X-linked SCID

The theoretical complications posed by random chromosomal integration became a medical reality in 2002, when two children who had received retroviral-based gene therapy 2 years previously developed a leukaemic-like condition. The initial clinical trial aimed to treat X-linked severe combined immunodeficiency (SCID-X1), a hereditary disorder in which T-lymphocytes and NK cells in particular do not develop, due to a mutation in the gene coding for the yc cytokine receptor subunit. The clinical consequence is near abolition of a functional immune system. 

In 2000, French researchers announced the first gene therapy cure in nine children with X-linked severe combined immune deficiency (X-SCID). This rare condition is caused by the inherited loss of a protein that is part of the docking site for critical immune system signal proteins. Because of this defect, children with X-SCID have no mature, working lymphocytes—critical immune system cells. 

X-linked severe combined immune deficiency (X-SCID)— Absence of a functioning immune system inherited with the X chromosome. X-linked refers to inheritance with the X chromosome, one of the chromosomes involved in determining gender. In humans, women have two X chromosomes, and men have an X and a Y chromosome. X-linked genes can only be inherited by a boy from his mother, since his father would have given him his Y chromosome. 

Finally, in 2000, successful treatment of an X-linked form of SCID (SCID-Xl) by gene therapy was reported by a French medical team. Almost a year after a normal gene was introduced into their cells, two children were still synthesizing the enzyme that they lacked. This was the first success for gene therapy in curing a disease after years of effort. 

In X-linked severe combined immunodeficiency disease (SCID), the most common form of SCID, circulating T lymphocytes are not formed, and B lymphocytes are not active. The affected gene encodes the gamma chain of the interleukin 2 receptor. Mutant receptors are unable to activate JAK3, and the cells are unresponsive to the cytokines that stimulate growth and differentiation. Recall also that adenosine deaminase deficiency (see Chapter 41), which is not X-linked, also leads to a form of SCID, but for different reasons. 

Gansbacher B (2003). Report of a second serious adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID). Position of the European Society of Gene Therapy (ESGT). /. Gene Med. 5 261-262. 

Among the four Jak kinases, Jak-1, Jak-2, Jak-3, and Tyk-2, the yc users all signal via Jak-1 and Jak-3 [30, 31]. This could be explained by the ability of Jak-1 to associate with the chain conferring the specificity for each receptor, namely 1L-2R3 [32, 33], IL-4Ra [34], IL-7Ra [35], and IL-9Ra [36], and probably lL-21Ra [37], whereas Jak-3 associates primarily with yc [33, 35]. The importance of the yc was demonstrated by the discovery that mutations in yc cause X-linked severe combined immunodeficiency (SCID) [30, 38], also named the bubble boy disease. In this disease, both cellular and humoral immunity are defective. In fact, T and NK cells do not develop and even if B cells are present, they are nonfunctional [30, 38]. Interestingly, mutations in Jak-3 were found to cause an autosomal recessive form of SCID [39] and the essential role of Jak-3 in lymphoid development was established [40]. This clearly demonstrated the important role of the Jak-STAT signaling pathway. 

PEG-adenosine deaminase (ADAGEN Enzon) was the first PEGylated protein to enter the market, in 1990 [50]. It is used to treat adenosine deaminase-deficient X-linked severe combined immunodeficiency disease (SCID), commonly known as the bubble boy disease . It is an alternative to bone marrow transplantation and enzyme replacement by gene therapy. Since the introduction of ADAGEN, a large number of PEGylated-protein and -peptide pharmaceuticals have followed (Table 1). 

Hendrickson, E.A., Qin, X.-Q., Bump, E.A., Schatz, D.G., Oettinger, M., Weaver, D.T. (1991). A link between double-strand break-related repair and V(D)J recombination the scid mutation. Proc. Natl. Acad. Sci. USA 88,4061-4065. 

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