64th ASH Annual Meeting and Exposition: 113. Hemoglobinopathies, Excluding Thalassemia: Basic and Translational: Targeting the Red Blood Cell: Novel Therapeutic Approaches in Sickle Cell Disease

Symposia: Hemoglobinopathies, Excluding Thalassemia: Basic and Translational Oral and Poster Abstracts
Oral

Research, adult, Sickle Cell Disease, Fundamental Science, Translational Research, Clinical Research, bioinformatics, Combination therapy, Hemoglobinopathies, hematopoiesis, drug development, Diseases, cell expansion, Therapies, metabolism, Biological Processes, Technology and Procedures, molecular biology, Study Population, Human, pathogenesis, omics technologies

343-345 (Ernest N. Morial Convention Center)

Moderators:

Julia Z Xu, MD, MScGH, University of Pittsburgh and Santosh L Saraf, MD, University of Illinois at Chicago

Disclosures:

Xu: GSK: Membership on an entity's Board of Directors or advisory committees. Saraf: Agios: Consultancy; Forma Therapeutics: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; ORIC: Consultancy.

9:30 AM

391

AG-946 Normalizes Glycolysis and Improves Red Cell Indices in a Humanized Sickle Cell Mouse Model

Rohitash Jamwal, PhD¹^*, Lily C. Wain, BA²^*, Christopher Copeland, PhD¹^*, Penelope A. Kosinski, MS³^*, Megan Wind-Rotolo, PhD³^*, Ilya Gertsman, PhD⁴^*, William Eaton, MD⁵, David M Bodine, PhD², Lenny Dang, PhD¹^* and Swee Lay Thein, MBBS, DSc, FRCP, FRCPath, MRCP, MRCPath⁶

¹Agios Pharmaceuticals Inc., Cambridge, MA
²NHGRI, National Institutes of Health, Bethesda, MD
³Agios Pharmaceuticals, Inc., Cambridge, MA
⁴Clarus Analytical, San Diego, CA
⁵National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
⁶Sickle Cell Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

9:45 AM

392

Inhibition of MRP1 Induces Fetal Hemoglobin through NRF2 Activation to Protect Human Erythroid Cells from Sickling

Yannis Hara, PhD^1,2, Emily Kawabata³^*, Viktor T. Lemgart⁴^*, Paola G. Bronson⁵^*, Alexandra Hicks^1,6^*, Sriram Krishnamoorthy⁶, Nicholas Watkins⁷^*, Robert Peters⁶^*, David J. Roberts⁸^*, Emanuele Di Angelantonio³^*, John Danesh³^*, William Astle³^*, Dirk S. Paul³^*, Samuel Lessard^6,9^* and Adam S. Butterworth³^*

¹Immunology and Inflammation, Sanofi, Cambridge, MA
²Rare Blood Disorders, Sanofi, Cambridge, MA
³University of Cambridge, Cambridge, United Kingdom
⁴Tidal Therapeutics Protein Science, Sanofi, Cambridge, MA
⁵Human Target Validation Core, RED Translational Biology, Biogen, Cambridge, MA
⁶Rare Blood Disorders, Sanofi, Waltham, MA
⁷National Health Service Blood and Transplant, Cambridge, United Kingdom
⁸National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom
⁹Precision Medicine and Computational Biology, Sanofi, Cambridge

10:00 AM

393

Pklr Variants Associated with Acute Pain in Sickle Cell Disease Influence ATP Concentrations in Red Blood Cells

Xunde Wang, PhD¹^*, Yi-Ping Fu, PhD²^*, Quan Li, PhD³^*, Emily B Dunkelberger, PhD³^*, Mickias Tegegn, BS⁴^*, Penelope A. Kosinski, MS⁵^*, Heidi Mangus, BS⁵^*, John Hamre, PhD⁶^*, Sam M. Mbulaiteye, MBBChir, MPhil⁷^*, Ludmila Prokunina-Olsson, PhD⁸^*, Stephen J. Chanock, MD⁹^*, Nancy Asomaning, MS¹^*, Neal Jeffries, PhD¹⁰^*, William Eaton, MD¹¹ and Swee Lay Thein, MBBS, DSc, FRCP, FRCPath, MRCP, MRCPath¹

¹Sickle Cell Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
²Office of Biostatistics Research, National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda
³National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
⁴Sickle Cell Branch, National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, MD
⁵Agios Pharmaceuticals, Inc., Cambridge, MA
⁶1Sickle Cell Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
⁷Division of Cancer Epidemiology and Genetics, National Cancer Institute, Silver Spring, MD
⁸Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
⁹Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
¹⁰National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
¹¹National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD

10:15 AM

394

Preclinical Development and Screening of a Quinone-Nitroalkene Molecule for Sickle Cell Anemia

Fabliha A Chowdhury, MSc¹^*, Megan P Miller, BSc.²^*, Katherine C Wood, PhD³, Malini Sharma, BA⁴^*, Shuai Yuan, PhD²^*, Stefanie N Taiclet, BSc.²^*, Derek J Sinchar, BSc.²^*, Elizabeth R Rochon, PhD⁵^*, Francisco J Schopfer, PhD¹^*, Bruce A Freeman, PhD¹^* and Adam C Straub, PhD¹^*

¹Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
²Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
³Heart, Lung, Blood and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
⁴University of Pittsburgh School of Medicine, Pittsburgh, PA
⁵Department of Medicine, University of Maryland School of Medicine, Baltimore, MD

10:30 AM

395

Proteomic and Lipidomic Investigation of an Ex-Vivo Human Model of Sickle Cell Disease Erythropoiesis and Patient Erythrocytes Reveals the Abnormal Localization and Dysfunction of the Proteasome, Disrupted Antioxidant Defenses and Altered Lipid Profiles

Julien Delobel, PhD¹^*, Romain Hamelin, MSc²^*, Viviane Praz, PhD¹^*, Hector Gallart-Ayala, PhD³^*, Florence Armand, PhD²^*, Manfredo Quadroni, PhD⁴^*, Katia Balmas-Bourloud¹^*, Diego Chiappe, PhD²^*, Carlo Brugnara, MD⁵, Julijana Ivanisevic, PhD³^* and Raffaele Renella, MD, PhD¹

¹Pediatric Hematology-Oncology Research Laboratory, Lausanne University Hospital, Lausanne, Switzerland
²Proteomics Core Facility, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
³Metabolomics Platform, University of Lausanne, Lausanne, Switzerland
⁴Proteomic Analysis Facility, University of Lausanne, Lausanne, Switzerland
⁵Department of Laboratory Medicine, Harvard Medical School, Boston Children's Hospital, Boston, MA

10:45 AM

396

Prolonged Combinatorial Pharmacological Therapy Targeting the Epigenome Increases Fetal Hemoglobin to Clinically Relevant Levels in Normal, Nonanemic Baboons

Vinzon Ibanez, B.S.¹^*, Kestis Vaitkus¹^*, Robert E. Molokie, MD¹, Jagadeesh Ramasamy, PhD²^*, Yogenthiran Saunthararajah, MD³ and Donald Lavelle, PhD¹

¹Department of Medicine, University of Illinois at Chicago, Jesse Brown VA Medical Center, Chicago, IL
²University of Illinois at Chicago, Chicago, IL
³Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH

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^*signifies non-member of ASH

113.O2.6 113. Hemoglobinopathies, Excluding Thalassemia: Basic and Translational: Targeting the Red Blood Cell: Novel Therapeutic Approaches in Sickle Cell Disease