IN-VITRO CORRECTION OF JAK3-DEFICIENT SEVERE COMBINED IMMUNODEFICIENCY BY RETROVIRAL-MEDIATED GENE TRANSDUCTION

Mutations affecting the expression of the Janus family kinase JAK3 wer e recently shown to be responsible for autosomal recessive severe comb ined immunodeficiency (SCID). JAX3-deficient patients present with a c linical phenotype virtually indistinguishable fi-om boys affected by X -linked SCID, a disease caused by genetic defects of the common gamma chain (gamma(c)) that is a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. The specific interaction of JAK3 and gam ma(c) represents the biochemical basis for the similarities between th ese two immunodeficiencies. Both forms of SCID are characterized by re current, severe infections leading to death in infancy unless successf ully treated by allogeneic bone marrow transplantation. Because of the potentially lethal complications associated with allogeneic bone marr ow transplantation and the frequent lack of suitable marrow donors, th e development of alternative forms of therapy is highly desirable. To this end, we investigated a retroviral-mediated gene correction approa ch for JAK3-deficiency. A vector carrying a copy of JAK3 cDNA was cons tructed and used to transduce B cell lines derived from patients with JAK3-deficient SCID. We demonstrate restoration of JAK3 expression and phosphorylation upon IL-2 and IL-4 stimulation. Furthermore, patients ' cells transduced with JAK3 acquired the ability to proliferate norma lly in response to IL-2. These data indicate that the biological defec ts of JAK3-deficient cells can be efficiently corrected in vitro by re troviral-mediated gene transfer, thus providing the basis for future i nvestigation of gene therapy as treatment for JAK3-deficient SCID.