Innovative therapies for ß-hemoglobinopathies
|
|
- Tracey McCarthy
- 5 years ago
- Views:
Transcription
1 Innovative therapies for ß-hemoglobinopathies Stefano Rivella, PhD Dept. of Pediatrics, Division of Hematology at Children s Hospital of Philadelphia (CHOP) Cell and Molecular Biology Graduate Group (CAMB) University of Pennsylvania
2 Disclosures Consultant Isis Pharmaceuticals Medgenics Pharmaceuticals Bayer Healthcare Pharmaceuticals Novartis Pharmaceuticals Collaboration Acceleron Pharmaceuticals Restricted Stock Merganser Biotech Research Grants R1DK95112-NIDDK R1HL12449-NHLBI R1DK9554-NIDDK European Community-FP AVLT-Italy Isis Pharmaceuticals Merganser Biotech Bayer Healthcare Pharmaceuticals Medgenics LLC Meira GTX
3 Sickle Cell Anemia and ß-Thalassemia Adult Hemoglobin Mutations that alter the structure Sickling Hb and red cells α α Heme β β (Glutamic acid to Valine at position 6) Mutations that reduce the synthesis α α α Heme Alpha/Heme Aggregates or hemichromes Consequences of Abnormal ß-Globin Chain Structure Vaso-Occlusion Pain Hemolysis Anemia Pulmonary hypertension Iron overload Consequences of Reduced ß-Globin Chain Production Ineffective Erythropoiesis Anemia Iron Overload Erythroid Marrow Expansion Splenomegaly Thrombosis
4 Epo Erythropoiesis and iron absorption EpoR ß-Thalassemia: Apoptosis & ROS GDF11 Increased survival & decreased cell differentiation Increased number of progenitor erythroid cells pjak2 pjak2 Erythroid factor(s) Erythroferrone,? pstat5 Protection from apoptosis Cell Replication Hepcidin Increased iron absorption
5 JAK2 inhibitors Anaemia/IE Hemichromes and ROS Erythroid cell replication Erythroid cell differentiation Activin receptor II trap ligands SEMA inhibitors Erythroid progenitor cells Apo-Transferrin Erythroferron (ERFE) Erythroid iron intake ERFE inhibitors or antagonists Hepcidin Iron absorption Minihepcidins and TMPRSS6 inhibitors
6 Potential use of erythroid modulators for the treatment of ß-thalassemia
7 Potential use of JAK2 inhibitors for the treatment of ß-thalassemia
8 Potential effect of JAK2 inhibitors on ineffective erythropoiesis ß-thalassemia Ineffective erythropoiesis High EPO levels pjak2: JAK2 inhibitor Erythroid progenitors Red cell Spleen
9 Increased erythroid cell proliferation in spleens of human β-thalassaemic specimens Normal Patient Ki67 Ki67 + glycophorin-c and spectrin Libani IV, et al. Blood. 28;112:
10 Potential use of Jak2 inhibitors for the treatment of ß-thalassemia In ß-thalassemia anemia is associated with increased EPO levels This leads to increased activation of the Jak2/Stat5 pathway One of the main consequences is increased proliferation and expansion of the pool of erythroid progenitors, leading to EMH and exacerbation of IE Therefore, administration of Jak2 inhibitors might be helpful to reverse splenomegaly and ameliorate IE
11 Reduction of splenomegaly following administration of a Jak2 inhibitor in mice affected by β-thalassaemia intermedia is dose-mediated 12 Spleen size (%placebo ctl) ** Placebo (7) Tg (1)(5) Tg (15)(6) Placebo TG 1 Spleen size of normal mice Hemoglobin Haemoglobin g/dl(g/dl) RBC(x1e6ul) 6 /µl) * * ** Placebo(7) Tg(1)(5) Tg(15)(6) TG 15 Pedro Ramos, Carla Casu
12 JAK2 inhibitor increases efficacy of transfusion in transfusion-dependent mice affected by β-thalassaemia major * ** ** ** ** Non-Txf Placebo + Txf Tg (15) + Txf (5) (4) (7) Hemoglobin (g/dl) RBC (#x1e6/ul (x 6 /µl) Spleen weight as a percent of non-tfx mice Non-Txf Placebo + Txf Tg (15) + Txf (5) (5) (7) ** Spleen size of normal mice Pedro Ramos, Carla Casu, Luca Melchiori, ASH 211, San Diego
13 Use of JAK2i in ß-thalassemia major TM: No Transfusion TM + Transfusion TM + Jak2i: Reduced Transfusion & iron overload Erythroid progenitors + Jak2i RBC Iron overload Iron overload
14 Potential use of Hepcidin agonist or inducers for the treatment of ß-thalassemia
15 Iron overload and anemia worsen over time in mice affected by ß-thalassemia intermedia Organ total iron content (ug) Hemoglobin (g/dl) Anemia worsens with time in th3/+ mice Iron overload increases with time in th3/+ mice /+ th3/+ 2. Months 12. Spleen Liver Hepcidin is expressed at low levels in iron overloaded th3/+ mice Hamp1 mrna level/iron liver /+ 2M 5M 12M th3/+ +/+ th3/+ 2M Gardenghi et al. Blood 27. +/+ th3/+ 5M +/+ th3/+ 12M
16 Hepcidin, the iron hormone regulator, acts on Ferroportin, the iron exporter Hepatocyte Enterocyte Fe 2+ Macrophage Fe 2+ P FPN Release Fe 2+ FPN P Hepcidin P FPN Absorption Recycling
17 Hepcidin, iron metabolism and erythropoiesis Absorptive enterocyte Fe DMT1 Hepcidin regulates dietary iron absorption and distribution by triggering the degradation of Fpn1. Fe HAMP Ferroportin Hepcidin is up-regulated by increased iron levels and inflammation. Liver Duodenal villi Hepcidin is down-regulated by erythropoiesis, anemia, and hypoxia.
18 Hepcidin, a major player in hemochromatosis, iron overload and anemia of chronic disease Hemochromatosis Secondary Hemochromatosis (i.e. ß-thalassemia, MDS) IRIDA Anemia of Inflammation Bacterial infections Cancer Hepcidin Too little: Increased iron absorption Increased macrophage iron release Iron overload Too much: Decreased iron absorption Macrophage iron retention Anemia
19 Hypothesis: Increased levels of Hepcidin in thalassemia intermedia are beneficial to prevent iron overload and ameliorate erythropoiesis Anemia Hepcidin Hepcidin Decreased iron absorption & hemichrome formation Increased iron absorption Amelioration of organ iron content & erythropoiesis
20 Minihepcidins (MH): background Minihepcidins are short peptide mimetics (9 retro-inverso AA) of hepcidin (25 AA) Derived from the N-terminal amino acid sequence and modified for in vivo activity MH are effective in reducing iron overload in animal models of HFE- and HAMP-related hemochromatosis HOOC H N O N H H N OH H N O N O N H M4 O N O H N O N H SH H N O O N H O H N N H H N O N O CONH 2 HN H N NH 2 H N HN NH 2
21 Very high stability of the minihepcidin M4 in vivo Blood levels and effect on transferrin saturation following a single dose of 7.5 mg/kg of M4 in the rat 3 25 Plasma Concentration (ng/ml) Drug in Plasma TSAT TSAT % Hours
22 Experimental Protocol th3/+ animals treated by SC injection with M4 (52.5 µg twice weekly) for six weeks. CBC assessment at four and six weeks. Serum and tissue iron assessment at six weeks
23 Minihepcidin administration significantly reduces liver, spleen and kidney iron concentration in thalassemic mice Total kidney iron (ug) KIDNEY IRON ** vehicle 52.5 ug/g wt Total liver iron (ug) LIVER IRON ** * vehicle 52.5 ug/g wt Total spleen iron (ug) SPLEEN IRON ** vehicle 52.5 ug/g wt Carla Casu
24 Minihepcidin administration induces a mild functional iron deficiency % MCV Vehicle 52.5 ug wt Transferrin Saturation * ** vehicle 52.5 ug wt g/l CHr Vehicle 52.5 ug wt Carla Casu
25 Minihepcidin administration significantly ameliorates hemoglobin levels Hb (% Change) Vehicle M4 g/dl HGB Weeks Vehicle 52.5 ug wt Carla Casu
26 Minihepcidin administration significantly ameliorates erythropoiesis and spleen weight in thalassemic mice 1 6 cells/ul * RBC 1 9 cells/l RETIC * Vehicle 52.5 ug wt Vehicle 52.5 ug wt Spleen size/body weight,2,15,1,5, SPLEEN WEIGHT vehicle 52.5 ug wt Carla Casu
27 Administration of minihepcidin is associated with reduced MCH in thalassemic mice WT + MH Hb RBCs Tf sat MCH Th3/+ + MH Hb RBCs Tf sat MCH Carla Casu
28 Administration of minihepcidin is associated with reduced erythroid cell damage β α standard Th3/+ Vehicle Th3/+ Minihepcidin WT % * * * Time D28 D33 D39 D46 wt vehicle 52.5 ug th3/+ Vehicle th3/+ minihepcidin wt Carla Casu
29 Combination of MH and iron chelation Using mice affected by ß-thalassemia intermedia, we evaluated if the simultaneous use of the iron chelator deferiprone (DFP) with MH can combine the positive effects of MH on erythropoiesis with the chelation benefit on organ iron content
30 Combination of MH with iron chelation improves organ iron content and erythropoiesis g/dl HEMOGLOBIN wt th3/+ Mock th3/+ Deferiprone * ** th3/+ Minihepcidin th3/+ Minihepcidin & Deferiprone Ug TOTAL LIVER IRON wt th3/+ Mock th3/+ Deferiprone th3/+ Minihepcidin th3/+ Minihepcidin & Deferiprone Carla Casu and Paraskevi Rea Oikonomidou
31 MH, but not Deferiprone, improves RBC morphology and reduces ROS in erythroid cells 7 6 REACTIVE OXYGEN SPECIES (ROS) IN ERYTHOID CELLS Th3/+ Mock Th3/+ Deferiprone % of cells th3/+ mock th3/+ Deferiprone th3/+ Minihepcidin th3/+ Minihepcidin & Deferiprone WT Th3/+ Minihepcidin Th3/+ Minihepcidin & Deferiprone Carla Casu and Paraskevi Rea Oikonomidou
32 Polycythemia vera and ß-thalassemia Polycythemia vera (PV) is caused by neoplastic proliferation and maturation of erythroid, megakaryocytic and granulocytic elements. In contrast to secondary polycythemias, PV is associated with a low serum level of the hormone erythropoietin (EPO). Disorder Mutation Main features Main treatment Hemoglobinopathies ß-thalassemia ß-globin gene IE, anemia Increased number of erythroid progenitor cells TX, iron chelation, BMT, Gene therapy (?) Myeloproliferative disorder Polycythemia vera Mostly Jak2 V617F Erythrocytosis Increased number of erythroid progenitor cells Phlebotomy, Jak2i
33 A mouse model to study Polycythemia vera
34 Administration of MH improves erythropoiesis in mice affected by Polycythemia vera
35 Administration of MH corrects Hb levels and HTC in mice affected by Polycythemia vera ** ** ** ** **
36 Tmprss6 as a potential target to treat NTDT TMPRSS6 Hepcidin Decreased iron absorption and Normal iron absorption recycling Deletion of Tmprss6 improves iron overload and erythropoiesis in a mouse model of NTDT
37 Antisense mechanism of action RNase H-mediated degradation
38 x1^6cell/ul Tmprss6-ASO treatment significantly improves anemia in thalassemic mice (th3/+) RBC 1^5cell/ul RETIC PBS Tmprss6-ASO D D42 D D42 D D42 D D42 D D42 D D42 D D42 D D42 g/dl Males Hb Females g/dl Males HCT Females D D42 D D42 D D42 D D42 D D42 D D42 D D42 D D42 Males Shuling Guo & Carla Casu Females Males Females
39 TMPRSS6 ASO treatment improves thalassemic red cell parameters and morphology % PBS Red Cell Distribution Width (RDW) Tmprss6-ASO PBS Tmprss6-ASO Normal values Males Females Carla Casu & Shuling Guo th3/+ PBS th3/+ Tmprss6-ASO WT
40 Use of Tmprss6 inhibitors improves iron overload in a mouse model of HFE-related hemochromatosis and erythropoiesis and organ iron content in NTDT
41 TMPRSS6 ASO treatment significantly reduces serum iron and transferrin saturation in non-human primates TMPRSS6-ASO candidates has been selected µg/dl Well tolerated in mice and in monkeys Demonstrated excellent activity and pharmacology in both transgenic mice and non-human primates Serum Iron Saline MOE GalNAc-MOE GalNAc-cEt % Transferrin Saturation Saline MOE GalNAc-MOE GalNAc-cEt Study Day Study Day Initiation of the Phase 1 clinical trial is expected in 216 Shuling Guo, Isis P.
42 Potential effects of Hepcidin agonists or activators on iron absorption and erythropoiesis in ß-thalassemia in presence or absence of iron chelation Hepcidin activity Normal Conditions ß-Thalassemia ß-Thalassemia +DFO ß-Thalassemia Hepcidin correct activity ß-Thalassemia Hepcidin correct activity +DFO Iron absorption Iron absorption Iron absorption Iron absorption Iron absorption α-chain/heme aggregates α-chain/heme aggregates Normal organ iron concentrations Iron overload Iron overload Iron overload Amelioration of erythropoiesis Iron overload Amelioration of erythropoiesis
43 Severe hemoglobinopathies: Gene therapy approach
44 Gene Therapy Schematic Approach Rivella S; Haematologica 215
45 Human ß-globin gene Locus Control Region ε G γ A γ ß δ ß 5 kb e + pa e + Promoter/5 UTR Ex1 IVS1 Ex2 IVS2 Ex3 3 UTR
46 Therapeutic levels of Hb in mice affected by Cooley s anemia Hb 13-15g/dL 5 LTR ß-globin LCR 3 LTR Transfusion independent TNS9 Hb 2-4g/dL WT th3/th3 th3/th3 + TNS9
47 Beta thalassemia patients: ß/ß, ß/ß+ and ß+/ß+ Based on the ß-globin protein synthesis, all mutations can be classified as: ß, where no ß-globin protein is produced, or ß+, where some, but not sufficient ß- globin chain is made Therefore, all patients can be classified as ß/ß, ß/ß+ or ß+/ß+, according to all possible combinations of these mutations
48 AnkT9W Increases significantly the HbA in ß/ specimens ß /ß no-vector α 2 /β 2 α 2 /γ 2 α 2 /δ 2 ß /ß + vector Laura Breda
49 Patient Genotype Still Matters Therapeutic Hb synthesis in ß+/+ and ß+/ cells is reached at lower VCN compared to ß/ cells Breda L, Casu C; PloS One 212
50 Transgenic Endogenous Transfusion Endo Transgenic M Walters, ASH 215, Children s Hospital of Oakland
51 New vector: ASL1 1. Elimination of the WPRE element. Modification of the vector backbone to preserve high titer viral production also in absence of WPRE. 2. Inclusion of the full second ß- globin intron. It contains enhancers and Oct1 binding site that help with LCR looping globin synthesis ß-globin gene Locus Control Region LTR RRE e + p HS2 HS3 HS4 Ankyrin-sinLTR SD 1 Kb SA ASL1 84 bp 138 bp 169 bp Laura Breda, Carla Casu, Alisa Dong
52 ASL1 performs significantly better in ßß patient cells compared to AnkT9W N=5 N=6 The goals are: Compare ALS1 to vectors already in clinical trial Generate GMP-quality vector and file and IND application 4.46 ±15.87 Alisa Dong and Laura Breda ±12.35 Clinical trial for ß- thalassemia and SCD
53 High level of curative hemoglobin in patient cells from sickle cell patients HbA=% CD34-derived + vector ctrl HbA=6% VCN = 1.3
54 Acknowledgments IRON & ERYTHOPOIESIS David Geffen School of Medicine-UCLA, LA Elizabeta Nemeth Tom Ganz Duke University School of Medicine, Durham Nancy C Andrews Karin Finberg Cindy N Roy New York Blood Center Yelena Ginzburg Xiu Li An Narla Mohandas St Louis University, St Louis Robert Fleming University of Ferrara, Italy Roberto Gambari CHOP, Philadelphia Jeremy Rupon Wulan Deng Gerd Blobel PHARMACEUTICALS Merganser Pharmaceuticals, Philadelphia Brian McDonald Isis Pharmaceuticals, San Diego Shuling Guo Sheri Booten Brett P. Monia Mount Sinai Medical Center, New York Saghi Ghaffari
55 Rivella Lab CHOP Laura Breda Carla Casu Emir O Hara Paraskevi Rea Oikonomidou Vania Lo Presti Ping La Ho Sun Lam Amaliris Gonzalez Osheiza Abdulmalik Kazuhiko Adachi Valentina Ghiaccio Alisa Dong Silvia Lourenco Ritama Gupta Roberta Chessa
Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of b-thalassemia intermedia and major
Published Ahead of Print on November 2, 2017, as doi:10.3324/haematol.2017.181511. Copyright 2017 Ferrata Storti Foundation. Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models
More informationIron age: novel targets for iron overload
IRON HOMEOSTASIS &CHRONIC DISEASE:DISORDERS OF IRON OVERLOAD Iron age: novel targets for iron overload Carla Casu 1 and Stefano Rivella 1,2 1 Department of Pediatrics, Division of Hematology-Oncology,
More informationIron: a global issue in hematology. Clara Camaschella, MD
Iron: a global issue in hematology Clara Camaschella, MD Università Vita Salute San Raffaele e IRCCS San Raffaele - Milano Firenze, 18-19 settembre 2015 Clara Camaschella I have nothing to disclose Iron
More informationHHS Public Access Author manuscript Ann N Y Acad Sci. Author manuscript; available in PMC 2017 March 01.
New strategies to target iron metabolism for the treatment of beta thalassemia Paraskevi Rea Oikonomidou 1, Carla Casu 1, and Stefano Rivella 1,2 1 Department of Pediatrics, Division of Hematology, Children
More informationTen years of Highlights from EHA: Red cells and Iron
Ten years of Highlights from EHA: Red cells and Iron Achille Iolascon Medical Genetics Dpt of Molecular Medicine and Medical Biotechnology University Federico II, Naples E-Mail: achille.iolascon@unina.it
More information2011 ASH Annual Meeting Targeting the Hepcidin Pathway with RNAi Therapeutics for the Treatment of Anemia. December 12, 2011
211 ASH Annual Meeting Targeting the Hepcidin Pathway with RNAi Therapeutics for the Treatment of Anemia December 12, 211 Hepcidin is Central Regulator of Iron Homeostasis Hepcidin is liver-expressed,
More informationReducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice
Related Commentary, page 1424 Research article Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice Shuling Guo, 1 Carla Casu, 2 Sara Gardenghi, 2 Sheri Booten, 1 Mariam Aghajan, 1 Raechel
More informationSickle Cell Anemia and ß-Thalassemia
Sickle Cell Anemia and ß-Thalassemia Adult Hemoglobin Heme Mutations that alter the structure (Glutamic acid to Valine at position 6) Mutations that reduce the synthesis Heme Sickling Hb and red cells
More informationAnemia s. Troy Lund MSMS PhD MD
Anemia s Troy Lund MSMS PhD MD lundx072@umn.edu Hemoglobinopathy/Anemia IOM take home points. 1. How do we identify the condtion? Smear, CBC Solubility Test (SCD) 2. How does it present clincally? 3. How
More informationThalassemias:general aspects and molecular pathology
Thalassemias:general aspects and molecular pathology Prof. Renzo Galanello Pediatric Clinic 2 University of Cagliari Ospedale Regionale Microcitemie-ASL8 HEMOGLOBINOPATHIES CLASSIFICATION Structurally
More informationHepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice
Research article Related Commentary, page 4187 Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice Sara Gardenghi, 1 Pedro Ramos, 1,2 Maria Franca Marongiu, 1
More informationIn adults, the predominant Hb (HbA) molecule has four chains: two α and two β chains. In thalassemias, the synthesis of either the α or the β chains
Thalassaemias Thalassemia Thalassemia is an inherited autosomal recessive blood disease. Associated with absence or reduction in a or b globin chains. Reduced synthesis of one of the globin chains can
More informationDiscovery. Hepcidin Today. Hepcidin: discovery June 2000: Man: Plasma ultrafiltrate Liver Expressed Antimicrobial Peptide
Hepcidin Today Rachel van Swelm 10 05 2018 ISLH www.radboud ironcenter.com; www.hepcidinanalysis.com Discovery Hepcidin: discovery June 2000: Man: Plasma ultrafiltrate Liver Expressed Antimicrobial Peptide
More informationRED BLOOD CELLS AND IRON: best presentations from 21 st EHA Meeting Copenhagen
RED BLOOD CELLS AND IRON: best presentations from 21 st EHA Meeting Copenhagen A.Iolascon Dpt of Molecular Medicine and Medical Biotechnology University Federico II, Naples RED BLOOD CELLS AND IRON: -
More informationPart I. Pathophysiology and management of Thalassemia Intermedia. M. Domenica Cappellini Fondazione IRCCS Policlinico University of Milan
Pathophysiology and management of Thalassemia Intermedia M. Domenica Cappellini Fondazione IRCCS Policlinico University of Milan 4th European Symposium on Rare Anaemias 3rd Bulgarian Symposium on Thalassaemia
More informationThe Harvard community has made this article openly available. Please share how this access benefits you. Your story matters.
Combination therapy with a Tmprss6 RNAi-therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β-thalassemia intermedia The Harvard community
More informationMacrophages support pathological. erythropoiesis in Polycythemia Vera and Beta-Thalassemia.
Macrophages support pathological erythropoiesis in Polycythemia Vera and Beta-Thalassemia The Harvard community has made this article openly available. Please share how this access benefits you. Your story
More informationDr Banu Kaya Consultant Haematologist Barts Health NHS Trust Royal London Hospital, London, UK SICKLE CELL AND THALASSAEMIA OVERVIEW
Dr Banu Kaya Consultant Haematologist Barts Health NHS Trust Royal London Hospital, London, UK SICKLE CELL AND THALASSAEMIA OVERVIEW Objectives Gain awareness of haemoglobinopathy inheritance, pathophysiology
More informationMicrocytic Hypochromic Anemia An Approach to Diagnosis
Microcytic Hypochromic Anemia An Approach to Diagnosis Decreased hemoglobin synthesis gives rise to microcytic hypochromic anemias. Hypochromic anemias are characterized by normal cellular proliferation
More informationANEMIA & HEMODIALYSIS
ANEMIA & HEMODIALYSIS The anemia of CKD is, in most patients, normocytic and normochromic, and is due primarily to reduced production of erythropoietin by the kidney and to shortened red cell survival.
More information4 Jumana Jihad Dr. Ahmad Mansour Dr. Ahmad Mansour
4 Jumana Jihad Dr. Ahmad Mansour Dr. Ahmad Mansour Anemia Decreased blood production Increased blood loss Hemolytic Hemorrhage Extravascular Intravascular Hemolytic (Further classification( Extrinsic Intrinsic
More informationManagement of anemia in CKD
Management of anemia in CKD Pierre Cochat, MD PhD Professor of Pediatrics Chair, Pediatrics & Pediatric Surgery Department Head, Center for Rare Renal Diseases Néphrogones Hospices Civils de Lyon & University
More informationCOEXISTENCE OF β-thalassemia AND POLYCYTHEMIA VERA: A CHICKEN-AND-EGG DEBATE?
COEXISTENCE OF β-thalassemia AND POLYCYTHEMIA VERA: A CHICKEN-AND-EGG DEBATE? M. DE SLOOVERE (1), L. HARLET (2), S. VAN STEENWEGHEN (3), E. MOREAU (1), D. DE SMET (1) (1) DEPARTMENT OF LABORATORY MEDICINE,
More informationDisclosures and Funding
S894 A Phase 1, Open-Label Study to Determine the Safety, Tolerability, and Pharmacokinetics of Escalating Doses of LJPC-41 (Synthetic Human Hepcidin) in Patients With Iron Overload Ashutosh Lal, 1 Antonio
More informationDONE BY : RaSHA RAKAN & Bushra Saleem
DONE BY : RaSHA RAKAN & Bushra Saleem Hemolytic anemias (2 of 2) Sickle Cell Anemia The most common familial hemolytic anemia in the world Sickle cell anemia is the prototypical (and most prevalent) hemoglobinopathy
More informationPedro A. Martinez, PhD June 10 th, 2016
(Murine ACE-536/Luspatercept) Inhibits Smad2/3 Signaling and Promotes Erythroid Differentiation By Restoring GATA1 Function in Murine β-thalassemia Pedro A. Martinez, PhD June 10 th, 2016 ACE-536 is a
More informationEffects of monotherapy and combined therapy on LPI
Effects of monotherapy and combined therapy on LPI 14 12 DFO 40 mg/kg/day 14 12 Deferiprone 75 mg/kg/day 14 12 Deferiprone 75 mg/kg/day DFO 40 mg/kg/day DFO 40 mg/kg/day LPI (μm) 10 8 6 LPI (μm) 10 8 6
More informationThalassemia Maria Luz Uy del Rosario, M.D.
Thalassemia Maria Luz Uy del Rosario, M.D. Philippine Society of Hematology and Blood Transfusion Philippine Society of Pediatric Oncology What is Thalassemia Hereditary Hemoglobin disorder Hemolytic anemia
More informationHemolytic anemias (2 of 2)
Hemolytic anemias (2 of 2) Sickle Cell Anemia The most common familial hemolytic anemia in the world Sickle cell anemia is the prototypical (and most prevalent) hemoglobinopathy Mutation in the β-globin
More informationNew therapeutic targets in transfusion-dependent and -independent thalassemia
EMERGING ISSUES IN CLINICAL CARE IN THALASSEMIA New therapeutic targets in transfusion-dependent and -independent thalassemia M. Domenica Cappellini 1,2 and Irene Motta 1 1 Fondazione IRCCS, Cà Granda
More informationAnemia 1: Fourth year Medical Students/ Feb/22/ Abdallah Awidi Abbadi.MD.FRCP.FRCPath Professor
Anemia 1: Fourth year Medical Students/ Feb/22/ 2018 Abdallah Awidi Abbadi.MD.FRCP.FRCPath Professor Email: abdalla.awidi@gmail.com Kidney EPO O2 Sensor Blood vessel Definition: Anemia is operationally
More informationHaemoglobin BY: MUHAMMAD RADWAN WISSAM MUHAMMAD
Haemoglobin BY: MUHAMMAD RADWAN WISSAM MUHAMMAD Introduction is the iron-containing oxygen transport metalloprotein in the red blood cells Hemoglobin in the blood carries oxygen from the respiratory organs
More informationHemoglobinopathies Diagnosis and management
Hemoglobinopathies Diagnosis and management Morgan L. McLemore, M.D. Hematology/Leukemia Department of Hematology and Oncology Winship Cancer Institute at Emory University mlmclem@emory.edu Disclosures
More informationLaboratory diagnosis of iron deficiency: The interpretation of automated counting parameters. Dr Wayne Thomas Derriford Hospital, Plymouth
Laboratory diagnosis of iron deficiency: The interpretation of automated counting parameters. Dr Wayne Thomas Derriford Hospital, Plymouth Why does it matter? Over 30% of the Worlds population are anaemic,
More informationChapter 2. ERYTHROPOIESIS and ANEMIA
Chapter 2 ERYTHROPOIESIS and ANEMIA Red Cell Production The Production of red cells, known as erythropoiesis, is a developmental system fundamentally under genetic control but modulated and regulated by
More informationExtra Notes 3. Warm. In the core (center) of the body, where the temperature is 37 C.
Extra Notes 3 *The numbers of the slides are according to the last year slides. Slide 33 Autoimmune hemolytic anemia : Abnormal circulating antibodies that target normal antigen on the RBC and cause lysis.
More informationPedro A. Martinez, PhD December 7 th, 2015
RAP-536 (Murine ACE-536/Luspatercept) Inhibits Smad2/3 Signaling and Promotes Erythroid Differentiation By Restoring GATA-1 Function in Murine β-thalassemia Pedro A. Martinez, PhD December 7 th, 2015 Outline
More informationFourth European Symposium on Rare Anaemias. Vita-Salute University - San Raffaele Scientific Institute, Milano
Fourth European Symposium on Rare Anaemias Clara Camaschella Vita-Salute University - San Raffaele Scientific Institute, Milano Sofia, Bulgaria, November 19-20, 2011 The iron cycle Hepcidin (Jordan et
More informationRed cell disorder. Dr. Ahmed Hasan
Red cell disorder Dr. Ahmed Hasan Things to be learned in this lecture Definition and clinical feature of anemia. Classification of anemia. Know some details of microcytic anemia Question of the lecture:
More informationLuspatercept Increases Hemoglobin, Decreases Transfusion Burden, and Improves Patient-Reported Outcomes in Adults with Beta-Thalassemia
Luspatercept Increases Hemoglobin, Decreases Transfusion Burden, and Improves Patient-Reported Outcomes in Adults with Beta-Thalassemia Antonio G. Piga, MD 1, Immacolata Tartaglione, MD 2, Rita Gamberini,
More informationThe Thalassemias in Clinical Practice. Ashutosh Lal, MD Director Comprehensive Thalassemia Program UCSF Benioff Children s Hospital Oakland
The Thalassemias in Clinical Practice Ashutosh Lal, MD Director Comprehensive Thalassemia Program UCSF Benioff Children s Hospital Oakland Outline Thalassemia: definitions and pathophysiology Epidemiology
More informationFaculty of Medicine Dr. Tariq Aladily
Iron deficiency anemia The most common anemia worldwide Only 10% of ingested iron is absorbed Most dietary iron occurs in meat products Absorbed in duodenum Hepcidin By inhibiting ferroportin, hepcidin
More informationNo Disclosures 03/20/2019. Learning Objectives. Renal Anemia: The Basics
Renal Anemia: The Basics Meredith Atkinson, M.D., M.H.S. Associate Professor of Pediatrics Johns Hopkins School of Medicine 16 March 2019 No Disclosures Learning Objectives At the end of this session the
More informationGeneral Characterisctics
Anemia General Characterisctics Definition: anemia is a decrease in red blood cells. Happens due to underproduction, increased destruction or loss of red cells. Diagnosis of anemia: Hgb < 135 (men) Hgb
More informationReview Article Crosstalk between Iron Metabolism and Erythropoiesis
Advances in Hematology Volume 2010, Article ID 605435, 12 pages doi:10.1155/2010/605435 Review Article Crosstalk between Iron Metabolism and Erythropoiesis Huihui Li and Yelena Z. Ginzburg Lindsley F.
More informationرناد زكريا Dr. ahmad Dr. ahmad. P a g e 1
5 رناد زكريا Dr. ahmad Dr. ahmad P a g e 1 Before we start. -This sheet was written according to section 2 s record and reviewed according to section 1 s record by Ruba Hussien with all thanks and I referred
More informationHEMOLYTIC ANEMIA DUE TO ABNORMAL HEMOGLOBIN SYNTHESIS
Hemolytic Anemia Due to Abnormal Hemoglobin Synthesis MODULE 19 HEMOLYTIC ANEMIA DUE TO ABNORMAL HEMOGLOBIN SYNTHESIS 19.1 INTRODUCTION There are two main mechanisms by which anaemia is produced (a) Thalassemia:
More informationRecent Advances in Erythroid Iron Homeostasis: Implications for Pathophysiology of Microcytic Anemias
Recent Advances in Erythroid Iron Homeostasis: Implications for Pathophysiology of Microcytic Anemias Prem Ponka Department of Physiology Lady Davis Institute, Jewish General Hospital McGill University,
More informationHemoglobin and anemia BCH 471
Hemoglobin and anemia BCH 471 OBJECTIVES Quantitative determination of hemoglobin in a blood sample. Hemoglobin structure Hemoglobin (Hb) is a porphyrin iron (II) protein in RBCs that transport oxygen
More informationGene Therapy for Sickle Cell Disease: A Safety/Efficacy Trial
Gene Therapy for Sickle Cell Disease: A Safety/Efficacy Trial Elizabeth Hexner A. Introduction Sickle cell disease (SCD) is an autosomal recessive disease of red blood cells (RBCs). A single amino acid
More informationMaking Hope A Reality December 10, Nasdaq : BLUE
Making Hope A Reality December 10, 2014 Nasdaq : BLUE Forward Looking Statement These slides and the accompanying oral presentation contain forward-looking statements and information. The use of words
More informationTHALASSEMIA AND COMPREHENSIVE CARE
1 THALASSEMIA AND COMPREHENSIVE CARE Melanie Kirby MBBS, FRCP (C), Hospital for Sick Children, Toronto Associate Professor of Paediatrics, University of Toronto. Objectives 2 By the end of this presentation,
More informationPitfalls in the premarital testing for thalassaemia
Pitfalls in the premarital testing for thalassaemia Dr. Riad Amer MB ChB, MSc, FRCP, FRCPath, JBH Assistant Professor of Medicine Al Najah University Consultant Haematologist Case 1 Husband and Wife are
More informationAn overview of Thalassaemias and Complications
An overview of Thalassaemias and Complications Haemoglobin Haemoglobin is the most abundant protein in blood, and exists as three main types in normal adults: HbA ( ) - 97% HbA 2 ( ) - 2.5% HbF ( ) - 0.5%
More informationIron Overload Disorders and Iron Chelation Therapy
Iron Overload Disorders and Iron Chelation Therapy T. Lodewyck BHS seminar November 2014 Outline Iron overload (IO) disorders Mechanisms and pathophysiology of IO Clinical impact of IO Assessment of IO
More informationIntroduction 5/2/2013 IRON RELATED GENES AND OXIDATIVE STRESS IN NON- ALCOHOLIC STEATOHEPATITIS. Iron Physiology. Iron Physiology
// IRON RELATED GENES AND OXIDATIVE STRESS IN NON- ALCOHOLIC STEATOHEPATITIS DIANA MOYA, MD PEDIATRIC GASTROENTEROLOGY FELLOW DIGESTIVE DISEASES & NUTRITION CENTER MAY,. Iron Physiology. /NAFLD. Iron Metabolism
More informationPolycthemia Vera (Rubra)
Polycthemia Vera (Rubra) Polycthemia Vera (Rubra) Increased red cells Clonal Myeloid lineages also increased 2-13 cases per million Mean age: 60 years Sites of Involvement Bone marrow Peripheral blood
More informationRBCs Disorders 2. Dr. Nabila Hamdi MD, PhD
RBCs Disorders 2 Dr. Nabila Hamdi MD, PhD ILOs Discuss the classification of anemia into hypochromic-microcytic, normochromicnormocytic and macrocytic. Categorize laboratory test procedures used in the
More informationNon-transfusion-dependent thalassemias
Non-transfusion-dependent thalassemias REVIEW ARTICLES Khaled M. Musallam, 1 Stefano Rivella, 2 Elliott Vichinsky, 3 Eliezer A. Rachmilewitz 4 1 Department of Medicine and Medical Specialties, IRCCS Ca
More informationPreface: Thalassemia Bernard G. Forget
Thalassemia Preface: Thalassemia Bernard G. Forget xiii Thalassemia: An Overview of 50 Years of Clinical Research 1005 Vijay G. Sankaran and David G. Nathan The thalassemias are attributable to the defective
More informationThalassemias. Emanuela Veras, M.D. 01/08/2006
Thalassemias Emanuela Veras, M.D. 01/08/2006 Structure and Function of normal Hemoglobin molecules: 2/3 1/3 β: increases from 6 th week of fetal life to 12 months of age At birth: HbF: 75-90% HbA: 10-25%
More informationNuovi Approcci alla Ferrochelazione
Il Deficit di PKD 1 patient day Nuovi Approcci alla rrochelazione M. Domenica Cappellini Fondazione Ca Granda Policlinico Università di Milano Milano May 16 2015 Genetic and acquired iron overload Genetic
More informationBeta-thalassemia:clinical findings,molecular defects and genotype/phenotype relationships
Beta-thalassemia:clinical findings,molecular defects and genotype/phenotype relationships Maria Domenica Cappellini Fondazione Ca Granda Policlinico IRCCS University of Milan Disclosure Member of Advisory
More informationSICKLE CELL DISEASE. Dr. MUBARAK ABDELRAHMAN MD PEDIATRICS AND CHILD HEALTH. Assistant Professor FACULTY OF MEDICINE -JAZAN
SICKLE CELL DISEASE Dr. MUBARAK ABDELRAHMAN MD PEDIATRICS AND CHILD HEALTH Assistant Professor FACULTY OF MEDICINE -JAZAN Objective: The student should be able: To identify the presentation, diagnosis,
More informationSickle Cell Disease and impact on the society
Sickle Cell Disease and impact on the society Professor Z.A.Jeremiah Ph.D, FRCPath (London) Professor of Haematology and Blood Transfusion Science Niger Delta University, Wilberforce Island Outline What
More informationEvidence for the Safety of Fortifying Flour with Iron in the Presence of Thalassemia and Other Blood Disorders
Evidence for the Safety of Fortifying Flour with Iron in the Presence of Thalassemia and Other Blood Disorders Althea M Grant, PhD Chief, Epidemiology and Surveillance Branch, Division of Blood Disorders,
More informationAround million aged erythrocytes/hour are broken down.
Anemia Degradation ofheme Around 100 200 million aged erythrocytes/hour are broken down. The degradation process starts in reticuloendothelial cells in the spleen, liver, and bone marrow. [1] The tetrapyrrole
More informationMetabolismo del ferro in condizioni normali e patologiche
Metabolismo del ferro in condizioni normali e patologiche Clara Camaschella Università Vita-Salute e IRCCS San Raffaele, Milano Simposio SIES 41 Congresso Nazionale SIE - Bologna 14-17 ottobre 2007 Metabolismo
More informationBiochimica et Biophysica Acta
Biochimica et Biophysica Acta 1823 (2012) 1434 1443 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr Review Hepcidin and
More informationAnemia 1: Fourth year Medical Students/ October/21/ 2015/ Abdallah Abbadi.MD.FRCP Professor
Anemia 1: Fourth year Medical Students/ October/21/ 2015/ Abdallah Abbadi.MD.FRCP Professor Email: abdalla.awidi@gmail.com Main Hematological diseases A- Benign Hematology 1- Anemias 2- Bleeding disorders
More informationThe Nucleated Red Blood Cell (NRBC) Count in Thalassaemia Syndromes Paolo Danise and Giovanni Amendola
7. The Nucleated Red The Nucleated Red Blood Cell (NRBC) Count in Thalassaemia Syndromes Paolo Danise and Giovanni Amendola Introduction The purpose of this study was to evaluate the performance of the
More informationHAEMOGLOBINOPATHIES. Editing file. References: 436 girls & boys slides 435 teamwork slides. Color code: Important. Extra.
HAEMOGLOBINOPATHIES Objectives: normal structure and function of haemoglobin. how the globin components of haemoglobin change during development, and postnatally. the mechanisms by which the thalassaemias
More informationInternational Journal of Drug Research and Technology
Int. J. Drug Res. Tech. 2012, Vol. 2 (7), 472-478 ISSN 2277-1506 International Journal of Drug Research and Technology Available online at http://www.ijdrt.com Original Research Paper SCREENING, ANALYSIS
More informationAnatomy and Physiology
Anatomy and Physiology For The First Class 2 nd Semester Erythrocytes = Red Blood Cells (RBC) Erythrocytes = Red Blood Cells Red blood cells are biconcave discs, they have no nucleus and cytoplasmic organelles.
More informationBMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice
SUPPLEMENTARY MATERIALS BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice Elena Corradini, Paul J. Schmidt, Delphine Meynard, Cinzia Garuti, Giuliana
More informationHemoglobinopathies NORMAL HEMOGLOBINS
Hemoglobinopathies Millicent Sutton MD October 28, 2005 NORMAL HEMOGLOBINS Consist of 2 alpha chains and 2 non alpha chains Hb A = α2β2 Hb F= α 2γ2 Hb A2 = α2δ2 1 Hemoglobin Variants Altered the conformational
More informationMICO Maggio 2016 Laboratory Diagnosis of Thalassemia
MICO 11-15 Maggio 2016 Laboratory Diagnosis of Thalassemia Maria Domenica Cappellini Fondazione Ca Granda Policlinico IRCCS University of Milan Disclosure Member of Advisory Board: - Novartis - Genzyme/Sanofi
More informationIron and hepcidin: a story of recycling and balance
HAM-WASSERMAN MANUSCRIPT Iron and hepcidin: a story of recycling and balance Clara Camaschella 1 1 Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy To avoid iron deficiency and
More informationManaging peri-operative anaemiathe Papworth way. Dr Andrew A Klein Royal Papworth Hospital Cambridge UK
Managing peri-operative anaemiathe Papworth way Dr Andrew A Klein Royal Papworth Hospital Cambridge UK Conflicts of interest: Unrestricted educational grants/honoraria from CSL Behring, Brightwake Ltd,
More informationMyeloproliferative Disorders in the Elderly: Clinical Presentation and Role of Bone Marrow Examination
Myeloproliferative Disorders in the Elderly: Clinical Presentation and Role of Bone Marrow Examination Arati V. Rao, M.D. Division of Medical Oncology and Geriatrics Duke University Medical Center Durham
More informationLatest updates in Myeloproliferative Neoplasms. Elizabeth Hexner, MD, MSTR
Latest updates in Myeloproliferative Neoplasms Elizabeth Hexner, MD, MSTR Disclosures Nothing to disclose Agenda/Goals Treatment goals in PV Indications for cytoreduction in patients polycythemia vera
More informationAnemia. A case-based approach. David B. Sykes, MD, PhD Hematology, MGH Cancer Center June 8, 2017
Anemia A case-based approach David B. Sykes, MD, PhD Hematology, MGH Cancer Center June 8, 2017 Recognizing trends Learning Objectives MCV, RDW, Ferritin, LDH, Reticulocytes Managing complex patients 1.
More informationDiagnostic difficulties in prevention and control program for thalassemia in Thailand: atypical thalassemia carriers
Diagnostic difficulties in prevention and control program for thalassemia in Thailand: atypical thalassemia carriers Pranee Winichagoon Fucharoen Thalassemia Research Center Institute of Molecular Biosciences
More informationHow to Write a Life Care Plan for a Child with Hemoglobinopathy
How to Write a Life Care Plan for a Child with Hemoglobinopathy Tamar Fleischer, BSN, MSN, CNLCP & Mona Yudkoff, RN, MPH, CRRN, CNLCP BalaCare Solutions March 2018 St. Peterburg, Florida What is Hemoglobinopathy?
More informationINTERELATIONSHIP BETWEEN IDA AND VITAMIN D DEFICIENCY IS NOW ESTABLISHED
INTERELATIONSHIP BETWEEN IDA AND VITAMIN D DEFICIENCY IS NOW ESTABLISHED Rationale for Combining Iron & Vit-D Vit D deficiency and Iron deficiency Anaemia the two most menacing disorders - are inter-related
More informationBiol Chapter 17 Cardiovascular & Blood
Collin County Community College Biol. 2402 Chapter 17 Cardiovascular & Blood 1 CVS and Public Health 2 1 CVS and Public Health 3 Cardio Vascular System 4 2 Cardio Vascular System: BLOOD Functions of Blood
More information27/01/2019. Anaemia, Transfusion and TACO Lise Estcourt. Anaemia. What is anaemia?
Anaemia, Transfusion and TACO Lise Estcourt 1 Anaemia 2 What is anaemia? 3 1 Anaemia according to WHO 4 Anaemia in palliative care Common (77% men 68% women) Symptoms often non-specific Some causes potentially
More informationThe Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders
UPDATES ON DISORDERS OF IRON UTILIZATION AND DISTRIBUTION The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders Tomas Ganz 1 and Elizabeta Nemeth 1 1 Department
More informationIron and hepcidin: a story of recycling and balance
Iron and hepcidin: a story of recycling and balance Domenico Girelli (Medicina Generale a indirizzo Immuno-Ematologico e Emocoagulativo, Azienda Ospedaliera Universitaria Integrata VERONA) Special Conference
More informationCardiac Deformities in Thalassemia Major could be an Immune System Disorder. Moh Middib Abstract Introduction Back ground
Cardiac Deformities in Thalassemia Major could be an Immune System Disorder. Moh Middib College of Medicine/Dept Head of Microbiology, University of Al Muthanna Abstract β-thalassemia: HiJAKing Ineffective
More informationWhen do you have to perform the molecular biology in the hemoglobinopathies diagnosis
When do you have to perform the molecular biology in the hemoglobinopathies diagnosis Maria Domenica Cappellini MD, FRCP;FACP Fondazione Ca Granda Policlinico IRCCS University of Milan Disclosure Member
More informationNext Generation Sequencing as a tool for breakpoint analysis in rearrangements of the globin-gene clusters
Next Generation Sequencing as a tool for breakpoint analysis in rearrangements of the globin-gene clusters XXXth International Symposium on Technical Innovations in Laboratory Hematology Honolulu, Hawaii
More informationNovita dell EHA: Globuli Rossi
Novita dell EHA: Globuli Rossi Lucia De Franceschi Dept of Medicine, University of Verona-AOUI Verona; Verona Firenze, 22-23 Settembre 2017 10 th EHA Highlights from EHA EHA 2017: Red cells & Iron metabolism
More informationIntroduction and II. Blood Cells A. Introduction
Chapter 14: Blood 1. Blood is three to four times more viscous than water. Introduction and II. Blood Cells A. Introduction 2. Most blood cells form in red bone marrow. 3. Types of blood cells are red
More informationYear 2003 Paper two: Questions supplied by Tricia
QUESTION 93 A 24-year-old woman, who has recently arrived in Australia from Vietnam, presents for evaluation of abnormal menstrual bleeding. There are no abnormalities on examination. Results of investigations
More information3) The sheer number of and inconsistency between different animal models used make the paper difficult to follow and may impact data interpretation:
Reviewers' comments: Reviewer #1 (Remarks to the Author): In this manuscript, Pasricha et al. show that iron deficiency (ID) and stimulated erythropoiesis suppress hepcidin via distinct processes. They
More informationGenetics of Thalassemia
Genetics of Thalassemia Submitted by : Raya Samir Al- Hayaly Sura Zuhair Salih Saad Ghassan Al- Dulaimy Saad Farouq Kassir Sama Naal Salouha Zahraa Jasim Al- Aarajy Supervised by : Dr. Kawkab Adris Mahmod
More informationWhat is Thalassaemia?
What is Thalassaemia? Introduction The thalassaemias are a diverse group of genetic blood diseases characterized by absent or decreased production of normal hemoglobin, resulting in a microcytic anemia
More information5/1/2017 DISCUSSION POINTS. Clinical Utility of Immature Cell Indices Beyond the Routine CBC John E. Donnelly BSN, RN
DISCUSSION POINTS Importance of hematological immature cell indices Clinical Utility of Immature Cell Indices Beyond the Routine CBC John E. Donnelly BSN, RN Investigate the evidence for clinical utility:
More information