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.
Front Cover 1
Emerging Therapies Targeting
2
copyright
3
Contributors 4
Consulting Editors 4
Editor 4
Authors 4
Contents 8
Hematology/Oncology
12
Preface
14
References 18
Dedication 20
Hemoglobin S Polymerization and Red Cell Membrane Changes 22
Key points 22
Introduction 22
Polymerization 23
Effects of HbS on membranes 25
Oxidative stress 26
Microparticles 28
Membrane lipid 28
Lipid turnover 29
Lipid asymmetry 30
PS exposure in RBCs 30
PS exposure in SCD 31
Consequences of PS exposure 33
Summary 34
References 36
Ischemia-reperfusion Injury in Sickle Cell Anemia 48
Key points 48
Introduction 48
I/R injury 49
Initiation of I/R 49
The Further Evolution of I/R 49
Differential Organ Susceptibilities 50
Systemic Implications 50
Endothelial Dysfunction 51
ROI 51
Ischemic Preconditioning 51
I/R in human biomedicine 52
Sickle mice and experimental I/R 52
I/R Induction in Sickle Mice 52
Clinical sickle disease and I/R 53
Cause of Sickle I/R 55
Sickle Complexity and the I/R Paradigm 55
Hemolytic anemia 57
Genetic polymorphisms 57
Epigenetic effects 57
Environmental stressors 57
Sickle preconditioning? 57
Clinical examples of sickle I/R 57
Clinical Endothelial Dysfunction 57
ACS 57
Arterial Vasculopathy 58
Inflammatory Pain 58
Implications of I/R for therapeutics 59
References 61
Gene Therapy for Hemoglobinopathies 66
Key points 66
Introduction 67
Rationale 68
Prerequisites for successful gene therapy in ß-hemoglobinopathies 69
Understanding the developmental switch of ß-globin and its regulation in postnatal life 69
Introduction to gene therapy 70
Initial vector development for ß-thalassemia 74
Initial development of LV-based vectors for ß-thalassemia 75
Human gene therapy for thalassemia 75
Gene therapy for SCD 76
Recent advances 77
Role of Mobilizing Agents to Achieve Adequate Stem Cell Dose 77
In Vivo Selection: Giving Survival Advantage to Transduced Stem Cells 77
Newer Vectors 77
Transcriptional Manipulation to Increase HbF 77
Induced pluripotent stem cell and gene editing approach 78
References 79
Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin 84
Key points 84
Oxygen affinity of sickle erythrocytes 84
The allosteric states of Hb and sickle cell disease 85
Hb: a target for drug design 86
Development of allosteric modifiers of Hb to treat sickle cell disease 87
Clinical development 91
Summary 92
Disclosure and funding 92
References 93
Targeted Fetal Hemoglobin Induction for Treatment of Beta Hemoglobinopathies 100
Key points 100
Introduction 100
Experience in trials of prior generation HbF inducers 101
Molecular targets: HBG globin transcription and the fetal globin program 103
HBS1L-MYB Intergenic Interval 104
KLF-1 (EKLF) 104
BCL11A 104
Targeted gamma globin activation through the CACCC element 104
Therapeutic approaches directed to increasing gamma globin transcription 105
Demethylation of the Silenced Gamma Globin Genes 106
A novel mechanism of HDAC3 displacement and recruitment of EKLF 107
Dual-action inducers, including translation and enhanced erythroid cell survival 108
The influence of quantitative trait loci 109
Summary 111
Acknowledgments 111
References 111
Does Erythropoietin Have a Role in the Treatment of ß-Hemoglobinopathies? 116
Key points 116
Epo and erythropoiesis 117
Epo and HbF 117
Epo and iron overload 119
Epo and oxidative stress 120
Epo and nonhematopoietic cells 122
Epo and malignancy 123
References 124
Inflammatory Mediators of Endothelial Injury in Sickle Cell Disease 132
Key points 132
Introduction 132
Overview of sickle cell disease pathophysiology 134
Cytoprotective mediators 135
Nitric Oxide 135
Endothelin-1 135
Adenosine 137
Heme oxygenase-1 137
Soluble mediators of inflammation 137
Histamine, Leukotrienes, and Secretory Phospholipase A2 137
Histamine 137
Leukotrienes 137
sPLA2 139
Coagulation Mediators of Inflammation 139
Platelet-associated CD40 Ligand 140
Platelet-associated TNFSF14 140
Cytokines and Chemokines 140
Neutrophil activation 140
Neutrophil extracellular traps 141
Mast cells in inflammation 141
Therapeutic implications 142
Inhibitors of Cellular Adhesion 142
Intravenous gammaglobulin 142
Pan-selectin inhibitor (GMI-1070) 142
Anti–P-selectin monoclonal antibody (SelG1) 142
Anti–P-selectin aptamer 143
Platelet ADP receptor antagonist (prasugrel) 143
Leukotriene Blockade 143
5-Lipoxygenase inhibitor (zileuton) 143
NF-.B Inhibition 143
Statins 144
Adenosine 2A receptor agonist (regadenosan) 144
References 145
The Role of Adenosine Signaling in Sickle Cell Therapeutics 154
Key points 154
Introduction 154
Adenosine signaling pathway 155
Adenosine Physiology 155
Current Therapeutic Uses of Adenosine and Adenosine Derivatives 155
Role of A2AR in sickle cell disease 156
A2AR 156
A2AR Agonist Decreases Inflammation After Ischemia-Reperfusion Injury by Interfering with iNKT-Cell Activation 158
A2AR Agonists Decrease iNKT-Cell Activation and Reduce Inflammation in SCD Mice 158
Phase 1 Study of the A2AR Agonist Regadenoson in Patients with SCD: Study Design and Rationale 159
Phase 1 Study of the A2AR Agonist Regadenoson in Patients with SCD: Study Results 159
Role of A2BR in sickle cell disease 160
A2BR 160
Adenosine Signaling Through A2BR is Implicated in Priapism and Penile Fibrosis 160
Sickle Erythrocyte Formation Promoted Through A2BR 161
Can adenosine have both protective and deleterious roles in SCD? 161
Effects of Adenosine Levels and Receptor Density on A2AR Versus A2BR Signaling in SCD 161
Adenosine Measurements Have Limitations 162
Limitations of adenosine therapeutics in SCD 163
Future directions: combined A2AR and A2BR therapies for SCD? 163
References 163
Alterations of the Arginine Metabolome in Sickle Cell Disease 168
Key points 168
An altered arginine metabolome in sickle cell disease 168
Altered NO homeostasis 170
Altered arginine homeostasis 171
Increased Arginase Activity and Concentration 172
Intracellular Arginine Transport 173
Renal Dysfunction 173
Endogenous NOS Inhibitors 173
Impact of arginine therapy on NO production: a potential explanation for a varied response to therapy 173
Arginine coadministration with hydroxyurea 174
Arginine therapy for clinical complications of SCD 175
Leg Ulcers 175
Pulmonary Hypertension Risk 175
Priapism 178
VOE: Results of a Randomize Double-Blinded Placebo-Controlled Trial 178
Safety data for arginine supplementation 180
Why arginine therapy when other NO-based therapies have failed in SCD? 181
The arginine metabolome: a novel therapeutic target for SCD 181
References 181
Cellular Adhesion and the Endothelium 190
Key points 190
Introduction 190
Abnormal blood flow in sickle cell disease 191
Determinants of sickle cell blood flow 191
Importance of SRBC adhesion to blood flow 191
Cellular mechanisms of SRBC adhesion 192
Molecular mechanisms of cell adhesion 193
Chronic expression of endothelial P-selectin in SCD 194
Therapeutic and commercial potential of P-selectin blocking 195
Considerations for development of antiadhesion therapies 196
Antiadhesive agents under development or consideration for treating SCD 196
Perspective 198
Summary 198
References 199
Cellular Adhesion and the Endothelium 208
Key points 208
Introduction 208
Selectins and selectin-mediated adhesion 209
Structural Characteristics of Selectins 210
E-Selectin 210
L-Selectin 211
Preclinical studies of the role of E- and L-selectins in SCD 211
L-Selectin in Sickle Cell Disease 211
E-Selectin in Sickle Cell Disease 212
In Vivo Studies in Animal Models of Sickle Cell Disease 213
Therapeutic approaches to E-selectin-mediated adhesion in human SCD 214
Clinical Studies Focusing on Selectins in Human Disease 214
GMI-1070 Phase 1 Studies 214
GMI-1070 Phase 2 Study 216
L- and E-selectin targeted therapy: a broader picture 217
Bimosiamose, an E- and P-Selectin Inhibitor 217
GI270384X—Inhibition of E-Selectin Expression 217
Aselizumab—L-Selectin Inhibition 218
YSPSL (rPSGL-Ig)—A Pan-Selectin Inhibitor Targeting P- and E-Selectins 218
Summary 218
References 218
Role of the Hemostatic System on Sickle Cell Disease Pathophysiology and Potential Therapeutics 222
Key points 222
Introduction 222
Evidence for increased thromboembolic events in SCD 223
Evidence of hemostasis system alteration in SCD 224
Activation of the Coagulation Cascade 224
Reduction in Physiologic Anticoagulant Level 225
Impaired Fibrinolysis 225
Activated Platelets 225
Pathophysiology of hemostasis system activation in SCD 226
Role of RBC Membrane 226
Role of Hemolysis-Free Hemoglobin-NO-Spleen Axis 227
The Microparticles 227
Genetic predisposition for thrombophilia in SCD 228
Thrombophilic Mutations 228
Human Platelet Alloantigen Polymorphism 229
Therapeutic implications of hemostatic system activation in SCD 229
Trials of Platelet Inhibitors in SCD 229
Anticoagulant Therapy for Sickle Cell Disease 231
Summary 233
References 233
Modulators of Erythropoiesis 242
Key points 242
JAK2 and disorders associated with chronic stress erythropoiesis 242
Potential use of JAK2 inhibitors in ß-thalassemia 243
Activins, members of the transforming growth factor ß family signaling 243
Cancer-related anemia and ineffective erythropoiesis 245
Effect of activin signaling in bone 246
Effect of activin signaling in cancer 246
Effect of activin signaling in hematopoiesis and erythropoiesis 247
Therapeutic interventions that target activin signaling 247
Small molecules targeting type 1 receptors 248
Preclinical and clinical studies with ACE-011/RAP-011 248
Preclinical and clinical studies with ACE-536/RAP-536 249
Summary 249
References 250
Modulation of Hepcidin as Therapy for Primary and Secondary Iron Overload Disorders 254
Key points 254
Introduction to iron metabolism 254
The Hepcidin-Ferroportin Iron Regulatory Axis 255
Iron-Responsive Hepcidin Expression by the Hepatocyte 255
Preclinical investigation of hepcidin mimetic and hepcidin-induction therapies in murine models of HH 257
Transgenic Hepcidin Overexpression in HFE HH 258
Exogenous BMP6 for the Treatment of HFE HH 258
Genetic and Pharmacologic Inhibition of Tmprss6 in HFE HH 259
Minihepcidins Correct Hepcidin Deficiency in HH 261
Small Molecule Modulation of Hepcidin Expression 261
Preclinical investigation of hepcidin-induction therapies in murine models of ß-thalassemia intermedia 261
Transferrin Therapy to Modulate Iron Metabolism in ß-Thalassemia Intermedia 262
Genetic and Pharmacologic Induction of Hepcidin in ß-Thalassemia Intermedia 262
Summary and future directions 263
References 264
Index 270
Preface
Emerging Therapy in Hemoglobinopathies: Lessons from the Past and Optimism for the Future
Elliott P. Vichinsky, MD, Children's Hospital and Research Center Oakland, 747 52nd Street, Oakland, CA 94609, USA. Email: evichinsky@mail.cho.org
Elliott P. Vichinsky, MD, Editor
Hemoglobinopathies are a worldwide public health problem. Millions of people are affected, with over 400,000 annual births of new cases. Major, recent advances in understanding the complex pathophysiology of hemoglobinopathies have led to the development of several promising therapeutic options. This issue reviews these bench-to-bedside discoveries.1
The investigation of these disorders has always provided a unique window to understand basic biology and disease pathophysiology. Yet these molecular and biologic discoveries have had limited clinical impact on the hemoglobinopathy population. Supportive care, transfusion therapy, and hydroxyurea remain the only available therapies for most patients, and these options have not changed in decades. As a clinician and investigator, I am optimistic that the accomplishments described within this issue will result in decreased morbidity and improved quality of life for the patient population. However, it is important to view these discoveries in a historical context to understand the scientific chain of events that led us to these advances and the disappointment of earlier, promising therapeutic discoveries that did not achieve efficacy for the medical and patient community.
Historically, clinical symptoms of hemoglobinopathies appear to be mentioned in Hippocratic writings and have long been observed in African tribal histories. Centuries ago, the diseases were given onomatopoeic names that indicate severe pain and suffering.2 The African medical literature of the 1870s referred to a disease called “ogbanjes” (“children who come and go”) because of the high infant mortality rate with this syndrome.3 In 1910, Drs Herrick and Irons described the sickle cell erythrocyte in the peripheral smear of Dr Noel, a dental student from Granada.4 This was rapidly followed by the work of Emmel and Hahn, who demonstrated that sickling was an oxygen-dependent phenomenon.5 In 1934, Drs Diggs and Ching concluded that the symptoms of sickle cell disease were caused by occlusion of the microvasculature.6 Sherman, in 1940, noted that polymerization was a key factor in the sickling process and secondary vascular obstruction.7 A decade later Singer and Singer observed this polymerization was inhibited in the presence of fetal hemoglobin.8 This was followed by Hofrichter and Eaton, who found that the delay time for the initiation of deoxy-hemoglobin-S polymerization was dependent on hemoglobin S concentration and the transit time of red cells.9
Sickle cell was classified as the first molecular disease by Pauling and colleagues10 in 1949, who concluded from their electrophoretic studies that the basic pathology was due to a change in the amino acid structure of hemoglobin. Ingram then identified that sickle hemoglobin differed from normal hemoglobin by a single amino acid substitution of valine for glutamic acid, utilizing the newly developed fingerprinting technique to identify amino acid changes.11 In the early 1970s, recombinant DNA technology resulted in nucleic acid sequencing showing there was an A → T DNA change in the sickle hemoglobin DNA, which changes the glutamine codon to valine.12
In 1980, the understanding that sickle cell disease is a complex vasculopathy was initiated by the seminal work of Hebbel and colleagues,13 who wrote that sickled red cells abnormally adhere to endothelium and correlate with disease severity. These observations led to the central role of ischemia reperfusion injury and inflammation in sickle cell disease pathology. In 2002, Reiter and colleagues14 noted that nitric oxide depletion in sickle cell disease is induced by free hemoglobin and amplifies the vasculopathy.
Critical advances in the pathophysiology of thalassemia and iron regulation were occurring concomitantly to discoveries in sickle cell disease. Weatherall and colleagues15 utilized quantitative methods of hemoglobin synthesis to determine that defective and imbalanced globin synthesis were an essential part of the pathophysiology in the thalassemia syndromes. Finch and Sturgeon,16 in studying iron and erythrokinetics in patients, demonstrated that marked ineffective erythropoiesis is a hallmark of thalassemia and is responsible for marrow expansion and increased iron absorption regardless of body iron stores. In 1978, Hershko and colleagues17 described the toxic non-transferrin-bound fraction of plasma iron, which leads to iron-induced free radical damage. In 2001, Park and colleagues18 discovered the peptide hepcidin, which drives the increased gastrointestinal iron absorption in thalassemia.
In the last 50 years, several promising therapies have been proposed based on biologic discoveries. In the 1970s, anti-sickling agents designed to impair polymerization by altering hemoglobin ligands entered clinical trials. Urea, initially claimed to decrease sickling, was ineffective in clinical trials and may have increased morbidity.19 Cyanate, which appeared to increase oxygen affinity, resulted in severe neurologic toxicity.20 Many other anti-sickling agents designed to alter noncovalent and covalent ligands were clinically ineffective. These were followed by clinical trials with membrane-active drugs designed to increase cell hydration. Initial studies with the antidiuretic hormone DDAVP were encouraging, but were discontinued due to lack of efficacy and toxicity.21 Cetiedil induced significant improvement in red cell deformability and hydration by inhibiting the Gardos pathway. Initial clinical observations were positive, but definitive pharmaceutical trials were never undertaken.22 Several other membrane-active agents were initiated. A novel Gardos channel inhibitor, senicapoc, significantly increased hemoglobin levels and improved red cell deformability, but increased pain in phase III trials resulted in its abrupt abandonment.23 The results of these trials support the theory of different subphenotypes of sickle cell disease with the possibility of drug-induced phenotypic shifts.24 Agents that alter red cell rheology and vascular flow entered clinical studies in the early 1980s. Pluronic F-68 (poloxamer 188), a nonionic copolymer surfactant, showed promise in phase II trials for acute pain but was disappointing in phase III trials, with a benefit seen only in a subpopulation of children—again suggesting that drug response may be not be the same in all populations.25
The only successful FDA-approved pharmacologic approach to sickling has been in fetal hemoglobin induction. Following the seminal observations by DeSimone and colleagues26,27 that 5-azacytidine therapy increases hemoglobin F, multiple clinical trials were undertaken with different agents. 5-Azacytidine increased hemoglobin in both thalassemia and sickle cell patients. Its utilization was abandoned because of mutagenic and carcinogenic risks. Initially, it was thought to activate hemoglobin F synthesis by increased gamma gene expression by affecting methylation. However, several studies with multiple S-phase cytoxic drugs showed a similar hemoglobin F response. It was concluded that hemoglobin F was indirectly increased due to alteration of erythroid progenitor kinetics. Hydroxyurea, the least toxic, orally available agent underwent the most clinical studies, leading to its eventual FDA approval for use in adults with sickle cell disease.28 Exciting work with butyrate and other histone deacetylase inhibitors in the mid-1980s suggested they would be efficacious. However, clinical trials were less encouraging possibly due to drug metabolism and/or inhibition of erythropoiesis.29 Stimulation of fetal hemoglobin synthesis by erythropoietin has been demonstrated for decades, but the modest response and potential toxicity have prevented larger trials.30
The biologic advances in sickle cell disease and therapeutic options described in this issue grew out of the scientific foundation described above. The first two articles give an overview of the evolving understanding of the pathophysiology. Dr Kuypers discusses the red cell membrane changes—including increased phosphatidyl serine (PS) exposure—that result in the sickle cell initiating a red cell vasculopathy. He briefly discusses potential therapies to address membrane alterations such as D-annexin binding to PS surfaces. Dr Hebbel provides an insightful discussion of how ischemia reperfusion injury is most likely responsible for much of the clinical syndrome of sickle cell disease, and he reviews the therapeutic options for ischemic reperfusion injury.
Therapeutic interventions can attack sickle cell pathology from the primary mutation to its downstream effects such as inflammation and thrombosis. Drs Chandrakasan and Malik discuss the advances in gene transfer vector technology and self-inactivating lentivirus...
| Erscheint lt. Verlag | 23.5.2014 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizinische Fachgebiete ► Innere Medizin ► Hämatologie |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie | |
| ISBN-10 | 0-323-29000-0 / 0323290000 |
| ISBN-13 | 978-0-323-29000-5 / 9780323290005 |
| Haben Sie eine Frage zum Produkt? |
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