BOOK
Emerging Therapies Targeting the Pathophysiology of Sickle Cell Disease, An Issue of Hematology/Oncology Clinics, E-Book
(2014)
Additional Information
Book Details
Abstract
This issue of Hematology/Oncology Clinics, guest edited by Dr. Elliott Vichinsky, is devoted to Sickle Cell Disease, and focuses on pathophysiology of hemoglobinopathies, therapeutic targets, and new approaches to correcting ineffective erythropoiesis and iron dysregulation. Articles in this issue include Polymerization and red cell membrane changes; Overview on reperfusion injury in the pathophysiology of SCD; Regulation of ineffective erythropoiesis in iron metabolism; Altering oxygen affinity; Cellular adhesion and the endothelium; Arginine therapy; Role of the hemostatic system on SCD pathophysiology and potential therapeutics; Adenosine signaling and novel therapies; New approaches to correcting ineffective erythropoiesis and iron dysregulation; New approaches to correcting ineffective erythropoiesis and iron dysregulation; Fetal hemoglobin induction; Gene therapy for hemoglobinopathies; and Oxidative injury and the role of antioxidant therapy.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | Cover | ||
| Emerging Therapies Targeting\rthe Pathophysiology of Sickle Cell Disease | i | ||
| copyright\r | ii | ||
| Contributors | iii | ||
| Consulting Editors | iii | ||
| Editor | iii | ||
| Authors | iii | ||
| Contents | vii | ||
| Hematology/Oncology\rClinics Of North America\r | xi | ||
| Preface\r | xiii | ||
| References | xvii | ||
| Dedication | xix | ||
| Hemoglobin S Polymerization and Red Cell Membrane Changes | 155 | ||
| Key points | 155 | ||
| Introduction | 155 | ||
| Polymerization | 156 | ||
| Effects of HbS on membranes | 158 | ||
| Oxidative stress | 159 | ||
| Microparticles | 161 | ||
| Membrane lipid | 161 | ||
| Lipid turnover | 162 | ||
| Lipid asymmetry | 163 | ||
| PS exposure in RBCs | 163 | ||
| PS exposure in SCD | 164 | ||
| Consequences of PS exposure | 166 | ||
| Summary | 167 | ||
| References | 169 | ||
| Ischemia-reperfusion Injury in Sickle Cell Anemia | 181 | ||
| Key points | 181 | ||
| Introduction | 181 | ||
| I/R injury | 182 | ||
| Initiation of I/R | 182 | ||
| The Further Evolution of I/R | 182 | ||
| Differential Organ Susceptibilities | 183 | ||
| Systemic Implications | 183 | ||
| Endothelial Dysfunction | 184 | ||
| ROI | 184 | ||
| Ischemic Preconditioning | 184 | ||
| I/R in human biomedicine | 185 | ||
| Sickle mice and experimental I/R | 185 | ||
| I/R Induction in Sickle Mice | 185 | ||
| Clinical sickle disease and I/R | 186 | ||
| Cause of Sickle I/R | 188 | ||
| Sickle Complexity and the I/R Paradigm | 188 | ||
| Hemolytic anemia | 190 | ||
| Genetic polymorphisms | 190 | ||
| Epigenetic effects | 190 | ||
| Environmental stressors | 190 | ||
| Sickle preconditioning? | 190 | ||
| Clinical examples of sickle I/R | 190 | ||
| Clinical Endothelial Dysfunction | 190 | ||
| ACS | 190 | ||
| Arterial Vasculopathy | 191 | ||
| Inflammatory Pain | 191 | ||
| Implications of I/R for therapeutics | 192 | ||
| References | 194 | ||
| Gene Therapy for Hemoglobinopathies | 199 | ||
| Key points | 199 | ||
| Introduction | 200 | ||
| Rationale | 201 | ||
| Prerequisites for successful gene therapy in β-hemoglobinopathies | 202 | ||
| Understanding the developmental switch of β-globin and its regulation in postnatal life | 202 | ||
| Introduction to gene therapy | 203 | ||
| Initial vector development for β-thalassemia | 207 | ||
| Initial development of LV-based vectors for β-thalassemia | 208 | ||
| Human gene therapy for thalassemia | 208 | ||
| Gene therapy for SCD | 209 | ||
| Recent advances | 210 | ||
| Role of Mobilizing Agents to Achieve Adequate Stem Cell Dose | 210 | ||
| In Vivo Selection: Giving Survival Advantage to Transduced Stem Cells | 210 | ||
| Newer Vectors | 210 | ||
| Transcriptional Manipulation to Increase HbF | 210 | ||
| Induced pluripotent stem cell and gene editing approach | 211 | ||
| References | 212 | ||
| Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin | 217 | ||
| Key points | 217 | ||
| Oxygen affinity of sickle erythrocytes | 217 | ||
| The allosteric states of Hb and sickle cell disease | 218 | ||
| Hb: a target for drug design | 219 | ||
| Development of allosteric modifiers of Hb to treat sickle cell disease | 220 | ||
| Clinical development | 224 | ||
| Summary | 225 | ||
| Disclosure and funding | 225 | ||
| References | 226 | ||
| Targeted Fetal Hemoglobin Induction for Treatment of Beta Hemoglobinopathies | 233 | ||
| Key points | 233 | ||
| Introduction | 233 | ||
| Experience in trials of prior generation HbF inducers | 234 | ||
| Molecular targets: HBG globin transcription and the fetal globin program | 236 | ||
| HBS1L-MYB Intergenic Interval | 237 | ||
| KLF-1 (EKLF) | 237 | ||
| BCL11A | 237 | ||
| Targeted gamma globin activation through the CACCC element | 237 | ||
| Therapeutic approaches directed to increasing gamma globin transcription | 238 | ||
| Demethylation of the Silenced Gamma Globin Genes | 239 | ||
| A novel mechanism of HDAC3 displacement and recruitment of EKLF | 240 | ||
| Dual-action inducers, including translation and enhanced erythroid cell survival | 241 | ||
| The influence of quantitative trait loci | 242 | ||
| Summary | 244 | ||
| Acknowledgments | 244 | ||
| References | 244 | ||
| Does Erythropoietin Have a Role in the Treatment of β-Hemoglobinopathies? | 249 | ||
| Key points | 249 | ||
| Epo and erythropoiesis | 250 | ||
| Epo and HbF | 250 | ||
| Epo and iron overload | 252 | ||
| Epo and oxidative stress | 253 | ||
| Epo and nonhematopoietic cells | 255 | ||
| Epo and malignancy | 256 | ||
| References | 257 | ||
| Inflammatory Mediators of Endothelial Injury in Sickle Cell Disease | 265 | ||
| Key points | 265 | ||
| Introduction | 265 | ||
| Overview of sickle cell disease pathophysiology | 267 | ||
| Cytoprotective mediators | 268 | ||
| Nitric Oxide | 268 | ||
| Endothelin-1 | 268 | ||
| Adenosine | 270 | ||
| Heme oxygenase-1 | 270 | ||
| Soluble mediators of inflammation | 270 | ||
| Histamine, Leukotrienes, and Secretory Phospholipase A2 | 270 | ||
| Histamine | 270 | ||
| Leukotrienes | 270 | ||
| sPLA2 | 272 | ||
| Coagulation Mediators of Inflammation | 272 | ||
| Platelet-associated CD40 Ligand | 273 | ||
| Platelet-associated TNFSF14 | 273 | ||
| Cytokines and Chemokines | 273 | ||
| Neutrophil activation | 273 | ||
| Neutrophil extracellular traps | 274 | ||
| Mast cells in inflammation | 274 | ||
| Therapeutic implications | 275 | ||
| Inhibitors of Cellular Adhesion | 275 | ||
| Intravenous gammaglobulin | 275 | ||
| Pan-selectin inhibitor (GMI-1070) | 275 | ||
| Anti–P-selectin monoclonal antibody (SelG1) | 275 | ||
| Anti–P-selectin aptamer | 276 | ||
| Platelet ADP receptor antagonist (prasugrel) | 276 | ||
| Leukotriene Blockade | 276 | ||
| 5-Lipoxygenase inhibitor (zileuton) | 276 | ||
| NF-κB Inhibition | 276 | ||
| Statins | 277 | ||
| Adenosine 2A receptor agonist (regadenosan) | 277 | ||
| References | 278 | ||
| The Role of Adenosine Signaling in Sickle Cell Therapeutics | 287 | ||
| Key points | 287 | ||
| Introduction | 287 | ||
| Adenosine signaling pathway | 288 | ||
| Adenosine Physiology | 288 | ||
| Current Therapeutic Uses of Adenosine and Adenosine Derivatives | 288 | ||
| Role of A2AR in sickle cell disease | 289 | ||
| A2AR | 289 | ||
| A2AR Agonist Decreases Inflammation After Ischemia-Reperfusion Injury by Interfering with iNKT-Cell Activation | 291 | ||
| A2AR Agonists Decrease iNKT-Cell Activation and Reduce Inflammation in SCD Mice | 291 | ||
| Phase 1 Study of the A2AR Agonist Regadenoson in Patients with SCD: Study Design and Rationale | 292 | ||
| Phase 1 Study of the A2AR Agonist Regadenoson in Patients with SCD: Study Results | 292 | ||
| Role of A2BR in sickle cell disease | 293 | ||
| A2BR | 293 | ||
| Adenosine Signaling Through A2BR is Implicated in Priapism and Penile Fibrosis | 293 | ||
| Sickle Erythrocyte Formation Promoted Through A2BR | 294 | ||
| Can adenosine have both protective and deleterious roles in SCD? | 294 | ||
| Effects of Adenosine Levels and Receptor Density on A2AR Versus A2BR Signaling in SCD | 294 | ||
| Adenosine Measurements Have Limitations | 295 | ||
| Limitations of adenosine therapeutics in SCD | 296 | ||
| Future directions: combined A2AR and A2BR therapies for SCD? | 296 | ||
| References | 296 | ||
| Alterations of the Arginine Metabolome in Sickle Cell Disease | 301 | ||
| Key points | 301 | ||
| An altered arginine metabolome in sickle cell disease | 301 | ||
| Altered NO homeostasis | 303 | ||
| Altered arginine homeostasis | 304 | ||
| Increased Arginase Activity and Concentration | 305 | ||
| Intracellular Arginine Transport | 306 | ||
| Renal Dysfunction | 306 | ||
| Endogenous NOS Inhibitors | 306 | ||
| Impact of arginine therapy on NO production: a potential explanation for a varied response to therapy | 306 | ||
| Arginine coadministration with hydroxyurea | 307 | ||
| Arginine therapy for clinical complications of SCD | 308 | ||
| Leg Ulcers | 308 | ||
| Pulmonary Hypertension Risk | 308 | ||
| Priapism | 311 | ||
| VOE: Results of a Randomize Double-Blinded Placebo-Controlled Trial | 311 | ||
| Safety data for arginine supplementation | 313 | ||
| Why arginine therapy when other NO-based therapies have failed in SCD? | 314 | ||
| The arginine metabolome: a novel therapeutic target for SCD | 314 | ||
| References | 314 | ||
| Cellular Adhesion and the Endothelium | 323 | ||
| Key points | 323 | ||
| Introduction | 323 | ||
| Abnormal blood flow in sickle cell disease | 324 | ||
| Determinants of sickle cell blood flow | 324 | ||
| Importance of SRBC adhesion to blood flow | 324 | ||
| Cellular mechanisms of SRBC adhesion | 325 | ||
| Molecular mechanisms of cell adhesion | 326 | ||
| Chronic expression of endothelial P-selectin in SCD | 327 | ||
| Therapeutic and commercial potential of P-selectin blocking | 328 | ||
| Considerations for development of antiadhesion therapies | 329 | ||
| Antiadhesive agents under development or consideration for treating SCD | 329 | ||
| Perspective | 331 | ||
| Summary | 331 | ||
| References | 332 | ||
| Cellular Adhesion and the Endothelium | 341 | ||
| Key points | 341 | ||
| Introduction | 341 | ||
| Selectins and selectin-mediated adhesion | 342 | ||
| Structural Characteristics of Selectins | 343 | ||
| E-Selectin | 343 | ||
| L-Selectin | 344 | ||
| Preclinical studies of the role of E- and L-selectins in SCD | 344 | ||
| L-Selectin in Sickle Cell Disease | 344 | ||
| E-Selectin in Sickle Cell Disease | 345 | ||
| In Vivo Studies in Animal Models of Sickle Cell Disease | 346 | ||
| Therapeutic approaches to E-selectin-mediated adhesion in human SCD | 347 | ||
| Clinical Studies Focusing on Selectins in Human Disease | 347 | ||
| GMI-1070 Phase 1 Studies | 347 | ||
| GMI-1070 Phase 2 Study | 349 | ||
| L- and E-selectin targeted therapy: a broader picture | 350 | ||
| Bimosiamose, an E- and P-Selectin Inhibitor | 350 | ||
| GI270384X—Inhibition of E-Selectin Expression | 350 | ||
| Aselizumab—L-Selectin Inhibition | 351 | ||
| YSPSL (rPSGL-Ig)—A Pan-Selectin Inhibitor Targeting P- and E-Selectins | 351 | ||
| Summary | 351 | ||
| References | 351 | ||
| Role of the Hemostatic System on Sickle Cell Disease Pathophysiology and Potential Therapeutics | 355 | ||
| Key points | 355 | ||
| Introduction | 355 | ||
| Evidence for increased thromboembolic events in SCD | 356 | ||
| Evidence of hemostasis system alteration in SCD | 357 | ||
| Activation of the Coagulation Cascade | 357 | ||
| Reduction in Physiologic Anticoagulant Level | 358 | ||
| Impaired Fibrinolysis | 358 | ||
| Activated Platelets | 358 | ||
| Pathophysiology of hemostasis system activation in SCD | 359 | ||
| Role of RBC Membrane | 359 | ||
| Role of Hemolysis-Free Hemoglobin-NO-Spleen Axis | 360 | ||
| The Microparticles | 360 | ||
| Genetic predisposition for thrombophilia in SCD | 361 | ||
| Thrombophilic Mutations | 361 | ||
| Human Platelet Alloantigen Polymorphism | 362 | ||
| Therapeutic implications of hemostatic system activation in SCD | 362 | ||
| Trials of Platelet Inhibitors in SCD | 362 | ||
| Anticoagulant Therapy for Sickle Cell Disease | 364 | ||
| Summary | 366 | ||
| References | 366 | ||
| Modulators of Erythropoiesis | 375 | ||
| Key points | 375 | ||
| JAK2 and disorders associated with chronic stress erythropoiesis | 375 | ||
| Potential use of JAK2 inhibitors in β-thalassemia | 376 | ||
| Activins, members of the transforming growth factor β family signaling | 376 | ||
| Cancer-related anemia and ineffective erythropoiesis | 378 | ||
| Effect of activin signaling in bone | 379 | ||
| Effect of activin signaling in cancer | 379 | ||
| Effect of activin signaling in hematopoiesis and erythropoiesis | 380 | ||
| Therapeutic interventions that target activin signaling | 380 | ||
| Small molecules targeting type 1 receptors | 381 | ||
| Preclinical and clinical studies with ACE-011/RAP-011 | 381 | ||
| Preclinical and clinical studies with ACE-536/RAP-536 | 382 | ||
| Summary | 382 | ||
| References | 383 | ||
| Modulation of Hepcidin as Therapy for Primary and Secondary Iron Overload Disorders | 387 | ||
| Key points | 387 | ||
| Introduction to iron metabolism | 387 | ||
| The Hepcidin-Ferroportin Iron Regulatory Axis | 388 | ||
| Iron-Responsive Hepcidin Expression by the Hepatocyte | 388 | ||
| Preclinical investigation of hepcidin mimetic and hepcidin-induction therapies in murine models of HH | 390 | ||
| Transgenic Hepcidin Overexpression in HFE HH | 391 | ||
| Exogenous BMP6 for the Treatment of HFE HH | 391 | ||
| Genetic and Pharmacologic Inhibition of Tmprss6 in HFE HH | 392 | ||
| Minihepcidins Correct Hepcidin Deficiency in HH | 394 | ||
| Small Molecule Modulation of Hepcidin Expression | 394 | ||
| Preclinical investigation of hepcidin-induction therapies in murine models of β-thalassemia intermedia | 394 | ||
| Transferrin Therapy to Modulate Iron Metabolism in β-Thalassemia Intermedia | 395 | ||
| Genetic and Pharmacologic Induction of Hepcidin in β-Thalassemia Intermedia | 395 | ||
| Summary and future directions | 396 | ||
| References | 397 | ||
| Index | 403 |