The T-cell signalling defect that is associated with Wiskott-Aldrich syndrome (WAS) can be improved by gene therapy, according to a recent paper in Blood.

WAS, an X-linked primary deficiency caused by mutations in the WASP gene, is characterized by a range of immunological abnormalities, including thrombocytopaenia, a progressive decline in T-cell numbers, impaired antibody production and defective T-cell receptor (TCR) signalling. Previous studies have shown that retroviral infection of human WASP−/− cells with WASP can rescue some of these defects in vitro.

Here, Klein et al. tested whether this approach would work in vivo, by transplanting Wasp-transfected Wasp−/− haematopoietic stem cells (HSCs) into irradiated recipient mice. Wasp−/− mice develop several of the clinical features that are characteristic of WAS, including defective TCR-induced T-cell proliferation and aberrant regulation of the actin cytoskeleton. However, in addition, severe colitis occurs in these mice following radiation, so the authors used lymphopenic Rag2 −/− mice as the recipients in this study.

Transplantation of Wasp-transfected HSCs resulted in the development of normal numbers of T and B cells in the recipient mice, and there was no evidence of abnormal expression of activation markers by these cells. T cells obtained from these mice proliferated after stimulation with antibodies specific for CD3, indicating that the TCR-signalling defect was corrected, at least partially, in these cells. This approach resulted in clinical benefits in these mice, as the susceptibility to colitis, which develops in Rag2−/− mice after transfer of Wasp−/− cells, was markedly reduced by transplantation of Wasp-expressing cells. Finally, the authors showed that Wasp-expressing cells have a selective survival advantage over Wasp−/− cells, a situation that is thought to improve the outcome of gene-therapy approaches.

Although antibiotic treatments and other supportive therapies can prolong the life of individuals with WAS, the only curative treatment that is available at present is allogeneic HSC transplantation, and only then if a donor is available. Despite recent concerns over the use of retroviral vectors for immunotherapy, these results are encouraging for the development of gene-therapy approaches for this disease.