X-SCID

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. 

Kaiser, J. Seeking the Cause of Induced Leukemias in X-SCID Trial. Sdence 299, 495 (2003). [An article about the search for information about why two patients receiving gene therapy developed leukemia.]... 

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. 

Human immunodeficiency virus (HIV) type 1 ELDKWA epitope Potato virus X in tobacco leaf Sera from normal and hu-PBL-SCID mice showed anti-HIV-1 neutralizing activity. Immunogenic in mice when delivered parenterally or nasally. 18... 

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. 

Mutation in the adenosine deaminase gene on chromosome 20 can cause severe combined immunodeficiency due to absence of T cells, B cells, and natural killer cells (T cell-negative, B cell-negative, natural killer cell-negative autosomal recessive SCID). The lack of the enzyme adenosine deminase results in the accumulation of adenosine and toxic deoxyadenosine nucleotides. The latter can cause apoptosis of lymphocytes. Lymphocyte counts can be as low as 0.5 x 10 /L, affecting primarily T cells which are absent (105). While therapy of missing enzyme has been shown to effect improvement, bone marrow transplantation is the preferred treatment. Milder forms of adenosine deaminase deficiency have been reported (116). 

The clinical trial was later expanded to include two more ADA-SCID patients, and included treatment follow-ups at 10, 15, 29 and 35 months after therapy [515038], [516040], [643376]. The results from the most recent follow-up matched those found in the initial study of two patients. PBL counts in all patients were 2.5 x 9 , 0.2 x 109/1, 1.3 x 109/1 and 0.7 x 109/1 for Ptl, Pt2, Pt3 and Pt4, respectively. The overall level of myeloid engraftment and the speed and degree of immune reconstitution correlated with both the dose of infused transduced CD34+ cells and the degree of myelosuppression [643376]. 

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. 

Xie, X., Brunner, N., Jensen, G., Albrectsen, J., Gotthardsen, B. and Rygaard, J. (1992). Comparative studies between nude and scid mice on the growth and metastatic behavior of xenografted human tumors. Clin. Exptl. Metastasis 10, 201-210. 

In addition to T-ceUs, other cell types have been found to play important roles in EAE induced by both active immunization and adoptive transfer. CD8-t cells play a variable role in EAE. In the absence of CD8+ T-ceUs, more severe disease is observed. However, MOG-specific CD8+ T-cells have been observed and are capable of transferring EAE in SCID mice. In addition, H2k MBP-specific CD8-t T-cell clones recognizing the peptide fragment MBP 79-87 (Huseby et al., 1999). B cells are generally believed to be dispensable in EAE as B-cell deficient (B10.PL x SJL/J) mice develop EAE after immunization (Dittel et al., 2000). In B6 mice, the absence of B-cells exacerbates EAE suggesting a protective role for these cells. However, MOG-induced EAE is aggravated by administration of anti-MOG antibodies, suggesting an important role for the humoral response in some models of EAE. 

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