Severe combined immunodeficient 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. 

Recently, it has been possible to grow cells of the human immune system in special mice. These mice carry a genetic defect called severe combined immunodeficiency (SCID), which leaves them with crippled immune systems, much like those in AIDS patients. Because SCID mice lack functional cellular immunity, it is possible to implant them with human cells without tissue rejection taking place. Researchers have recently developed techniques to implant human fetal tissues containing stem cells for the blood into SCID mice. It is then possible to reconstitute these mice with functional human immune system cells, including T lymphocytes and B lymphocytes. They have also found that if these SCID mice are infected by HIV, the virus will establish infection in the human tissue and destroy the T helper lymphocytes, just as it does in humans. Thus, it may be possible to study some of the mechanisms by which HIV attacks the immune system in these mice. In addition, they may be very useful for testing potential antiviral drugs. 

Adenosine deaminase (ADA) deficiency, an autosomal recessive disorder, produces severe combined immunodeficiency (SCID). Lacking both B-cell and T-cell function, children are multiply infected with many organisms Pneumocystis carinii, Candida) and do not survive without treatment. Enzyme replacement therapy and bone marrow transplantation may be used. Experimental gene therapy trials have not yet yielded completely successfiil cures. 

The answer is D. Impaired immune function in severe combined immunodeficiency (SCID) is the direct result of blocked DNA synthesis due to inadequate supplies of de-oxyribonucleotides in B and T cells. This effect arises by dATP-induced allosteric inhibition of ribonucleotide reductase, which catalyzes reduction of the 2 -hydroxyl groups on ADP and GDP to form dADP and dCDP. The ultimate cause of many cases of SCID is adenosine deaminase deficiency, which leads to accumulation of dATP and consequent inhibition of ribonucleotide reductase. Although the other enzymes mentioned are also involved in purine nucleotide metabolism, their deficiencies do not lead to SCID. 

Another early genetic disease for correction by gene therapy was severe combined immunodeficiency (SCID). This disease is caused by a lack of adenosine deaminase (ADA) activity. ADA is an enzyme that plays a central role in the degradation of purine nucleosides (it catalyzes the removal of ammonia from adenosine, forming inosine which, in turn, is usually eventually converted to uric acid). This leads to T and B lymphocyte dysfunction. Lack of an effective immune system means that SCID sufferers must be kept in an essentially sterile environment. 

L Severe combined immunodeficiency (SCID) syndromes are excellent models for gene therapy because of the genetic basis of these disorders and significant advances in the technology to transfer therapeutic genes into hematopoietic precursor cells. For all these reasons, which of the following syndromes represents an ideal candidate for gene therapy ... 

Adenosine deaminase (ADA) is a ubiquitous enzyme that is essential for the breakdown of the purine base adenosine, from both food intake and the turnover of nucleic acids. ADA hydrolyzes adenosine and deoxyadenosine into inosine and deoxyinosine, respectively, via the removal of an amino group. Deficiency of the ADA enzyme results in the build-up of deoxyadenosine and deoxyATP (adenosine triphosphate), both of which inhibit the normal maturation and survival of lymphocytes. Most importantly, these metabolites affect the ability of T-cells to differentiate into mature T-cells [656430], [666686]. ADA deficiency results in a form of severe combined immunodeficiency (SCID), known as ADA-SCID [467343]. 

Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). Chan, B., Wara, D., Bastian, J., Hershfield, M.S., Bohnsack, J., Azen, C.G., Parkman, R., Weinberg, K., Kohn, D.B. (2005). Clin Immunol, 117 (2) 133-143. 

Gene therapy of severe combined immunodeficiencies (SCID). Fischer, A. (2005). Euroconference - Gene Cell Ther, December 01-02. 

Cavazzana-Calvo, M., Hacein-Bey, S., de Saint Basile, G., Gross, F., Yvon, E., Nusbaum, P. et al. (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science, 288, 669-672. 

Cavazzana-Calvo M, Hacein-Bey S, Basile GS, Gross F, Yvon E, Nusbaum P, Selz F, Flue C, Certain S, Casanova J-L, Bousso P, Le Deist F, Fisher A (2000), Gene therapy of human severe combined immunodeficiency (SCID)-Xl disease, Science 288 669-672. 

A follow-up study of severe combined immunodeficiency (SCID) children concluded that 8 of 10 treated seemed to have been cured. 

The limitations of the primate or cat models of human HIV-1 CNS infection include the costs, special facility requirements, the necessity of using mixtures of viral strains (in order to develop reproducible CNS infection), and the relatively small numbers of animals studied that preclude meaningful statistical analyses. These obstacles have urged researchers to develop small animal models. Several rodent models were established including transgenic mice (expressing viral proteins or relevant inflammatory factors seen in HAD), mice infected primarily with murine retroviruses, or severe combined immunodeficient (SCID) mice inoculated intracerebrally with human HIV-1 infected macrophages and reconstituted with human peripheral blood lymphocytes (PBL). 

---