3, 4 In view of the many physiological roles of γ c, SCID-X1 is characterized by (1) the absence of circulating T and NK cells and (2) normal to elevated numbers of poorly functional mature B cells. The IL-21 receptor is a major factor in the survival and proliferation of memory/switched B cells and (in contrast to the IL-4R) cannot be functionally replaced by other receptors. 2 Whereas defective IL-7 and IL-15 pathways are responsible for the early block in T and natural killer (NK) cell differentiation, respectively, abrogation of IL-21 receptor functions is the substrate for humoral dysfunctions. 1 The γ c chain is shared by several hematopoietic cytokine receptors, including the interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations of the γ c-encoding gene and accounts for 30–40% of patients with SCID. This review puts into perspective the clinical experience of gene therapy for SCID-X1, with the development and implementation of new generations of safer vectors such as self-inactivating gammaretroviral or lentiviral vectors as well as major advances in integrome knowledge. The success of these pioneering trials paved the way for the extension of gene-based treatment to many other diseases of the hematopoietic system, but the unfortunate serious adverse events led to extensive investigations to define the retrovirus integration profiles. Natural killer and B cell defects were only partially restored, most likely due to the absence of a conditioning regimen. This gene therapy has successfully enabled correction of the T cell defect. The seminal SCID-X1 clinical studies, based on first-generation gammaretroviral vectors, demonstrated good long-term immune reconstitution in most treated patients despite the occurrence of vector-related leukemia in a few of them. More than 20 years ago, X-linked severe combined immunodeficiency (SCID-X1) appeared to be the best condition to test the feasibility of hematopoietic stem cell gene therapy.
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