RETROVIRAL-MEDIATED GENE CORRECTION FOR X-LINKED SEVERE COMBINED IMMUNODEFICIENCY

X-linked severe combined immunodeficiency (XSCID) is a lethal disease caused by a defect in the gene encoding the common gamma chain (gamma( c)) of the receptor for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL -15. Allogeneic bone marrow transplantation, the current therapy of ch oice for this defect, is often complicated by graft-versus-host diseas e and/or incomplete reconstitution of B-lymphocyte functions. Correcti on of the gene defect at the level of the autologous lymphohematopoiet ic progenitors could therefore represent an improvement in the medical management of these patients. To study the feasibility of a gene ther apy approach for XSCID, a retroviral vector expressing gamma(c) was us ed to transduce Epstein-Barr virus-transformed B-cell lines derived fr om patients with XSCID. After transduction, XSCID cells newly expresse d gamma(c) on the cell surface at levels comparable to those observed on B-cell lines obtained from normal donors. Moreover, the reconstitut ed gamma(c) restored function to the IL-2 and IL-4 receptors as shown by signal transduction mediated by phosphorylation of the JAK1 and JAK 3 members of the Janus family of tyrosine kinases and by restoration o f cellular proliferation in response to IL-2. This is a US government work. There are no restrictions on its use.