X-linked severe combined

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. 

Currently, more than 400 human somatic cell gene therapy protocols are being tested. Most of these involve the use of genetically modified cells to treat noninherited diseases. For example, normal copies of the p53 tumor suppressor gene are inserted into lung tumors to halt tumor progression, and genetically modified cells have been used to create new coronary vessels in patients with coronary heart disease. Success has also been achieved in the treatment of hereditary disease (most notably, the recent successful treatment of X-linked severe combined immune deficiency see Clinical Correlate). 

McCormack MP, Rabbitts TH. Mechanisms of disease activation of the T-cell oncogene LM02 after gene therapy for X-linked severe combined immimodeficiency. N Engl J Med 2004 350 913-22. 

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. 

X-Linked severe combined immunodeficiency Mutation in gene coding for y chain of IL-2 receptor. 

As an example, at least one of the trials was criticized after a volunteer died following poor clinical practices. In another trial three patients were successfully treated for an x-linked severe combined immunodeficiency disease but 2 years after the treatment two of the patients developed T-cell acute lymphoblast leukemia. The FDA promptly placed a ban on any further similar clinical studies. 

A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., McIntyre, E., Radford, I., Villeval, J.L., Fraser, C.C., Cavazzana-Calvo, M., Fischer, A. (2003). N Engl J Med, 348 (3) 255-256. 

Wengler, G S, Allen, R C., Parolmi, 0, Smith, H., and Conley, M. E. (1993) Nonrandom X chromosome inactivation m natural killer cells from obligate carriers of X-linked severe combined immunodeficiency J Immunol 150, 700-704. 

Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBridge OW, Leonard WJ (1993), Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans, Cell 73 147-157. 

Hacein-Bey-Abina S, von Kalle C, Schimidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser C, Cavazzana-Calvo M, Fischer A (2003), A serious adverse event after successful gene-therapy for X-linked severe combined immunodeficiency, N. Engl. J. Med. 348 255-256. 

Although the a-chain is very important (and fundamental for the appearance of high-affinity IL-2R), the y-chain has a key role based on its molecular pluripresence (found in IL-4, IL-7, IL-9, and IL-15 receptors but possibly not the IL-13 receptor), constitutive expression by lymphoid cells, and genetic defect in the immune response. The latter results in X-linked severe combined immunodeficiency (XSCID) characterized by profoundly diminished ceU-mediated and humoral immunity. 

Izuhara K, Heike T, Otsuka T, et al. Signal transduction pathway of interleukin-4 and interleukin-13 in human B cells derived from X-linked severe combined immunodeficiency patients. J Biol Chem 1996 271 619-22. 

Leonard WJ. The molecular basis of X-linked severe combined immunodeficiency defective cytokine receptor signaling. Annu Rev Med 1996 47 229-39. 

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. 

Gene therapy, which involves insertion and expression of a therapeutic gene into cells followed by production of the required proteins, emerged as a new paradigm in medicine with enormous therapeutic potential. In 2000, gene therapy research came into the picture by successful treatment of a genetic disease called X-linked severe combined immunodeficiency. However, adverse events such as T cell leukemia, which developed in some patients in clinical trials, raised many questions regarding associated risks. 

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). 

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