Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell (HSC) disorder in which an acquired somatic mutation of the X-linked PIGA gene results in a deficiency in GPI-anchored surface proteins. Clinically, PNH is dominated by a chronic hemolytic anemia, often associated with recurrent nocturnal exacerbations, neutropenia, thrombocytopenia, and thrombotic tendency. Allogenic bone marrow transplantation is the only potentially curative treatment for severe forms of PNH but is associated with a high treatment-related morbidity and mortality. HSC gene therapy could provide a new therapeutic option, especially when an HLA-matched donor is not available. To develop an efficient gene transfer approach, we have designed a new SIN lentiviral vector (TEPW) that contains the PIGA cDNA driven by the human elongation factor 1 alpha promoter, the central DNA flap of HIV-1, and the WPRE cassette. TEPW transduction led to a complete surface expression of the GPI anchor and CD59 in PIGA-deficient cell lines without any selection procedure. Moreover, efficient gene transfer was achieved in bone marrow and mobilized peripheral blood CD34(+) cells derived from two patients with severe PNH disease. This expression was stable during erythroid, myeloid, and megakaryocytic liquid culture differentiation. CD59 surface cell expression was fully restored during 5 weeks of long-term culture.
Mol Ther 2003 Mar
PMID:A SIN lentiviral vector containing PIGA cDNA allows long-term phenotypic correction of CD34+-derived cells from patients with paroxysmal nocturnal hemoglobinuria. 1266 26

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT-/-) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib. We demonstrate that the neutropenia is caused directly by the loss of G6PT activity; that chemotaxis and calcium flux, induced by the chemokines KC and macrophage inflammatory protein-2, are defective in G6PT-/- neutrophils; and that local production of these chemokines and the resultant neutrophil trafficking in vivo are depressed in G6PT-/- ascites during an inflammatory response. The bone and spleen of G6PT-/- mice are developmentally delayed and accompanied by marked hypocellularity of the bone marrow, elevation of myeloid progenitor cell frequencies in both organs and a corresponding dramatic increase in granulocyte colony stimulating factor levels in both GSD-Ib mice and humans. So, in addition to transient neutropenia, a sustained defect in neutrophil trafficking due to both the resistance of neutrophils to chemotactic factors, and reduced local production of neutrophil-specific chemokines at sites of inflammation, may underlie the myeloid deficiency in GSD-Ib. These findings demonstrate that G6PT is not just a G6P transport protein but also an important immunomodulatory protein whose activities need to be addressed in treating the myeloid complications in GSD-Ib patients.
Hum Mol Genet 2003 Oct 01
PMID:Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter. 1292 67

The use of granulocyte colony stimulating factor (G-CSF) for recovery from neutropenia has been established; however, acute lung injury due to G-CSF-induced polymorphonuclear leukocyte (PMN) activation is a serious complication. This study was designed to compare the activation of PMN with single bolus administration and continuous administration of G-CSF. Healthy volunteers (age 33.8 +/- 1.4 yr; n = 6) received a single bolus injection of 50 microm/m2 of G-CSF (SI; n = 6) or continuous subcutaneous injection of 50 microm/m2 of G-CSF for 24 h (CI; n = 6) and were followed for 48 h. Circulating leukocyte counts, markers of activation on PMN, and circulating levels of G-CSF, IL-6, and PMN elastase were measured. SI rapidly increased serum G-CSF levels, which peaked at 4 h, whereas CI gradually increased G-CSF levels, which remained at a steady level from 8 to 24 h. SI caused a rapid decrease in PMN counts at 0.5 h followed by sustained increase to peak at 12 h. CI gradually increased PMN counts, which peaked at 24 h, but the peak values were not significantly different between the groups. SI-induced activation of PMN, which was characterized by increased expression of CD11b, decreased expression of L-selectin, and increased F-actin content, led to increases in serum IL-6 and PMN elastase level. Such changes were all attenuated with CI (P < 0.05). We conclude that continuous subcutaneous injection of G-CSF resulted in a marrow response similar to that to a single injection but yielded reduced PMN activation.
Am J Physiol Lung Cell Mol Physiol 2004 Jan
PMID:Continuous subcutaneous injection reduces polymorphonuclear leukocyte activation by granulocyte colony-stimulating factor. 1452 31

Mutations in ELA2, encoding the human serine protease neutrophil elastase, cause cyclic and severe congenital neutropenia, and recent evidence indicates that the mutations alter the membrane trafficking of neutrophil elastase. These disorders feature impaired bone marrow production of neutrophils along with excess monocytes-terminally differentiated lineages corresponding to the two alternative fates of myeloid progenitor cells. We utilized a modified yeast two-hybrid system and identified a new, widely expressed gene, N2N, whose product is homologous to Notch2, that interacts with neutrophil elastase. N2N is a 36-kDa protein distributed throughout the cell and secreted. Its amino-terminal sequence consists of several EGF repeats identical to those of the extracellular region of Notch2, and its carboxyl terminus contains a unique 24-residue domain required for interaction with neutrophil elastase. Neutrophil elastase cleaves N2N within EGF repeats in vitro and in living cells, but the C-terminal domain retards proteolysis. In vitro, N2N represses transcriptional activities of Notch proteins. Disease-causing mutations of neutrophil elastase disrupt the interaction with N2N, impair proteolysis of N2N and Notch2, and interfere with Notch2 signaling, suggesting defective proteolysis of an inhibitory form of Notch as an explanation for the alternate switching of cell fates characteristic of hereditary neutropenia.
Mol Cell Biol 2004 Jan
PMID:A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia. 1467 43

Mutations in ELA2, the gene encoding neutrophil elastase (NE), cause the human diseases cyclic neutropenia (CN) and severe congenital neutropenia (SCN). Numerous mutations are known, but their lack of consistent biochemical effect has proven puzzling. The recent finding that mutation of AP3B1, which encodes the beta subunit of adaptor protein complex 3 (AP3), is the cause of canine CN suggests a model for the molecular basis of hereditary neutropenias, involving the mistrafficking of NE: AP3 recognizes NE as a cargo protein, and their interaction implies that NE is a transmembrane protein. Computerized algorithms predict two NE transmembrane domains. Most CN mutations fall within predicted transmembrane domains and lead to excessive deposition of NE in granules, whereas SCN mutations usually disrupt the AP3 recognition sequence, resulting in excessive transport to the plasma membrane.
Trends Mol Med 2004 Apr
PMID:Hereditary neutropenia: dogs explain human neutrophil elastase mutations. 1505 7

G3139 is a BCL-2 antisense oligonucleotide whose antitumor effects in preclinical models are enhanced when combined with taxane-based chemotherapy. This trial determined the safety and biologic activity of G3139 given with paclitaxel and docetaxel for the treatment of progressive solid tumors. Three cohorts of patients received weekly paclitaxel 100 mg/m2 on days 1, 8, and 15 concurrently with a 21-day continuous infusion of G3139 at 4.1, 5.3, and 6.9 mg/kg/d, depending on the cohort. Two subsequent cohorts received docetaxel (75 mg/m2) on day 5 of a 5-day infusion of G3139 at 5 or 7 mg/kg/d. Bcl-2 protein levels in peripheral blood mononuclear cells (PBMCs) were assayed on an exploratory basis. Fifteen patients were treated. Eight received a total of 14 cycles of G3139 and paclitaxel; seven received a total of 22 cycles of G3139 and docetaxel. Eight patients required dose modifications for either grade 4 neutropenia (6 patients) or grade 1-2 reversible transaminitis (2 patients). No radiographic responses were seen, although two of the six taxane-naive prostate cancer patients exhibited a prostate-specific antigen decline greater than 50%. Bcl-2 protein levels in PBMCs declined with treatment as assessed by immunohistochemistry. The authors conclude that G3139, whether given as a 5- or 21-day infusion, is well tolerated with taxane chemotherapy and is biologically active by immunohistochemistry at doses up to and including 7 mg/kg/d, using weekly paclitaxel (100 mg/m2) or docetaxel every 3 weeks (75 mg/m2). These data support the dose selection of ongoing phase 2 studies of G3139 at 7 mg/kg/d and docetaxel 75 mg/m2.
Appl Immunohistochem Mol Morphol 2005 Mar
PMID:Safety and biologic activity of intravenous BCL-2 antisense oligonucleotide (G3139) and taxane chemotherapy in patients with advanced cancer. 1572 87

The purpose of this study was to determine whether benign hereditary leukopenia-neutropenia in Yemenites may be reflective of an absent or a lesser degree of chronic low grade inflammation that has been documented to exist in most apparently healthy subjects. The white blood cell count (WBCC), fibrinogen as well as high sensitivity C-reactive protein (hs-CRP) concentrations were determined in a group of apparently healthy individuals during their routine health screening program. These inflammatory biomarkers in a group of 82 Yemenite Jews were compared to those measured in a group of 1817 individuals whose parents immigrated to Israel from Central and East Europe, from countries surrounding the Mediterranean Sea as well as the Middle East. The two study groups were matched for possible confounding factors that may have an influence on the intensity of the microinflammatory response including age, gender, body mass index, components of the metabolic syndrome and the Ten Year Calculated Coronary Heart Disease Framingham Risk Score. The expected reduced WBCC was noted in the group of Yemenite Jews (6.99 +/- 1.64 versus 5.88 +/- 2.06 x 10(3)/microL cells, P = 0.001). However, they had significantly enhanced concentrations of hs-CRP, the respective values being 2.1 +/- 2 versus 1.4 +/- 2.4 mg/L in men (P = 0.002) and 2.5 +/- 2.2 versus 1.4 +/- 2.9 in women (P < 0.0005). An increased concentration of fibrinogen was found in the Yemenite Jews, although the difference was not statistically significant in men. Thus, the leukopenia-neutropenia in Yemenite Jews is probably not an expression of an absent or lesser degree of chronic low grade inflammation. These findings shed more light on the potential mechanisms that are responsible for the low WBCC in this particular ethnic group.
Blood Cells Mol Dis
PMID:Benign hereditary leukopenia-neutropenia does not result from lack of low grade inflammation. A new look in the era of microinflammation. 1572 95

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor, that has been used as a therapeutic agent in facilitating bone marrow and stem cell transplantation and in other clinical cases like neutropenia. Although biologically active recombinant GM-CSF has been successfully produced in Escherichia coli, the reported levels are extremely poor. In this study we looked into the possible reasons for poor expression and found that protein toxicity coupled with protease-based degradation was the principal reason for low productivity. To overcome this problem we attached a signal sequence, as well as an amino-terminal His-tag fusion to the GM-CSF gene. This combination had a dramatic effect on expression levels, which increased from 0.8 microg/mL in the control to 40 microg/mL. When a larger fusion partner, such as the Maltose-binding protein (MBP-tag), was used the expression levels increased further to 69.5 microg/mL, which along with the MBP-tag represented approx 12% of the total cellular protein.
Mol Biotechnol 2005 Jun
PMID:Combined effect of protein fusion and signal sequence greatly enhances the production of recombinant human GM-CSF in Escherichia coli. 1592 Feb 80

Clinical and laboratory data indicate that the liver plays an important role in the incidence, pathogenesis, and outcome of acute lung injury/acute respiratory distress syndrome. To distinguish direct effects of endotoxin on the lungs from liver-dependent effects during the early phase of the response to endotoxemia, we used an in situ perfused piglet preparation in which only the ventilated lung or both the lung and liver could be included in a blood perfused circuit. We monitored pulmonary vascular resistance, oxygenation, neutrophil count, lung edema as reflected by wet-dry weights of lung tissue, perfusate concentrations of TNF-alpha, IL-6, and 8-isoprostane (a marker of oxidative stress), and activation of the transcription factor (NF-kappaB) in lung tissue before and for 2 h after endotoxin. When only the lung was perfused, endotoxin caused pulmonary hypertension and neutropenia; but oxygenation was maintained; TNF-alpha, IL-6, and 8-isoprostane levels were minimally elevated; and there was no lung edema. When both the liver and lung were perfused, endotoxin caused marked hypoxemia, large increases in perfusate TNF-alpha, IL-6, and 8-isoprostane concentrations, and severe lung edema. NF-kappaB activation in the lung was greatest when the liver was in the perfusion circuit. We conclude that the direct effects of endotoxemia on the lungs include vasoconstriction and leukocyte sequestration, but not lung injury. Intense activation of the inflammatory response and oxidative injury that results in pulmonary edema and hypoxemia (acute lung injury) requires interaction of the lungs with the liver.
Am J Physiol Lung Cell Mol Physiol 2005 Nov
PMID:Endotoxin-induced acute lung injury requires interaction with the liver. 1600 84

Tocols are a family of eight isomers consisting of four tocopherols and four tocotrienols that exist in four isomeric forms: alpha (alpha), beta (beta), gamma (gamma), and delta (delta). Recently, tocols were found to have important and unique biological effects on nutrition and health other than antioxidant properties and are, therefore, now receiving increased attention. We have demonstrated the radioprotective efficacy of various tocol analogs and some of their esters. Three forms of tocols - alpha-tocopherol, alpha-tocopherol succinate, and gamma-tocotrienol - significantly protected mice against lethal gamma irradiation when administered subcutaneously 24 h before irradiation. The radioprotective effects of tocols on survival were associated with peripheral blood cell recovery after radiation induced cytopenia. Hematopoietic cytokines are known to promote the proliferation and differentiation of blood cell progenitors. Therefore, we hypothesized that peripheral blood cell recovery is preceded by hematopoietic cytokine induction. To test this hypothesis and compare the various radioprotective and non-radioprotective analogs, we measured serum cytokines using a sandwich ELISA, Luminex, and cytokine array in mice treated with various tocols (alpha-tocopherol succinate, alpha-tocopherol, delta-tocopherol, gamma- tocopherol, gamma-tocotrienol, and tocopherol acetate). Among the serum cytokines measured, ELISA and Luminex studies indicated that alpha-tocopherol, alpha-tocopherol succinate, and gamma-tocotrienol increased G-CSF levels in mice. Alpha-tocopherol succinate was most effective in stimulating G-CSF. IL-6 was detected by Luminex in sera samples from mice treated with the above three analogs. The results of the cytokine array suggest that other cytokines and chemokines in addition to G-CSF and IL-6 are induced. Since G-CSF, IL-6, and certain chemokines are important hematopoietic factors, these results support our hypothesis that the protection of mice from radiation-induced hematopoietic death is mediated by cytokines and chemokines. These studies may indicate that alpha-tocopherol succinate can be used as an adjunct in cancer chemotherapy, where neutropenia is a serious problem with threatening infectious complications.
Exp Mol Pathol 2006 Aug
PMID:Induction of cytokines by radioprotective tocopherol analogs. 1642 3


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