Adenosine deaminase deficiency, gene therapy

Initially, the focus of gene therapy was for the treatment of inherited disorders such as cystic fibrosis, sickle cell anemia, hemophilia, and adenosine deaminase deficiency. Gene therapy trials were later expanded to include patients with acquired diseases such as cancer and heart disease. 

H3. Hershfield, M. S Chaffee, S., and Sorensen, R. U., Enzyme replacement therapy with polyethylene glycol-adenosine deaminase in adenosine deaminase deficiency Overview and case reports of three patients, including two now receiving gene therapy. Pediatr. Res. 33 (Suppl.), S42-S48 (1993). 

Hershfield MS (1995) PEG-ADA an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency. Hum Mutat 5 107-112... 

Gene engineering is the basis of gene therapy where genes are removed, replaced, or altered producing new proteins for the treatment of diseases such as muscular dystrophy, some cancers, adenosine deaminase deficiency, cystic fibrosis, and emphysema. 

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). 

Gene therapy holds great promise for the treatment of many diseases (e.g., cancer, AIDS, cystic fibrosis, adenosine deaminase deficiency, cardiovascular diseases, Gaucher disease, a 1-antitrypsin deficiency, rheumatoid arthritis, and several others) (1,2). Advances in genomics and molecular biology have revealed that almost all diseases have a genetic component. In some cases, such as cystic fibrosis or hemophilia,... 

San Raffaele Telethon Institute for Gene Therapy is developing an adenosine deaminase transduced hematopoietic stem cell therapy for the potential intravenous treatment of adenosine deaminase deficiency in severe combined immunocompromised individuals (ADA-SCID). 

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

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

Aiuti A, Ficara F, Cattaneo F, Bordignon C, Roncarolo MG (2003), Gene therapy for adenosine deaminase deficiency, Curr. Opin. Allergy Clin. Immunol. 3 461-466. 

R. Parkmann, K. Weinberg, G. Crooks, J. Nolta, N. Kapoor, and D. Kohn. 2000. Gene therapy for adenosine deaminase deficiency Rev. Med. 51 33-47. (PubMed)... 

Aiuti, A., Ficara, F., Cattaneo, F., Bordignon, C. and Roncarolo, M.G. (2003) Gene therapy for adenosine deaminase deficiency. Curr Opin Allergy Clin Immunol, 3, 461-6. 

The first clinical gene therapy trial began in 1990 for the treatment of adenosine deaminase deficiency. B and T lymphocytes fail to develop in this autosomal recessive disease, resulting in a severe combined immunodeficiency syndrome (SCID) made famous by the bubble boys whose lives were confined to tents in an effort to keep them in a germ-free environment. Only two patients were included in this trial, and although both continued to demonstrate clinical improvement 10 years later, gene therapy did not cure the disease, as investigators had hoped. 

Parkmann, R., Weinberg, K., Crooks, G., Nolta, J., Kapoor, N., and Kohn, D., 2000. Gene therapy for adenosine deaminase deficiency. Anmi. Rev. Med. 51 33M7. 

Onodera M, Sakiyama Y (2000). Adenosine deaminase deficiency as the first target disorder in gene therapy. Expert Opin. Investig. Drugs. 9 543-549. 

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). 

The results of the first gene therapy clinical trial were published in 1995. This trial involved the ex vivo retroviral treatment of T-cells from patients suffering from adenosine deaminase deficiency with severe combined immuno-deficiency (ADA-SCID). Two patients with ADA-SCID were chosen who had not fully responded to conventional treatment (PEG-ADA)... 

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. 

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