Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease

X-linked severe combined immunodeficiency (SCID-X1) is a recessive heredita ry disorder in which early T and Natural Killer (NK) lymphocyte development is blocked. The genetic disorder results from mutations in the common gamm ac chain that participates in several cytokine receptors including the inte rleukin-2 (II-2), II-4, II-7, II-9 II-15 receptors. SCID-XI offers a reliab le model for gene therapy as it is a lethal condition that is, in many case s, curable by allogeneic bone marrow transplantation. We have shown that re trovirus-mediated transfer of the gammac cDNA induced gammac chain expressi on and restored the function of the high-affinity IL-2 receptor on SCI-XI E BV-transformed B-cell lines. We have the designed culture conditions to stu dy NK-cell and T-cell development of CD34+ hematopoietic progenitor cells. in the culture systems, gammac transduced CD34+ marrow cells from two SCID- XI patients were able to mature into CD56+ and/or CD16+ NK cells and into C D4+ TCR alpha beta+ T cells. These preclinical results set the basis for a clinical study of ex-vivo gammac gene transfer into CD34+ cells from SCID-X I patients. (C) 2001 Editions scientifiques et medicales Elsevier SAS.