[Gene therapy of SCID-X1]

Abstract

X-linked severe combined immunodeficiency (SCID-X1) is an inherited disease caused by inactivating mutations in the gene encoding the interleukin 2 receptor common gamma chain (IL2RG), which is located on the X-chromosome. Affected boys fail to develop two major effector cell types of the immune system (T cells and NK cells) and suffer from a functional B cell defect. Although drugs such as antibiotics can offer partial protection, the boys normally die in the first year of life in the absence of a curative therapy. For a third of the children, bone marrow transplantation from a fully matched donor is available and can cure the disease without major side effects. Mismatched bone marrow transplantation, however, is complicated by severe and potentially lethal side effects. Over the past decade, scientists worldwide have developed new treatments by introducing a correct copy of the IL2RG-cDNA. Gene therapy was highly effective when applied in young children. However, in a few patients the IL2RG-gene vector has unfortunately caused leukaemia. Activation of cellular proto-oncogenes by accidental integration of the gene vector has been identified as the underlying mechanism. In future clinical trials, improved vector technology in combination with other protocol modifications may reduce the risk of this side effect.