Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Purine nucleoside phosphorylase (PNP) deficiency results in an autosomal recessive immunodeficiency disease characterized by initial involvement of cellular immunity and neurological manifestations with subsequent abnormalities of humoral immunity. The initial presentation and clinical course has varied widely in the relatively few published cases. The molecular basis has been reported in only 10 patients, precluding evaluation of phenotype-genotype relationships. We now report clinical, immunologic, and molecular findings in a new case of relatively early onset that emphasizes hypotonia and developmental delay as early manifestations. The patient carried two novel missense mutations (Gly56A1a and Val217Ile) on the same allele in apparent homozygosity. Expression of each of the mutant enzymes in vitro demonstrated that the Gly156A1a mutation abolished enzyme activity while the Val217Ile mutation was without obvious effect and is therefore a normal variant. Such "normal" polymorphisms might be associated with a variable response to the immunosuppressive PNP inhibitors currently in clinical trials.
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PMID:Purine nucleoside phosphorylase deficiency: a new case report and identification of two novel mutations (Gly156A1a and Val217Ile), only one of which (Gly156A1a) is deleterious. 1248 96

We report two siblings with purine nucleoside phosphorylase deficiency revealed by isolated spastic paraplegia, whereas symptoms of immune deficiency did not become apparent until 3 years of age. As the concurrence of immunodeficiency and neurologic problems strongly suggests the diagnosis of purine nucleoside phosphorylase deficiency, special attention should be paid to counts of lymphocytes in any infant with spastic paraplegia.
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PMID:Familial spastic paraplegia as the presenting manifestation in patients with purine nucleoside phosphorylase deficiency. 1269 83

Genetic deficiency of human purine nucleoside phosphorylase (PNP) causes T-cell immunodeficiency. The enzyme is therefore a target for autoimmunity disorders, tissue transplant rejection and T-cell malignancies. Transition state analysis of bovine PNP led to the development of immucillin-H (ImmH), a powerful inhibitor of bovine PNP but less effective for human PNP. The transition state of human PNP differs from that of the bovine enzyme and transition state analogues specific for the human enzyme were synthesized. Three first generation transition state analogues, ImmG (Kd = 42 pM), ImmH (Kd = 56 pM), and 8-aza-ImmH (Kd = 180 pM), are compared with three second generation DADMe compounds (4'-deaza-1'-aza-2'-deoxy-1'-(9-methylene)-immucillins) tailored to the transition state of human PNP. The second generation compounds, DADMe-ImmG (Kd = 7pM), DADMe-ImmH (Kd = 16 pM), and 8-aza-DADMe-ImmH (Kd = 2.0 nM), are superior for inhibition of human PNP by binding up to 6-fold tighter. The DADMe-immucillins are the most powerful PNP inhibitors yet described, with Km/Kd ratios up to 5,400,000. ImmH and DADMe-ImmH are orally available in mice; DADMe-ImmH is more efficient than ImmH. DADMe-ImmH achieves the ultimate goal in transition state inhibitor design in mice. A single oral dose causes inhibition of the target enzyme for the approximate lifetime of circulating erythrocytes.
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PMID:Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase. 1284 89

The disorders of purine and pyrimidine metabolism are unusual in their variety of clinical presentations and in the mechanisms by which these presentations result from the fundamental mutations. In the most common of the hyperuricemic metabolic disorders, deficiency of hypoxanthine phosphoribosyl transferase, the fundamental deficiency in the activity of an enzyme of purine salvage leads to enormous overactivity of de novo pathway of purine synthesis and purine overproduction. In the other hyperuricemic disorder, that of phosphoribosylpyrophosphate synthetase, mutation leads not to deficient activity, but superactivity of the enzyme in an early stage of the synthetic pathway leading to overproduction. A number of disorders of purine metabolism lead to immunodeficiency; these include adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. Marked susceptibility to infection is also seen in disorders of pyrimidine metabolism, classically in orotic aciduria, but also in pyrimidine nucleotide depletion syndrome. Orotic aciduria is a disorder of pyrimidine nucleotide synthesis, UMP synthetase deficiency, in which a single gene mutation can cause deficiency of two enzyme activities, orotic phosphoribosyltransferase and orotidine monophosphate decarboxylase which reside in a single protein. Pyrimidine degradation defects, dihydropyrimidine dehydrogenase and dihydropyrimidinase deficiencies leading to developmental delay are detected by analysis of the urine for pyrimidines and dihydropyrimidines. The recent discovery of aminoimidazolecarboxamideriboside deficiency points up the utility of simple colorimetric tests in bringing to light disorders of metabolism. Adenylosuccinatelyase deficiency and molybdenum cofactor deficiency illustrate the same point.
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PMID:Disorders of purine and pyrimidine metabolism. 1617 80

Purine nucleoside phosphorylase (PNP) is an intracellular enzyme crucial for purine degradation. PNP defects result in metabolic abnormalities and fatal T cell immunodeficiency. Protein transduction domains (PTD) transfer molecules across biological membranes. We hypothesized that fusion of PTD to PNP (PTD-PNP) would be an effective method for treating PNP deficiency. We find that PTD-PNP rapidly enters PNP-deficient lymphocytes and increases intracellular enzyme activity for 96 h. Similar to endogenous PNP, PTD-PNP is predominantly distributed in the cytoplasm. PTD-PNP improve viability and correct abnormal functions of PNP-deficient T lymphocytes including their response to stimulation and IL-2 secretion. Intracellular transduction protects PTD-PNP from antibody neutralization and from elimination, which may also provide significant in vivo therapeutic advantages to PNP. In conclusion, PTD fusion is an attractive method for extended PNP intracellular enzyme replacement therapy for PNP-deficient patients as well as for the intracellular delivery of other proteins.
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PMID:Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro. 1693 May 74

Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the central nervous system. Although the majority of cases are infected with the human immunodeficiency virus (HIV), other immunocompromised patients are also at risk. Purine nucleoside phosphorylase is an enzyme in the purine salvage pathway that reversibly converts inosine to hypoxanthine and guanosine to guanine. Purine nucleoside phosphorylase deficiency is a combined immunodeficiency with a profound cellular defect. Neurologic abnormalities are salient features of this syndrome. We describe for the first time a patient with this rare disorder presented with progressive multifocal leukoencephalopathy.
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PMID:Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency. 1694 40

Defects in purine nucleoside phosphorylase (PNP) enzyme activity result in abnormal nucleoside homeostasis, severe T cell immunodeficiency, neurological dysfunction, and early death. Protein transduction domain (PTD) can transfer molecules into cells and may help restore PNP activity in cases of PNP deficiency. However, long-term use of PTD to replace enzymes in animal models or patients has not previously been described. We fused human PNP to the HIV-TAT PTD and found that the fusion with TAT changed the retention and distribution of PNP in PNP-deficient mice. TAT induced rapid intracellular delivery of PNP into tissues, including the brain, prevented urinary excretion of PNP, and protected PNP from neutralizing antibodies, resulting in significant extension of the enzyme's biological activity in vivo. Frequent TAT-PNP injections in PNP-deficient mice corrected the metabolic disorder and immune defects with no apparent toxicity. TAT-PNP remained effective over 24 weeks of treatment, resulting in continued improvement in immune function and extended survival. Our data demonstrate that TAT changes the properties of PNP in vivo and that long-term intracellular delivery of PNP by TAT corrects PNP deficiency in mice. We provide evidence to promote further use of PTD to treat diseases that require repeated intracellular enzyme or protein delivery.
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PMID:TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice. 1696 10

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine-salvage metabolic pathway. In humans, the loss of functional PNP results in significant T-cell-mediated immunodeficiency (and may also affect B-cell function). Forodesine is a potent PNP inhibitor that acts by elevating plasma 2'-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate, which in turn affects deoxynucleotide-triphosphate pools and induces cell death by apoptosis. BioCryst Pharmaceuticals Inc, under license from the Albert Einstein College of Medicine, is developing intravenous and oral formulations of forodesine for the potential treatment of various T-cell and B-cell lymphomas and leukemias, as well as for solid tumors; MundiPharma AG is also investigating the drug for leukemia. Forodesine effectively inhibits T-cell proliferation in vitro in the presence of dGuo. In early clinical trials, forodesine has demonstrated an acceptable safety profile and indications of biological activity. Few drug-related serious adverse events have been reported, and generally only mild-to-moderate nonhematological toxicity has been observed. Forodesine has the potential to lead the development of other novel therapies with broad-based activity for hematological malignancies; the drug may also be useful for the treatment of a wide variety of other T-cell-mediated disorders, as well as for the potential treatment for other B-cell lymphomas/leukemias.
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PMID:Drug evaluation: forodesine - PNP inhibitor for the treatment of leukemia, lymphoma and solid tumor. 1701 79

After receiving BS and MS degrees from the University of Washington in Seattle, I entered its new medical school in 1947, receiving an MD degree in 1951. After internship and residency, I obtained a 2-year postdoctoral fellowship in hematology under the guidance of Dr Clement Finch. The last 6 months of the fellowship were spent in London, England, at Dr Patrick Mollison's Blood Transfusion Research Unit. There I met and worked with Marie Cutbush (later Crookston) who has been a long-term friend. On returning to Seattle, I joined the faculty of the medical school and became the associate director of the Puget Sound Blood Center. There, I supervised the blood typing and cross-matching laboratory, introducing methods I had learned in London and measuring the effectiveness of various cross-matching procedures. My own research was largely directed toward human genetic polymorphism, and I wrote a textbook published in 1969, describing the biochemical structure, function, inheritance, and geographic distribution of the genetic markers. Subsequently, I discovered that 2 forms of inherited immunodeficiency disease were due to deficiencies of the enzymes adenosine deaminase and purine nucleoside phosphorylase. In 1979, I became the director of the blood center and was shortly afterwards elected to the National Academy of Sciences. I retired in 1987 and have spent most of the intervening years relearning to play the violin and exploring the wonders of chamber music.
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PMID:Back to the beginnings: an autobiography. 1706 74

Purine nucleoside phosphorylase (PNP) deficiency is a rare, inherited immunodeficiency disorder in which the specific molecular defect was identified. Clinically, a lack of PNP manifests as profound T-cell deficiency with minor or variable changes in the humoral system. Biochemically, the absence of PNP results in an increase in plasma deoxyguanosine (dGuo) and a T-cell-specific increase in intracellular deoxyguanosine triphosphate (dGTP). This observation has been the impetus for the search for either inhibitors of the enzyme or PNP-resistant dGuo analogues as potential anti-T-cell-lineage agents over the past 30 years. Forodesine (an inhibitor of PNP) and nelarabine (a PNP-resistant dGuo analogue) proved to be T-cell selective when tested in clinic. This review summarises the preclinical, clinical and pharmacokinetic investigations with these novel agents.
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PMID:Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma. 1710 84


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