Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inherited deficiency in adenosine deaminase (ADA), which results in severe combined immunodeficiency, is generally regarded as an optimal model for the development of human somatic gene therapy. The ideal target for the correction of ADA deficiency and other lympho-hematopoietic disorders would be the hematopoietic stem cell. We have used a combination of recombinant human interleukins-3 and -6 to stimulate the proliferation of primitive human hematopoietic progenitor cells during a period of co-cultivation with irradiated cells producing high titers of an ADA-transducing retroviral vector packaged in amphotropic particles. In a series of nine experiments, an average of 83% of the clonogenic progenitors (CFU-E and CFU-GM) were found to have acquired the transferred sequence as determined by polymerase chain reaction analysis. In addition, in two experiments, 24-44% of the clonogenic progenitors derived from long-term myeloid cultures 9 weeks post-transduction were found to contain vector sequence. The latter cells are derived from so-called "long-term culture-initiating cells" (LTC-IC), which are primitive cells probably related to hematopoietic stem cells. Moreover, the transduced ADA enzyme was found to be expressed in both normal and ADA-deficient erythroid colonies, and in the nonadherent cells of long-term bone marrow culture for at least 2 weeks at levels that approximate the endogenous ADA levels of normal erythroid cells. These results indicate that the ADA coding sequence can efficiently be introduced by retroviral gene transfer into both committed and primitive human hematopoietic progenitor cells, and that this will result in adequate expression of the transduced enzyme in the progeny of committed hematopoietic progenitors.
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PMID:Gene transfer of adenosine deaminase into primitive human hematopoietic progenitor cells. 175 90

Severe combined immunodeficiency (SCID) represents a syndrome characterized by abnormal function of cellular and humoral immunity. Of the various types of SCID, approximately one-fourth are associated with adenosine deaminase (ADA) deficiency. Treatment consists of bone marrow transplantation, red blood cell transfusions, enzyme replacement, and, more recently, gene therapy. Pegademase bovine is the sole agent available for enzyme replacement therapy of SCID associated with ADA deficiency. The drug is administered intramuscularly to infants from birth and to children of any age at time of diagnosis. At present, few adverse effects or drug interactions have been documented. Although it is expensive (approximately $60,000 annually), pegademase bovine offers an alternative to standard means of therapy.
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PMID:Pegademase bovine: replacement therapy for severe combined immunodeficiency disease. 180 99

Deficiency of adenosine deaminase (ADA) results in severe combined immunodeficiency (SCID), a candidate genetic disorder for somatic cell gene therapy. Peripheral blood lymphocytes from patients affected by ADA- SCID were transduced with a retroviral vector for human ADA and injected into immunodeficient mice. Long-term survival of vector-transduced human cells was demonstrated in recipient animals. Expression of vector-derived ADA restored immune functions, as indicated by the presence in reconstituted animals of human immunoglobulin and antigen-specific T cells. Retroviral vector gene transfer, therefore, is necessary and sufficient for development of specific immune functions in vivo and has therapeutic potential to correct this lethal immunodeficiency.
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PMID:An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency. 184 69

The effect of polyethylene glycol-adenosine deaminase (PEG-ADA) therapy on biochemical, immunological and clinical abnormalities in an ADA-deficit child with severe combined immunodeficiency has been studied. Following PEG-ADA therapy, total lymphocytes, lymphocyte subsets (CD3, CD4 and CD8) and the response of lymphocytes to non specific mitogens increase significantly. The improvement of immunological functions is closely related to a decrease of erythrocyte deoxyadenosine triphosphate (dATP) concentrations. This study shows that PEG-ADA therapy is sufficiently effective to reduce and to maintain erythrocyte dATP levels at values compatible with normal immune functions. PEG-ADA represents an important progress for the treatment of ADA deficiency associated with severe combined immunodeficiency disease.
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PMID:[Polyethylene glycol-adenosine deaminase: a new adenosine deaminase deficiency therapy. Value of deoxyadenosine triphosphate determination for therapeutic monitoring]. 194 9

Amphotropic recombinant retroviruses were generated carrying sequences encoding human adenosine deaminase (ADA). Transcription of the human ADA gene was under control of a hybrid long terminal repeat in which the enhancer from the Moloney murine leukemia virus was replaced by an enhancer from the F101 host-range mutant of polyoma virus. Hemopoietic stem cells in murine bone marrow were infected with this virus under defined culture conditions. As a result, 59% of day-12 colony forming unit spleen (CFU-S) stem cells became infected without any in vitro selection. Infected CFU-S were shown to express human ADA before transplantation and this expression sustained upon in vivo maturation. Mice transplanted with infected bone marrow exhibited human ADA expression in lymphoid, myeloid, and erythroid cell types. Moreover, human ADA expression persisted in secondary and tertiary transplanted recipients showing that human ADA-expressing cells were derived from pluripotent stem cells. These characteristics of our amphotropic viruses make them promising tools in gene therapy protocols for the treatment of severe combined immunodeficiency caused by ADA deficiency. In this respect it is also relevant that the viral vector that served as backbone for the ADA vector was previously shown to be nonleukemogenic.
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PMID:Expression of human adenosine deaminase in mice transplanted with hemopoietic stem cells infected with amphotropic retroviruses. 197 14

We report two patients with severe combined immunodeficiency and short stature/short limb skeletal dysplasia. Case 1 presented at birth with rhizomelic shortening of the extremities and bowing of the femora. She developed clinical signs of severe combined immunodeficiency at 13 months and died at 21 months. Case 2 had severe prenatal shortening and bowing of the extremities and a small, malformed chest. Symptoms of severe combined immunodeficiency and severe failure to thrive developed soon after birth and she died at 5 months. The diagnosis of severe combined immunodeficiency in our patients was based on their clinical course and necropsy findings, supported in case 1 by the results of immune function tests. The results of investigation of immune function (immunoglobulins, lymphocyte subpopulations, lymphocyte function) are very variable in this syndrome as in other variants of severe combined immunodeficiency. Bone histopathology in both patients showed grossly irregular costochondral junctions, but normal transition of proliferating to hypertrophic chondrocytes. These cases belong to early lethal type 1 short limb skeletal dysplasia with severe combined immunodeficiency. Review of previously published cases with severe combined immunodeficiency and well documented skeletal findings show eight patients with prenatal onset of bowing and shortening of the extremities and metaphyseal abnormalities. These include two sib pairs concordant for the skeletal changes. In these cases, adenosine deaminase levels were not reported. An additional four published cases with associated adenosine deaminase deficiency had only mild metaphyseal abnormalities, but subsequently showed no linear growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Short stature/short limb skeletal dysplasia with severe combined immunodeficiency and bowing of the femora: report of two patients and review. 199 27

The application of bone marrow gene therapy has been stalled by the inability to achieve stable high-level gene transfer and expression in the totipotent stem cells. We show that retroviral vectors can stably introduce genes into antigen-specific murine and human T lymphocytes in culture. Murine helper T cells were transduced with the retroviral vector SAX to express both neomycin-resistance and human adenosine deaminase genes. These cells were expanded in culture and selected for expression of neomycin resistance with G418. The gene insertion, selection, and culture expansion did not alter antigen specificity or growth characteristics of the T cells in vitro. To determine if cultured T cells might be used for gene therapy, their persistence and continued expression of the introduced genes was evaluated in nude mice transplanted with the SAX-transduced T cells. G418-resistant cells could be readily recovered from the spleens of recipients of transduced T cells for several months. In addition, recovered cells continued to produce human adenosine deaminase. Based on these observations, we studied cultured human tumor-infiltrating lymphocytes as a candidate cell for a trial of gene transfer in man. Exponential cultures of interleukin-2-stimulated tumor-infiltrating lymphocytes were efficiently transduced with the neomycin-resistance gene using the retroviral vector N2. Gene insertion and subsequent G418 selection did not substantially alter the growth characteristics, interleukin 2 dependence, membrane phenotype, or cytotoxicity profile of the transduced T cells. These studies provided a portion of the experimental evidence supporting the feasibility of the presently ongoing clinical trials of lymphocyte gene therapy in cancer as well as in patients with adenosine deaminase deficiency.
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PMID:Lymphocytes as cellular vehicles for gene therapy in mouse and man. 201 35

Inherited deficiency of the purine salvage enzyme adenosine deaminase (ADA) is responsible for approximately half the cases of autosomal recessive Severe Combined Immunodeficiency (SCID). Deficiency of ADA can also result in a much later-onset, milder immunodeficiency, while lesser degrees of enzyme deficiency can result in either late-onset immunodeficiency or grossly normal immunologic function. The full clinical spectrum of ADA deficiency is currently being more fully defined. Florid pathology is primarily restricted to the immune system and appears to result from accumulation of substrates (adenosine and deoxyadenosine) and metabolites (deoxy ATP). Studies indicate that these metabolites may preferentially accumulate in lymphoid cells and can interfere with lymphoid proliferation and function. There is evidence for several mechanisms, including induction of chromosome breaks, inhibition of ribonucleotide reductase needed for normal DNA synthesis, and inactivation of SAH hydrolase needed for normal methylation reactions. The enzyme is a 40 Kd monomer that is ubiquitous, and diagnosis can be made with many cell types including erythrocytes, lymphocytes and fibroblasts. Prenatal diagnosis has been made with chorionic villous samples, amniotic cells and fetal blood. The gene for ADA resides on the long arm of human chromosome 20, and both the expressed and structural gene have been isolated and characterized. Most patients with ADA SCID have single base pair mutations resulting in amino acid substitutions, although a splicing mutation and a deletion have been described. The treatment of choice is currently bone-marrow transplantation from a histocompatible related donor, if available. Haploidentical transplants have also been successful but appear to have higher failure rates in ADA deficients than in other types of SCID. Enzyme replacement, now using an enzyme modified to increase the half-life and decrease immunogenicity, has been reported as successful but longer-term efficacy remains to be evaluated. The disorder, despite its rarity, is for several reasons considered a prime candidate for gene therapy. Recently success has been obtained in introducing the gene into lymphoid stem cells and achieving long-term expression.
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PMID:Adenosine deaminase deficiency. 207 32

Severe combined immunodeficiency disease (SCID) with adenosine deaminase (ADA) deficiency is a genetic autosomic recessive disorder with profound impairment of T-cell function, invariably complicated by fatal infections. The absence of ADA-enzyme and the accumulation of deoxy-ATP, with toxic effects on the T-lymphocytes is the common feature of this disease. As a consequence, lymphoid precursors failure to develop into mature T-cells, resulting in absolute lymphopenia and atrophy of the thymus. Bone marrow transplantation from an HLA-identical donor is considered the treatment of choice for this disease. We describe the case of a 1-month-old child with ADA deficiency SCID who underwent bone marrow transplantation (BMT) using paternal haploidentical, lectin-separated marrow, as a source of hemopoietic stem cells.
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PMID:Successful lectin-separated bone marrow transplantation in adenosine deaminase deficiency-related severe immunodeficiency. 209 97

The enzyme adenosine deaminase (ADA) catalyzes the conversion of adenosine and 2'-deoxyadenosine to inosine and 2'-deoxyinosine, respectively. In the absence of ADA activity, 2'-deoxyadenosine is phosphorylated to deoxyadenosine triphosphate. This study concerned the effects of the ADA inhibitor 2'-deoxycoformycin on the murine in vitro immune response to sheep red blood cells (Mishell-Dutton cultures). In the presence of 10(-7) M 2'-deoxycoformycin or 1 mM 2'-deoxyadenosine, there was a significant increase in the plaque-forming cell response when calculated as plaques per 10(6) viable cells recovered. Cultures containing 10(-7) M 2'-deoxycoformycin retained approximately 10% of residual ADA activity of control cultures. Partial ADA deficiency was not preferentially toxic for cells capable of suppressing plaque cell generation. However, there was a decrease of recovered viable cells in all ADA-deficient cultures. There was no change in the percentage of recovered cells which were L3T4+ or Lyt 2+. A significant decrease was observed in a population of cells expressing surface immunoglobulins. The number of plaque-forming cells/10(3) recovered B cells increased significantly. We conclude that partial ADA deficiency results in selective toxicity to a population of non-antigen-specific B cells. Further studies with antigen-specific cells are necessary to determine the possible mechanism(s) by which cellular activation may prevent susceptibility to the toxic effects of ADA deficiency.
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PMID:Enhanced antibody response in the presence of partial adenosine deaminase inhibition. 213 30


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