RESTORATION OF LYMPHOCYTE FUNCTION IN JANUS KINASE 3-DEFICIENT MICE BY RETROVIRAL-MEDIATED GENE-TRANSFER

Janus kinase-3 (JAK3) deficiency has recently been identified as a cau se of severe combined immunodeficiency (SCID) in humans. We used a mou se model of Jak3-deficient SCID to test a gene therapy approach for tr eatment of this disease. Transfer of a Jak3 retroviral vector to repop ulating hematopoietic stem cells resulted in increased numbers of T an d B lymphocytes, reversal of hypogammaglobulinemia, restoration of T-c ell activation upon stimulation with mitogens, and development of an a ntigen-specific immune response after immunization. Analysis for vecto r copy number in lymphoid and myeloid populations showed a large in vi vo selective advantage for Jak3-expressing lymphoid cells. These resul ts show that gene replacement is a feasible treatment strategy for thi s disease and that naturally occurring in vivo selection of corrected cells is an important advantage of this approach.