D.-G., A.F.), Hôpital Necker Enfants Malades, Paris; Unité de Biologie du Gène, Institut Pasteur, Paris (C.B.); the Molecular Immunology Unit, Institute of Child Health, London (A.J.T.); the Department of Immunology and Hematology, Wilhelmina Kinderziekenhuis Lundlaan, Utrecht, the Netherlands (N.W.); and the Department of Pediatrics, Louisiana State University Health Science Center, New Orleans (R.S.).

Other authors were E. Graham Davies, M.D., Great Ormond Street Hospital for Children, National Health Service Trust, London; Wietse Kuis, M.D., Ph.D., Department of Immunology and Hematology, Wilhelmina Kinderziekenhuis Lundlaan, Utrecht, the Netherlands; and Lilly Leiva, Ph.D., Department of Pediatrics, Louisiana State University Health Science Center, New Orleans.

Address reprint requests to Dr. Cavazzana-Calvo at the Laboratoire de Thérapie Cellulaire et Génique, Hôpital Necker Enfants Malades, 149 rue de Sèvres, 75015 Paris, France, or at cavazzan{at}necker.fr.

Full Text of this Article

Related Letters:

Gene Therapy for Severe Combined Immunodeficiency Disease
Handgretinger R., Koscielniak E., Niethammer D., Cavazzana-Calvo M., Hacein-Bey-Abina S., Fischer A.
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N Engl J Med 2002; 347:613-614, Aug 22, 2002. Correspondence

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