Assessing the Risk of T-cell Malignancies in Mouse Models of SCID-X1

Abstract

It has long been recognized that severe combined immunodeficiency disorders (SCIDs) are favorable settings for the application of stem cell gene therapy. This genetically heterogeneous group of disorders includes adenosine deaminase (ADA) deficiency and X-linked SCID (SCID-X1),1 the latter caused by mutations in the common gamma chain (γc) gene, which is required for a broad range of cell signaling events in lymphocytes and their precursors. The strong selective advantage for genetically corrected cells during development circumvents the requirement for high levels of transduction and engraftment, which remains a significant barrier for other blood diseases that lack an in vivo selection mechanism for transduced cells. Pioneering gene therapy trials for SCID-X1 have taken place in France,2,3 the United Kingdom,4 and—for ADA deficiency—Italy5; these have clearly demonstrated the curative potential of this approach. Retroviral vectors derived from the murine leukemia virus (MLV) were used to transfer a normal copy of the diseased gene to autologous CD34+ cells from the infant patient’s bone marrow. After reinfusion of these modified cells, most of the more than 30 treated patients have had full reconstitution of T-cell–mediated immunity, with restoration of B-cell function in fewer, but significant numbers of, cases. However, in both SCID-X1 trials, some patients developed T-cell malignancies that were clearly related to insertional mutagenesis from the integrated vector.6,7,8