[Gene therapy of X-linked severe combined immunologic deficiency (SCID-X1)].
X-linked severe combined immunodeficiency (SCID-X1) is a recessive hereditary disorder in which early T and Natural Killer (NK) lymphocyte development is blocked. The genetic disorder results from mutations in the common gamma c chain that participates in several cytokine receptors including the interleukin-2 (Il-2), Il-4, Il-7, Il-9, Il-15 receptors. SCID-X1 offers a reliable model for gene therapy as it is a lethal condition that is, in many cases, curable by allogeneic bone marrow transplantation. We have shown that retrovirus-mediated transfer of the gamma c cDNA induced gamma c chain expression and restored the function of the high-affinity IL-2 receptor on SCI-X1 EBV-transformed B-cell lines. We have the designed culture conditions to study NK-cell and T-cell development of CD34+ hematopoietic progenitor cells. In the culture systems, gamma c transduced CD34+ marrow cells from two SCID-X1 patients were able to mature into CD56+ and/or CD16+ NK cells and into CD4+ TCR alpha beta+ T cells. These preclinical results set the basis for a clinical study of ex-vivo gamma c gene transfer into CD34+ cells from SCID-X1 patients.
Hacein-Bey
S
S
INSERM U429, Hôpital Necker-Enfants-Malades, 149 rue de Sèvres, 75015 Paris, France.
Gross
F
F
Nusbaum
P
P
Yvon
E
E
Fischer
A
A
Cavazzana-Calvo
M
M
D018952:Antigens, CD34 / Q000032:analysis; D001853:Bone Marrow / Q000473:pathology; D015870:Gene Expression; D022761:Gene Transfer, Horizontal; D008040:Genetic Linkage; D015316:Genetic Therapy; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D009154:Mutation; D018121:Receptors, Cytokine / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000628:therapy*; D014162:Transfection; D014960:X Chromosome
D018952:Antigens, CD34; D018121:Receptors, Cytokine