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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-03-0782.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 3942-3949
GENE THERAPY
Gene therapy of RAG-2 / mice: sustained correction of
the immunodeficiency
Frank Yates,
Michèle Malassis-Séris,
Daniel Stockholm,
Cécile Bouneaud,
Frédérique Larousserie,
Patricia Noguiez-Hellin,
Olivier Danos,
Donald B. Kohn,
Alain Fischer,
Jean-Pierre de Villartay, and
Marina Cavazzana-Calvo
From the Institut National de la Santé et de la
Recherche Médicale (INSERM) U429, Hôpital
Necker-Enfants Malades; INSERM U277, Institut Pasteur; and
Laboratoire d'Anatomie Pathologique, Hôpital Necker-Enfants
Malades, Paris, France; Genethon III-Unité de Recherche
Associée au Centre National de Recherche Scientifique (CNRS URA)
1923, Evry, France; and the Division of Research Immunology/BMT,
Childrens Hospital, Los Angeles, CA.
Patients with mutations of either RAG-1 or RAG-2 genes
suffer from severe combined immunodeficiency (SCID) characterized by the lack of T and B lymphocytes. The only curative treatment today consists of hematopoietic stem cell (HSC) transplantation, which is
only partially successful in the absence of an HLA genoidentical donor,
thus justifying research to find an alternative therapeutic approach.
To this end, RAG-2-deficient mice were used to test whether
retrovirally mediated ex vivo gene transfer into HSCs could provide
long-term correction of the immunologic deficiency. Murine
RAG-2 /Sca-1+ selected bone marrow cells were transduced
with a modified Moloney leukemia virus (MLV)-based MND
(myeloproliferative sarcoma virus enhancer, negative control region
deleted, dl587rev primer-binding site substituted) retroviral vector
containing the RAG-2 cDNA and transplanted into RAG-2/ sublethally
irradiated mice (3Gy). Two months later, T- and B-cell development was
achieved in all mice. Diverse repertoire of T cells as well as
proliferative capacity in the presence of mitogens, allogeneic cells,
and keyhole limpet hemocyanin (KLH) were shown. B-cell function
as shown by serum Ig levels and antibody response to a challenge by KLH
also developed. Lymphoid subsets and function were shown to be stable
over a one-year period without evidence of any detectable toxicity.
Noteworthy, a selective advantage for transduced lymphoid cells was
evidenced by comparative provirus quantification in lymphoid and
myeloid lineages. Altogether, this study demonstrates the efficiency of ex vivo RAG-2 gene transfer in HSCs to correct the immune deficiency of
RAG-2/ mice, constituting a significant step toward clinical application.
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