Gene therapy severe combined immunodeficiency

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, there is stUl a gap for the potential of gene therapy to be fulfilled. Gene therapy clinical trials have been conducted for diseases such as severe combined immunodeficiency disease (SCID, bubble baby syndrome), sickle cell anemia, cystic fibrosis, familial hypercholesterolemia, and Gaucher disease. 

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. 

Severe combined immunodeficiency disease The enzyme adenosine deaminase degrades deoxyadenosine which is produced during DNA degradation (Chapter 10). Deficiency of the enzyme results in accumulation of deoxyadenosine which is a substrate for adenosine kinase and leads to production of deoxyadenosine and deoxyquanosine triphosphates, which reach high concentrations. This disturbs the balance of deoxy nucleotides which results in failure of DNA replication. This enzyme is normally present in lymphocytes so that a deficiency prevents proliferation of the lymphocytes, which is essential in combatting an infection. Consequently, patients are very susceptible to infections. This is one disease that is effectively treated by gene therapy. 

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). 

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 ... 

Fischer A et al. Gene therapy for human severe combined immunodeficiencies. Immunity 2001 15 1-4. 

Gene therapy for adenosine-deaminase-deficient severe combined immunodeficiency. Aiuti, A. (2004). Best Pract Res Clin Hematol, 17 (3) 505-516. 

An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency. Ferrari, G., Rossini, S., Giavazzi, R., Maggioni, D., Nobili, N., Soldati, M., Ungers, G., Mavilio, F., Gilboa, E., Bordignon, C. (1991). Science, 251 (4999) 1363-1366. 

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. 

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

Gene therapy for a patient with severe combined immunodeficiency caused by adenosine deaminase deficiency. 

Cavazzana-Calvo M, Fischer A. 2007. Gene therapy for severe combined immunodeficiency Are we there yet J Clin Inv. 117 1456-1465. 

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. 

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. 

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