Adenosine deaminase deficiency diseases

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Adenosine deaminase deficiency is associated with an immunodeficiency disease in which both thymus-derived lymphocytes (T cells) and bone marrow-derived lymphocytes (B cells) are sparse and dysfunctional. Purine nucleoside phosphorylase deficiency is associated with a severe deficiency of T cells but apparently normal B cell function. Immune dysfunctions appear to result from accumulation of dGTP and dATP, which inhibit ribonucleotide reductase and thereby deplete cells of DNA precursors. 

H4. Hershfield, M. S., and Mitchell, B. S., Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In Metabolic and Molecular Bases of Inherited Disease, 7th ed. (C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, eds.), pp. 1725-1768. McGraw-Hill, New York, 1995. 

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. 

E. Therapeutic response Adagen has been effective in reversing biochemical abnormalities in children with adenosine deaminase deficiency and severe combined immunodeficiency disease (SCID). It is... 

Dunbar, C., L. Chang, C. Mullen, et al.. Amendment to Clinical Research Project. Project 90-C-195. April 1,1993. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with autologous lymphocytes transduced with a human ADA gene. Hum Gene Ther, 1999.10(3) 477-88. 

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,... 

Volume III, Pharmacology and Therapy, addresses developments in basic science, translational and clinical research that are underway to bring stem cell research to therapy, particularly for the treatment of Batten s diseases, graft-versus-host disease and adenosine deaminase deficiency. This volume covers the importance of stem cell research for the understanding of drug activities and design. It also addresses the ethical issues and constraints involved in stem cell research, and its commercial applications. 

Adenosine deaminase deficiency results in an accumulation of adenosine, which is converted to its ribonucleotide or deoxyribonucleotide forms by cellular kinases. As dATP levels rise, they inhibit ribonucleotide reductase, thus preventing the production of deoxyribonucleotides, so that the cell cannot produce DNA and divide. This causes severe combined immunodeficiency disease, involving a lack of T cells and B cells. 

ADA (adenosine deaminase) deficiency Adaptation Addiction Addison s disease Addition... 

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. 

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. 

Two different immunodeficiency diseases are now known to result from defects in purine catabolic reactions. In adenosine deaminase deficiency, large concentrations of dATP inhibit ribonucleotide reductase. Consequently, DNA synthe- i= sis is depressed. For reasons that are not yet clear, this metabolic distortion is observed primarily in the T and B lymphocytes. ( / lymphocytes, or T cells, bear antibody-like molecules on their surfaces. They bind to and destroy foreign cells in a process referred to as cellular immunity. B lymphocytes, or B cells, produce antibodies that bind to foreign substances, thereby initiating their destruction by other immune system cells. The production of antibodies by B cells is referred to as the humoral immune response.) Children with adenosine deaminase deficiency usually die before the age of two because of massive infections. 

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. 

Expasure of lymphocytes to deoxyadenosine (dAdo) plus deoxycoformycin (dCF) also results in the accumulation of DNA strand breaks and the activation of poly(ADP-ribose) polymerase (4, 5). dCF is an inhibitor of adenosine deaminase, and when administered to cancer patients, dCF causes dAdo to increase in the plasma. Elevated plasma dAdo is also the most striking biochemical change in children with inherited adenosine deaminase deficiency, a condition that causes severe combined immunodeficiency disease. 

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). 

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

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. 

Indications Enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for—or who have failed— bone marrow transplantation... 

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