Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.4.17 (adenosine deaminase)
 5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficiency of the enzyme adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4; ADA) leads to severe combined immunodeficiency, a disorder that potentially could be corrected by gene transfer into hematopoietic cells. We have constructed retroviruses containing human ADA cDNA and a dominant selectable marker, a mutated dihydrofolate reductase gene (DHFR*) encoding methotrexate resistance. Human ADA cDNA was inserted alone (DHFR*-ADA) or with a simian virus 40 (SV40) promoter (DHFR*-SVADA). Although NIH 3T3 cells infected with either construct produced human ADA activity, substantially greater levels were attained with DHFR*-SVADA. Infection of murine lymphoid cells in culture with DHFR*-SVADA led to expression of human enzyme at a level well above the mouse endogenous level. ADA activity was also increased after infection of a human ADA-deficient B-cell line. Lethally irradiated mice that were reconstituted with syngeneic marrow infected with the DHFR*-SVADA virus contained unrearranged, integrated proviral DNA in total spleen DNA or in spleen hematopoietic stem cell (CFU-S)-derived colonies. Nevertheless, no human ADA was detectable. RNA analysis showed relatively low and variable expression from the retroviral long terminal repeat, and no detectable expression from the internal SV40 promoter. These data suggest that intrinsic biologic differences exist between cultured cells and CFU-S in vivo.
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PMID:Retrovirus-mediated transfer of human adenosine deaminase gene sequences into cells in culture and into murine hematopoietic cells in vivo. 345 18

Pentostatin (dCF), an inhibitor of adenosine deaminase, has shown activity in the treatment of several lymphoid malignancies, even in the earliest phase I trials. An analysis of the first 300 patients treated in such trials shows a high incidence of severe infection (8%) during the relatively brief period of treatment. Of 24 patients in whom infection was diagnosed, 17 had no evidence of myelosuppression. The causative organisms included viruses, fungi, and bacteria of both high and low pathogenicity. Two-thirds of the infections were fatal. It is suggested that dCF may cause a syndrome similar to severe combined immunodeficiency during the course of treatment. Patients treated with dCF who show evidence of infection, even in the absence of neutropenia, should receive vigorous and rapid diagnostic evaluation to establish the cause of their infection, and aggressive treatment of suspected organisms.
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PMID:Association of severe and fatal infections and treatment with pentostatin. 348 5

Skin fibroblasts might be considered suitable recipients for therapeutic genes to cure several human genetic diseases; however, these cells are resistant to gene transfer by most methods. We have studied the ability of retroviral vectors to transfer genes into normal human diploid skin fibroblasts. Retroviruses carrying genes for neomycin or hygromycin B resistance conferred drug resistance to greater than 50% of the human fibroblasts after a single exposure to virus-containing medium. This represents at least a 500-fold increase in efficiency over other methods. Transfer was achieved in the absence of helper virus by using amphotropic retrovirus-packaging cells. A retrovirus vector containing a human adenosine deaminase (ADA) cDNA was constructed and used to infect ADA-fibroblasts from a patient with ADA deficiency. The infected cells produced 12-fold more ADA enzyme than fibroblasts from normal individuals and were able to rapidly metabolize exogenous deoxyadenosine and adenosine, metabolites that accumulate in plasma in ADA-deficient patients and are responsible for the severe combined immunodeficiency in these patients. These experiments indicate the potential of retrovirus-mediated gene transfer into human fibroblasts for gene therapy.
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PMID:Efficient retrovirus-mediated transfer and expression of a human adenosine deaminase gene in diploid skin fibroblasts from an adenosine deaminase-deficient human. 349 85

Six monoclonal antibodies, designated EqT2, EqT3, EqT6, EqT7, EqT12, and EqT13, which identify T lymphocyte antigens present at different stages of T cell maturation were used to examine T lymphocyte development in foals with severe combined immunodeficiency (SCID). Flow microfluorimetry demonstrated the presence of EqT12+ and EqT13+ prothymocytes and a few phenotypically mature EqT2+ and EqT3+ thymocytes within the thymic remnants of SCID foals. However, very few EqT6+ and EqT7+ resident cortical thymocytes were detected. The near absence of EqT6+ and EqT7+ cortical thymocytes was confirmed by immunofluorescence analysis of thymic tissue from SCID foals. Those cells present were larger than normal cortical thymocytes. Furthermore, their activities of adenosine deaminase, adenosine monophosphate-deaminase, and 5' nucleotidase differed from those of normal cortical thymocytes. The combined evidence of monoclonal antibody analysis, size parameters, and purine enzyme activities demonstrate the near absence of cortical thymocytes in horses with this genetically defined immunodeficiency disorder.
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PMID:Defective thymocyte maturation in horses with severe combined immunodeficiency. 350 Sep 80

Severe combined immunodeficiency (SCID) was originally thought to be one disease. Accumulating evidence indicates that SCID is a heterogeneous group of diseases that are clinically similar but are caused by quite different biochemical abnormalities. The best-studied form of SCID is that associated with an autosomal recessive inheritance pattern of adenosine deaminase (ADA) deficiency. Several biochemical mechanisms have been postulated to explain how a deficiency of ADA causes immune dysfunction. In forms of SCID not associated with ADA deficiency, other biochemical abnormalities have been detected. These abnormalities include deficiency in biotin-dependent carboxylases, alteration in lymphocyte surface membranes and irregularities in cytokine production. Two animal models for SCID now exist. Neither of these models is associated with ADA deficiency. Evidence for a possible defect in purine metabolism in one model has been demonstrated.
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PMID:Metabolic defects in severe combined immunodeficiency in man and animals. 351 64

Recent advances in the prevention of graft-versus-host disease through postthymic T-cell depletion have allowed the use of haploidentical bone marrow cells for immunologic reconstitution of severe combined immunodeficiency disease. We report a male infant with severe combined immunodeficiency (with normal adenosine deaminase) who developed two IgG kappa and one IgA lambda paraproteins 7 weeks following the administration of 1.4 X 10(9) maternal bone marrow cells depleted of postthymic T cells by soy lectin agglutination and sheep erythrocyte rosetting. Serum IgG rose from 128 to 820 mg/dl, and IgA from 0 to 2400 mg/dl, peaking at 10 weeks postgrafting. By 14 weeks posttransplantation T-cell numbers and function had risen to normal (all dividing T cells had the donor karyotype) and paraprotein concentrations began to decline. These observations strongly suggest that the later-appearing T cells regulated the B-cell clones from which the paraproteins were derived. Failure of such function to appear could account for the increased incidence of B-cell lymphomas in severe combined immunodeficiency.
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PMID:Appearance of multiple benign paraproteins during early engraftment of soy lectin T cell-depleted haploidentical bone marrow cells in severe combined immunodeficiency. 351 54

Contemporary molecular techniques including gene cloning, DNA sequencing, and gene transfer permit precise and comprehensive analysis of genetic disorders. For example, the molecular basis of hemoglobin synthesis disorders (the thalassemias) can now be ascribed to more than 30 different specific mutations. These affect virtually all aspects of gene expression. The more recent capacity to reintroduce cloned genes into mammalian cells in a functional form has raised the prospect of gene therapy, that is, the replacement of an abnormal gene with its normal counterpart or merely the introduction of a normal gene into a cell containing a defective copy. Genetic correction of enzyme-deficiency disorders whose effects are manifest in bone-marrow-derived cells seems most likely to be amenable to "somatic" (as opposed to germ line) gene therapy. Treatment of severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency may be a suitable model for this approach. This report will review the molecular genetics of ADA, the methods by which ADA gene sequences may be transferred into various cells, and goals for current and future research.
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PMID:Molecular genetics and potential gene therapy. 352 68

A patient with adenosine deaminase-deficient severe combined immunodeficiency is described whose defect is secondary to deletion of a portion of the ADA structural gene. In Southern analyses, DNA from this patient does not hybridize to a genomic probe that includes the 3' end of exon 1. This implies that both his parents are heterozygous for deletions of exon 1 sequences. Consistent with this finding, the patient has no detectable adenosine deaminase mRNA by Northern analysis. This is the first report of a deletion mutation as the cause of adenosine deaminase deficiency.
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PMID:Identification of a deletion in the adenosine deaminase gene in a child with severe combined immunodeficiency. 357 74

The possibility that the mutant mouse wasted (wst/wst) may serve as an animal model for studies of severe combined immunodeficiency disease (SCID) and the role of adenosine deaminase (ADA, EC 3.5.4.4) in adenosine metabolism were investigated. The specific activity of ADA in wst/wst compared with control mice was significantly lower by 26% in thymus, but significantly higher by 18% in spleen and 32% in cerebellum. Vmax values of ADA in spleens were 43% higher in wst/wst mice and no changes were observed in Km values. In contrast, the Vmax of ADA was unchanged in erythrocytes from wst/wst mice, but the Km for adenosine was significantly elevated. Thus, based on ADA measurements alone, it may be premature to consider wst/wst mice as a model for ADA deficiency and SCID in humans.
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PMID:Lack of adenosine deaminase deficiency in the mutant mouse wasted. 378 Sep 80

Twenty-six patients with severe combined immunodeficiency (SCID) were examined. In 20 cases no defect of the biochemical pathways was found; 6 cases showed a deficiency in adenosine deaminase (ADA) activity. In 19 cases histological sections of the thymus were available. In 3 cases, in addition to the original thymuses, transplanted thymic allografts were microscopically examined. The thymus in SCID without abnormality of the ADA pathway showed a uniform dysplastic pattern with only moderate variations related to mode of inheritance and length of survival. The thymus in SCID with ADA deficiency displayed a heterogeneous pattern ranging from almost normal to a completely dysplastic structure, whereas the transplanted thymic allografts presented either a normal or a dysplastic appearance. The morphology of the thymus is not pathognomonic of any given biochemical defect, clinical course, or type of SCID. SCID with apparently normal biochemical pathways probably results from a variety of pathogenetic mechanisms.
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PMID:Morphology of original and transplanted thymuses in severe combined immunodeficiency. 378 59


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