Self-selection by genetically modified committed lymphocyte precursors reverses the phenotype of JAK3-deficient mice without myeloablation

Janus kinase 3 (JAK3) is an essential component of cytokine receptor signal transduction pathways required for normal lymphocyte development and funct ion. JAK3 deficiency in both mice and humans results in severe combined imm unodeficiency (SCID) and increased susceptibility to opportunistic infectio ns. We have previously shown that JAK3 gene transfer into irradiated recipi ents could restore immune function. However, since this toxic conditioning would be undesirable for infants in a clinical application, we have tested whether immune function could be restored in nonmyeloablated JAK3-deficient (-/-) mice. Murine JAK3 retroviral vectors were transduced into hematopoie tic stem cells from the livers of newborn JAK3(-/-) mice. These cells were then injected intraperitoneally into nonirradiated JAK3(-/-) neonates. Tran sduced cells were detectable in these mice at time points 4 to 6 months aft er injection and resulted in significant correction of T and B lymphocyte n umbers and circulating immunoglobulin (Ig) levels. After immune challenge w ith a dose of influenza A virus that was lethal to nonmanipulated JAK3(-/-) mice, mice injected with transduced cells showed development of circulatin g virus-specific IgG and enhanced survival. This work shows that the large selective advantage for JAK3-corrected lymphoid cells may be sufficient to overcome the need for myeloablative conditioning in JAK3 gene therapy proto cols.