SLN124, a Galnac-siRNA Conjugate Targeting TMPRSS6, for the Treatment of Iron Overload and Ineffective Erythropoiesis Such As in Beta-Thalassemia

Abstract Accumulation of excess iron in tissues causes organ damage and dysfunction and may lead to serious clinical consequences including liver cirrhosis, diabetes, growth retardation and heart failure. Iron overload is a major health threat in iron loading anemias, like beta-thalassemia, myelodysplastic syndrome and in hereditary hemochromatosis. In patients with beta-thalassemia major, iron overload develops due to frequent blood transfusions to control the severe anemia. In addition, iron overload also occurs in patients with beta thalassemia intermedia (non-transfusion dependent beta-thalassemia). In the later cases, iron overload develops through gastrointestinal iron hyperabsorption due to stressed and ineffective erythropoiesis. Importantly, expression of the peptide hormone hepcidin, which is the key modulator in iron homeostasis, is abnormally low and unable to block ferroportin-mediated intestinal iron absorption. In hereditary hemochromatosis, gene defects in the hepcidin-ferroportin axis controlling iron homeostasis, lead to hepatic iron overload. Therefore, in these indications, iron overload is caused by dysregulation or dysfunction of the hepcidin-ferroportin axis. Hepcidin is predominantly produced by the liver and is induced by activation of the BMP/SMAD signaling pathway. Furthermore, hepcidin is under the negative control of the transmembrane protease matriptase-2, encoded by the TMPRSS6 gene. RNA interference is a natural mechanism and a powerful approach for inhibiting the expression of disease-associated genes. Silence Therapeutics has developed short interfering RNA (siRNA) conjugate technology for the selective inhibition of target gene expression in the liver. GalNAc-conjugated siRNAs bind efficiently to the asialoglycoprotein (ASGP) receptor expressed predominantly by hepatocytes thereby providing a highly specific, safe and efficient delivery technology to enable a new class of therapeutic use. Here we present the pharmacological characterization of SLN124, our GalNAc-siRNA conjugate targeting TMPRSS6 expression, in preclinical models. A single subcutaneous administration is sufficient to achieve significant modulation of target gene expression in mice and in non-human primates over several weeks. SLN124 treatment reduces systemic iron levels, transferrin saturation and tissue iron levels in a rodent model for hereditary hemochromatosis type 1. In addition, we report for the first time the therapeutic efficacy of iron restriction by SLN124 in mice with established iron overload both as monotherapy and in combination with an oral iron chelator - current standard of care- over an extended treatment period. The effects of these treatments on red blood cell parameters and tissue iron levels will be presented. In addition, we assessed the therapeutic effects of SLN124 in an animal model for beta-thalassemia intermedia, showing dose-dependent and long-lasting effects on target gene expression as well as on modulation of iron stores and normalization of erythropoiesis and anemia. Safety and tolerability studies in relevant preclinical models confirmed that SLN124 is well tolerated and shows promise as an effective and safe treatment for unmet medical need in iron loading anemias, such as beta-thalassemia. SLN124 is currently in preclinical development. The first in human study is planned to commence in 2019 in patients with beta-thalassemia and in patients with myelodysplastic syndrome. Disclosures Muckenthaler: Novartis: Research Funding. Dames:Silence Therapeutics GmbH: Employment. Frauendorf:Silence Therapeutics GmbH: Employment. Schubert:Silence Therapeutics GmbH: Employment. Aleku:Silence Therapeutics GmbH: Employment. Zügel:Silence Therapeutics GmbH: Employment.

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Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?

Blood ◽

10.1182/blood-2019-129658 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 816-816 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Tomas Ganz ◽

Mary Therese Forsyth ◽

Elizabeta Nemeth ◽

Sherif M. Badawy

Keyword(s):

Gene Therapy ◽

Stem Cell ◽

Iron Overload ◽

Serum Ferritin ◽

Research Funding ◽

Iron Homeostasis ◽

Beta Thalassemia ◽

Ineffective Erythropoiesis ◽

Liver Iron ◽

Equity Ownership

BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in >3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p<0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

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Regulation of Iron Homeostasis By PTG-300 Improves Disease Parameters in Mouse Models for Beta-Thalassemia and Hereditary Hemochromatosis

Blood ◽

10.1182/blood-2019-129309 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3540-3540

Author(s):

Roopa Taranath ◽

Gregory Bourne ◽

Li Zhao ◽

Brian Frederick ◽

Chelsea King ◽

...

Keyword(s):

Iron Overload ◽

Iron Homeostasis ◽

Chronic Treatment ◽

Hereditary Hemochromatosis ◽

Iron Toxicity ◽

Beta Thalassemia ◽

Dietary Iron ◽

Beta Globin ◽

Labile Iron ◽

Disease Parameters

Hepcidin-Ferroportin axis dictates optimal absorption of dietary iron as well as systemic iron levels. This is crucial for providing sufficient iron needed for cellular functions while also preventing iron toxicity. PTG-300 (currently in a Phase 2 clinical study for beta-thalassemia) is a peptide mimetic of natural hepcidin that targets the major iron transporter, ferroportin, and causes its internalization & subsequent degradation. The pharmacodynamic effects of PTG-300 are the reductions in serum iron and transferrin-saturation (TSAT) due to reduced ferroportin expression on cells that store or recycle iron. We chose to demonstrate in two mouse models with iron dysregulation, that our hepcidin mimetics improve disease parameters by correcting dysregulated iron homeostasis. Beta-thalassemia is characterized by an imbalance in alpha-beta globin ratio in erythrocytes due to underlying beta-globin gene mutations. The excess alpha-globin, along with associated heme and iron, form "hemichrome" aggregates that integrate into the membranes of RBCs. The labile iron in these hemichromes generate ROS and are toxic to the cells, causing premature hemolysis of circulating RBCs and reduction in their lifespan. In a mouse model for beta-thalassemia, Hbbth3/+, we investigated the efficacy of a hepcidin mimetic in reducing hemichrome aggregation by limiting iron in the erythroid progenitors, and thereby reducing iron toxicity in RBCs. Subcutaneous injections of 1 mg/kg PN-8772 (analog of PTG-300 which has similar in vitro and in vivo potency) were administered every other day (Q2D) for a period of 4 weeks. At the end of the study, hemichrome aggregates were extracted from RBC membranes, and then analyzed on a TAU gel to quantify the cytoskeleton α-globin band intensities (Casu et al, Blood 2016). Hemichrome aggregates were reduced in groups treated with PN-8772 as compared to untreated controls, with concurrent improvements in hemoglobin and reductions in reticulocytes. Treatment with oral chelator Deferasirox (200 mg/kg; daily) did not show reduction in hemichrome aggregation, while it significantly lowered liver iron-overload. RBCs in Hbbth3/+ mice express aberrant morphologies due to the underlying hemichrome toxicity, similar to the phenotypes expressed in human beta-thalassemia. Chronic treatment with PN-8772 (as described above) also resulted in a significant reduction in aberrant morphologies that are indicative of hemolysis, viz. spherocytes & schistocytes. In a separate study, flow cytometry was used to monitor the survival of RBCs in Hbbth3/+ mice. At the end of 4 weeks of PTG-300 treatment (1 mg/kg, Q2D) the RBCs were marked by an in-life biotinylation method (Schmidt et al, Blood 2013) and subsequently followed over 49 days with continued treatment. There was a significant increase in survival of RBCs as compared to untreated controls. In summary, we demonstrate that by limiting iron in the developing erythroblasts and iron toxicity in RBCs, PTG-300 therapy has the potential to improve the quality of the RBCs and their oxygen carrying capacity, thereby ameliorating anemia. In beta-thalassemia, the clinical presentation includes secondary iron overload in various organs because of hyperabsorption of dietary iron, exacerbated by frequent blood transfusions that are required for management of anemia. Similarly, in hereditary hemochromatosis (HH) there is hyperabsorption of dietary iron leading to primary iron overload. We used a hemochromatosis mouse model (HFE) to demonstrate the effectiveness of PTG-300 therapy in limiting systemic iron toxicity by regulating TSAT and in preventing hyper-iron absorption. The model is characterized by homozygous deletion of HFE with severely low hepcidin levels and consequently very high TSAT (~100%). In this model, a single dose of PTG-300 at 2.5mg/kg reduced TSAT by ~60% at 10-hour post-dose, as compared to untreated controls. Sustained TSAT reduction by chronic treatment will therefore mitigate toxic effects of labile iron. Two weeks of chronic treatment with PTG-300 (2.5 mg/kg, Q2D) effectively prevented iron deposition in the liver. Overall our data suggests that PTG-300 has the potential to be an effective treatment in hemoglobinopathies, like beta-thalassemia, and Hereditary Hemochromatosis, by reducing systemic labile iron toxicity by limiting TSAT, preventing organ iron deposition & improving anemia (in case of thalassemia). Disclosures Taranath: Protagonist Therapeutics: Employment. Bourne:Protagonist Therapeutics: Employment. Zhao:Protagonist Therapeutics: Employment. Frederick:Protagonist Therapeutics: Employment. King:Protagonist Therapeutics: Employment. Liu:Protagonist Therapeutics: Employment.

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The Effect of the Flavonol Rutin on Serum and Liver Iron Content in a Genetic Mouse Model of Iron Overload

Bioscience Reports ◽

10.1042/bsr20210720 ◽

2021 ◽

Author(s):

Zachary Hawula ◽

Eriza Secondes ◽

Daniel Wallace ◽

Gautam Rishi ◽

V. Nathan Subramaniam

Keyword(s):

Mouse Model ◽

Iron Overload ◽

Transferrin Receptor ◽

Iron Homeostasis ◽

Binding Capacity ◽

Hereditary Hemochromatosis ◽

Transferrin Saturation ◽

Iron Loading ◽

Genetic Mouse Model ◽

Transferrin Receptor 2

The flavonol rutin has been shown to possess antioxidant and iron chelating properties in vitro and in vivo. These dual properties are beneficial as therapeutic options to reduce iron accumulation and the generation of reactive oxygen species resultant from excess free iron. The effect of rutin on iron metabolism has been limited to studies performed in wild type mice either injected or fed high iron diets. The effect of rutin on iron overload caused by genetic dysregulation of iron homeostasis has not yet been investigated. In this study we examined the effect of rutin treatment on tissue iron loading in a genetic mouse model of iron overload, which mirrors the iron loading associated with Type 3 hereditary hemochromatosis patients who have a defect in Transferrin Receptor 2. Male Transferrin Receptor 2 knockout mice were administered rutin via oral gavage for 21 continuous days. Following treatment, iron levels in serum, liver, duodenum, and spleen were assessed. In addition, hepatic ferritin protein levels were determined by western blotting, and expression of iron homeostasis genes by quantitative real-time PCR. Rutin treatment resulted in a significant reduction in hepatic ferritin protein expression and serum transferrin saturation. In addition, trends towards decreased iron levels in the liver and serum, and increased serum unsaturated iron binding capacity were observed. This is the first study to explore the utility of rutin as a potential iron chelator and therapeutic in an animal model of genetic iron overload.

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Hepcidin Therapeutics

Pharmaceuticals ◽

10.3390/ph11040127 ◽

2018 ◽

Vol 11 (4) ◽

pp. 127 ◽

Cited By ~ 21

Author(s):

Angeliki Katsarou ◽

Kostas Pantopoulos

Keyword(s):

Iron Homeostasis ◽

State Of The Art ◽

Hereditary Hemochromatosis ◽

Deficiency Anemia ◽

Iron Loading ◽

Ineffective Erythropoiesis ◽

Hepcidin Expression ◽

Inflammatory Stimuli ◽

Preclinical Animal Models ◽

Anemia Of Inflammation

Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art.

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Is Tmprss6 Required for Hepcidin Inhibition By Erythroferrone?

Blood ◽

10.1182/blood.v124.21.1347.1347 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1347-1347 ◽

Cited By ~ 2

Author(s):

Laura Silvestri ◽

Grazia Rita Gelsomino ◽

Antonella Nai ◽

Marco Rausa ◽

Alessia Pagani ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Overload ◽

Double Mutant ◽

Iron Homeostasis ◽

Conflicts Of Interest ◽

Beta Thalassemia ◽

The European Union ◽

Ineffective Erythropoiesis ◽

Deficient Diet ◽

Iron Deficient

Abstract Introduction Hepcidin, the main regulator of iron homeostasis, is inhibited when erythropoiesis is expanded. Several candidates, as GDF15 and TWSG1, have been proposed to mediate this effect but their role remains unproven. Recently, erythroferrone (ERFE), a member of the C1q/tumors necrosis factor-related protein family, has been identified as a new hepcidin inhibitor (Kautz et al., 2014). ERFE is an erythropoietin (EPO) target gene produced by bone marrow and spleen erythroblasts in conditions of stress erythropoiesis, as after bleeding or EPO treatment, and in ineffective erythropoiesis, as in beta thalassemia. Inhibiting hepatocyte hepcidin, ERFE coordinates erythroid differentiation with iron availability. In beta-thalassemia Hbbth3/+ mice, inactivation of Erfe partially reduces liver iron content, suggesting that increased Erfe production contributes to thalassemia iron overload (Kautz et al., 2014). Here we analyzed spleen Erfe expression in models of low (iron loaded Hjv-/- and Tfr2-/- mice) and high (iron deficient, Tmprss6-/- mice) hepcidin, in secondary iron overload (Hbbth3/+ mice), in Hbbth3/+ Tmprss6-/- and Tfr2-/- Tmprss6-/- double mutants and in mice with a diet-induced iron deficiency. Methods Mice were maintained in accordance with the European Union guidelines. The study was approved by the IACUC of San Raffaele Scientific Institute, Milan, Italy. Hjv-/-, Tfr2-/-, Tmprss6-/- and double mutant (Tfr2-/- Tmprss6-/- or Hbbth3/+ Tmprss6-/-) adult male mice were studied. A group of adult wild type mice was maintained an iron-deficient diet (ID, <3 mg/kg iron) for 3 weeks. Appropriate controls were studied. Gene expression levels were measured by quantitative real-time-PCR. Hematological and iron parameters and serum erythropoietin were studied using standard procedures. Results We confirm that Erfe is increased in the spleen of Hbbth3/+ mice, characterized by anemia, ineffective erythropoiesis, high EPO, low hepcidin and iron overload. Erfe is upregulated also in Tmprss6-/- iron deficient animals, consistent with their increased serum Epo. However, their high hepcidin levels suggest that Tmprss6 is indispensable for Erfe-mediated hepcidin inhibition. Consistent with this interpretation, in Hbbth3/+Tmprss6-/- double mutant mice, in which ineffective erythropoiesis and anemia are partially rescued (Nai et al., 2012), hepcidin levels are higher than in Hbbth3/+ and comparable to those of Tmprss6-/- mice, although Erfe remains high and serum Epo levels are similarly increased in all the three genotypes (Tmprss6-/-, Hbbth3/+, Hbbth3/+Tmprss6-/-). To further confirm the need of Tmprss6 for Erfe function, in diet-induced iron deficient animals, in which Tmprss6 is supposed to be active, Erfe expression is increased and hepcidin strongly downregulated. In the spleen of Hjv-/- and Tfr2-/- mice, the expression of the erythroid markers Tfr1 and Glycophorin A (Gypa) is decreased, suggesting that splenic erythropoiesis is reduced in iron overload. In agreement Erfe is downregulated in Tfr2-/- and mildly decreased in Hjv-/- mice. Genetic inactivation of Tmprss6 in Tfr2-/- mice enhances Erfe, Tfr1 and Gypa expression and serum Epo to levels comparable to Tmprss6-/- mice and increases hepcidin although at levels lower than those found in Tmprss6-/-. Conclusions Erfe upregulation in iron deficiency indicates that it is a general mediator of hepcidin inhibition. In Tmprss6-/- mice, notwithstanding Erfe upregulation, hepcidin levels are not suppressed, suggesting that Erfe acts upstream Tmprss6, although results in the double mutant Tfr2-/-Tmprss6-/- require further studies. In disease models of iron overload Erfe expression is downregulated, consistent with decreased splenic erythropoiesis. The mechanisms of hepcidin inhibition by Erfe still remain to be investigated. Disclosures No relevant conflicts of interest to declare.

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Pancreatic Iron and Fat Infiltration Are Diabetogenic Risk Factors In Patients With Iron Overload

Blood ◽

10.1182/blood.v122.21.2204.2204 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2204-2204

Author(s):

Regine Grosse ◽

Charlotte Pfeiffer ◽

Bjoern P Schoennagel ◽

Gritta E. Janka ◽

Peter Nielsen ◽

...

Keyword(s):

Iron Overload ◽

Hereditary Hemochromatosis ◽

Iron Accumulation ◽

Blood Parameter ◽

Iron Loading ◽

Fat Infiltration ◽

Body Iron ◽

Tissue Iron ◽

Fatty Replacement ◽

Signal Intensities

Abstract Introduction Chronically transfused patients and patients with hereditary hemochromatosis (HHC) are affected by complications due to excessive body iron accumulation. Therefore, early detection of tissue iron accumulation is mandatory for effective treatment. Besides serum ferritin (SF) as the traditional blood parameter indicating iron overload, the assessment of body iron stores by non-invasive magnetic resonance imaging (MRI) using R2- (T2) or R2*- (T2*) relaxometry is established in clinical routine. Especially the comparison of tissue iron burden and iron loading patterns is a current field of research in iron overload. Although the pancreas seems to play a major role in the endocrinological pathology of patients with siderosis, there are only few studies analyzing pancreatic iron content referring to the head, body and tail region of the pancreas. Method A total of 69 patients (age 9 - 78 years, 31 females) with ß-Thalassemia major (TM: n = 42; 16 splenectomized), Diamond-Blackfan anemia (DBA: n = 7; 1 splenectomized), hereditary hemochromatosis (HHC: n = 11) and iron overload from chronic blood transfusions (n = 9; sideroblastic anemia, aplastic anemia, myelodysplastic syndrome, leukemia post bone marrow transplantation) were scanned between 2007 and 2012 as part of their regular heart and liver iron monitoring by MRI, respectively. 10 healthy subjects (3 females, age 23 - 68 years), voluntarily served as controls. The study was approved by the local ethics committee and all subjects gave their written informed consent. For measuring pancreatic R2*, a stack of 4-8 of slices (thickness = 5.5 mm, no gap, inplane resolution 1.25x1.25 mm2) was selected, covering the whole pancreas. Pancreatic signal intensities were averaged from three different ROIs positioned in the tail, body and head of the pancreas with sufficient distance to the gland boundaries and excluding vascular structures. Only clearly identified and demarcated pancreas tissue was considered. Since fat infiltration is a common problem in the pancreas, especially with phase dependent GRE times, we applied a water/fat separation technique to the in-phase and out-of-phase signal intensities as described by Wehrli et al. Results For patients, the median hepatic R2* rate, pancreatic R2* rate and ferritin level were 261 s-1 (range 42 - 2326 s-1), 130 s-1 (range 23 – 1192 s-1) and 1445 µg/ml (range 62 – 21557 µg/ml), respectively. In 70% of all patients, fatty infiltration of the pancreas was above the range of controls (> 10%), with highest apparent fat content (aFC) in the pancreas of TM patients, especially, in TM patients with diabetes mellitus (median aFC = 29.1%). The highest aFC was found in the pancreatic tail (P = 0.2). Fat infiltration correlated with pancreatic R2* (rS = 0.67, P < 10-4). Conclusion We compared R2* rates in the different pancreatic regions involving patient groups of different iron loading diseases. Patients showed significantly higher pancreatic R2* rates and apparent fat contents than controls. The pancreas tail revealed the highest R2* rates and fat contents so we hypothesize that iron uploading initially occurs in the pancreas tail, especially in TM patients. Fatty replacement and degeneration of the pancreas seems to be an important risk factor on top of pancreatic iron burden for the development of diabetes and should be further investigated in longitudinal studies. Disclosures: No relevant conflicts of interest to declare.

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Ferroportin and Erythroid Cells: An Update

Advances in Hematology ◽

10.1155/2010/404173 ◽

2010 ◽

Vol 2010 ◽

pp. 1-12 ◽

Cited By ~ 10

Author(s):

Luciano Cianetti ◽

Marco Gabbianelli ◽

Nadia Maria Sposi

Keyword(s):

Iron Overload ◽

Iron Metabolism ◽

Therapeutic Intervention ◽

Erythroid Differentiation ◽

Beta Thalassemia ◽

Ineffective Erythropoiesis ◽

Tissue Iron ◽

Human Disorders ◽

The Relationship

In recent years there have been major advances in our knowledge of the regulation of iron metabolism that have had implications for understanding the pathophysiology of some human disorders like beta-thalassemia and other iron overload diseases. However, little is known about the relationship among ineffective erythropoiesis, the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. The principal aim of this paper is an update about the role of Ferroportin during human normal and pathological erythroid differentiation. Particular attention will be given to beta-thalassemia and other diseases with iron overload. Recent discoveries indicate that there is a potential for therapeutic intervention in beta-thalassemia by means of manipulating iron metabolism.

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2049-P: The Chd4 Helicase of the Nucleosome Remodeling and Deacetylase Complex Modulates Pdx1 Target Gene Expression In Vitro

Diabetes ◽

10.2337/db20-2049-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 2049-P

Author(s):

REBECCA K. DAVIDSON ◽

NOLAN CASEY ◽

JASON SPAETH

Keyword(s):

Gene Expression ◽

Target Gene ◽

Nucleosome Remodeling ◽

Target Gene Expression

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On the way toward regulatable expression systems in acetic acid bacteria: target gene expression and use cases

Applied Microbiology and Biotechnology ◽

10.1007/s00253-021-11269-z ◽

2021 ◽

Author(s):

Philipp Moritz Fricke ◽

Angelika Klemm ◽

Michael Bott ◽

Tino Polen

Keyword(s):

Gene Expression ◽

Acetic Acid ◽

Literature Search ◽

Target Gene ◽

Target Genes ◽

Recombinant Dna ◽

Acetic Acid Bacteria ◽

Homoserine Lactone ◽

Expression Systems ◽

Target Gene Expression

Abstract Acetic acid bacteria (AAB) are valuable biocatalysts for which there is growing interest in understanding their basics including physiology and biochemistry. This is accompanied by growing demands for metabolic engineering of AAB to take advantage of their properties and to improve their biomanufacturing efficiencies. Controlled expression of target genes is key to fundamental and applied microbiological research. In order to get an overview of expression systems and their applications in AAB, we carried out a comprehensive literature search using the Web of Science Core Collection database. The Acetobacteraceae family currently comprises 49 genera. We found overall 6097 publications related to one or more AAB genera since 1973, when the first successful recombinant DNA experiments in Escherichia coli have been published. The use of plasmids in AAB began in 1985 and till today was reported for only nine out of the 49 AAB genera currently described. We found at least five major expression plasmid lineages and a multitude of further expression plasmids, almost all enabling only constitutive target gene expression. Only recently, two regulatable expression systems became available for AAB, an N-acyl homoserine lactone (AHL)-inducible system for Komagataeibacter rhaeticus and an l-arabinose-inducible system for Gluconobacter oxydans. Thus, after 35 years of constitutive target gene expression in AAB, we now have the first regulatable expression systems for AAB in hand and further regulatable expression systems for AAB can be expected. Key points • Literature search revealed developments and usage of expression systems in AAB. • Only recently 2 regulatable plasmid systems became available for only 2 AAB genera. • Further regulatable expression systems for AAB are in sight.

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