Gene and Cell Therapies for Beta-Globinopathies (Advances in Experimental Medicine and Biology Book 1013)

Hemoglobin defects, specifically sickle cell disease & thalassemia, combined, constitute the most common monogenic disorders in the world. In fact, nearly 2% of the world’s population carries a globin gene mutation. The transfer of the corrective globin gene through the HSC compartment by allogeneic HSC transplantation (HSCT) has already proven curative in both SCD and thalassemia patients, and provides the proof of concept that genetic manipulation of the defective organ might be equally therapeutic. However, procedural toxicities and the requirement of an HLA-matched sibling donor limit this approach to a fraction of affected individuals. The editors review the progress & the state of the field in HSCT for hemoglobinopathies & shed light on the major changes expected in the next decade. Although allogeneic HSCT is a curative option, it is limited by the availability of matched donors, which are often available only to 15-20% of patients. An alternative to allogeneic HS CT is genetic correction of autologous HSCs, to overcome donor availability & immune side effects. This Book reviews the progress made on additive gene therapy approaches & the current state of the field. Finally, targeted genetic correction is emerging as a novel therapeutic strategy in the hemoglobinopathies. Although ideal, the inefficiency of targeted correction was rate limiting for translation of this technology to the clinic. With advancements in zinc finger nucleases and TALE endonuclease mediated targeted correction, correction frequencies in hematopoietic stem cells is now reaching levels that may become clinically relevant. Furthermore, the ability to generate autologous embryonic stem cell like cells from primary somatic cells (skin fibroblasts or hematopoietic cells) of the affected individual has allowed for the potential application of genetic correction strategies.This Book reviews upcoming genetic strategies to reactivate fetal hemoglobin production and research advances. Preface 5 Contents 6 Chapter 1: Clinical Features of β-Thalassemia and Sickle Cell Disease 11 Introduction 12 Hemoglobin: Structure and Function 12 Types of Hemoglobin 14 Classifying the Hemoglobin Disorders 14 β-Thalassemia 15 Overview and Historical Perspective 15 Epidemiology and Global Burden 15 Molecular Basis and Pathophysiology 16 Iron and β-Thalassemia 17 Classification and Clinical Manifestations of β-Thalassemia 17 β-Thalassemia Major 17 Hematological Manifestations 18 Skeletal Manifestations 18 Endocrine Manifestations 18 Hepatic Manifestations 19 Cardiac Manifestations 19 β-Thalassemia Intermedia 20 β-Thalassemia Minor 20 Sickle Cell Disease 21 Overview and Historical Perspective 21 Epidemiology and Global Burden 22 Molecular Basis and Pathophysiology 23 Classification of Sickle Cell Disease 24 Clinical Manifestations of Sickle Cell Disease 25 Hematologic Manifestations 25 Vaso-Occlusive Manifestations 25 Infectious Manifestations 26 Neurological Manifestations 26 Cardiac Manifestations 27 Pulmonary Manifestations 27 Splenic Manifestations 28 Hepatobiliary Manifestations 29 Renal Complications 29 Skeletal Complications 30 Other Complications 30 Sickle Cell Disease Treatment Options 30 Summary 31 References 31 Chapter 2: Genetic Basis and Genetic Modifiers of β-Thalassemia and Sickle Cell Disease 37 Introduction 37 The β-Globin Gene (HBB) and Normal Expression 38 Genetics of β-Thalassemia 40 Non-deletion β-Thalassemia 40 Transcriptional Mutations 41 Mutations Affecting RNA Processing 42 Translational Mutations 43 Deletions Causing β-Thalassemia 43 Dominantly Inherited β-Thalassemia 44 Unusual Causes of β-Thalassemia 44 Genetics of Sickle Cell Disease 45 Genetic Modifiers of β-Hemoglobinopathies 45 Update on the Genetic Control of Fetal Hemoglobin (HbF) 48 Genetic Modifiers of Sickle Cell Disease 51 Impact of HbF in SCD 51 Impact of α-Thalassemia on SCD Phenotype 53 Secondary Modifiers of Sub-phenotypes and Complications 53 Genetic Modifiers of β-Thalassemia 54 Effect of the Primary Modifiers: HbF Quantitative Trait Loci and α-Globin Genotype 55 Secondary Modifiers of Complications of β-Thalassemia 57 References 58 Chapter 3: Current Standards of Care and Long Term Outcomes for Thalassemia and Sickle Cell Disease 68 Introduction 68 Thalassemia 69 Molecular Basis and Classification 69 Clinical Presentation 70 Diagnosis 71 Preventive Care and Screening Measures (Table 3.3) 72 Growth and Development 72 Endocrine Studies 72 Iron Monitoring 72 Cardiac Studies 74 Infection 74 Bone Mineral Density 74 Ophthalmologic and Auditory Screening 74 Medical and Surgical Management of Patients with Thalassemia 75 Transfusion Therapy 75 Fetal Hemoglobin (Hb F) Inducing Agents 75 Demethylating Agents 76 Histone Deacetylase (HDAC) Inhibitors 76 Erythropoietin 77 Hydroxyurea 77 Iron Chelation Therapy 77 Splenectomy 79 Cure 79 Long Term Outcomes 79 Sickle Cell Disease 80 Molecular Basis, Pathophysiology and Diagnosis 81 Screening Tests and Prevention of Complications 82 Bacterial Infection 82 Acute Splenic Sequestration 83 Primary Prevention of Stroke 83 Health Maintenance and Screening (Table 3.6) 83 Growth and Development 83 Blood Counts and Serum Chemistries 84 Electrocardiogram and Echocardiography 84 TCD Ultrasonography 84 MRI of Brain and Silent Cerebral Infarction (SCI) 84 Immunizations 86 Educational Attainment 86 Management of Specific Complications 87 Acute Painful Episodes 87 Acute Chest Syndrome (ACS) 87 Overt Stroke 88 Acute Anemic Events 89 Priapism 89 Disease-modifying Therapies 89 Hydroxyurea 89 Chronic Transfusions 90 Cure 91 Long-Term Outcomes 91 References 92 Chapter 4: Allogeneic/Matched Related Transplantation for β-Thalassemia and Sickle Cell Anemia 97 Introduction 98 Thalassemia 98 History of HSCT in Thalassemia 99 Adults 100 Conditioning Regimen 100 GVHD Prophylaxis 104 Stem Cell Source 104 Spleen and HSCT 105 Chimerism 105 Donor Lymphocyte Infusions 106 ABO Incompatibility 106 Growth and Endocrinal Function 106 Costs and Cost-effectiveness 107 Sickle Cell Anemia 108 HSCT in SCA: Procedure and Results 113 Myeloablative 113 Non-myeloablative Geno-identical HSCT (Table 4.3) 114 Indications for Geno-identical HSCT (Table 4.4) 115 Costs 118 Barriers 119 Conclusions 121 References 121 Chapter 5: Alternative Donor/Unrelated Donor Transplants for the β-Thalassemia and Sickle Cell Disease 131 Introduction 132 Umbilical Cord Blood Transplantation for Patients with Hemoglobin Disorders 134 For Patients with Sickle Cell Disease (SCD) 135 Related Umbilical Cord Blood Transplantation 135 Unrelated Umbilical Cord Blood Transplantation 138 For Patients with Thalassemia Major (TM) 138 Related Umbilical Cord Blood Transplantation 138 Unrelated Umbilical Cord Blood Transplantation 142 Summary and Future Directions for Umbilical Cord Blood Transplantation 143 Optimizing Supportive Care and Conditioning Regimen 144 Allelic HLA Matching 145 Double Cord Blood Transplant 145 Ex vivo Expansion 145 Haploidentical (and Mismatch Related) Transplantation for Patients with Hemoglobin Disorders 146 For Patients with Sickle Cell Disease (Table 5.3) 146 For Patients with Thalassemia Major (Table 5.4) 147 Matched Unrelated Donor Transplantation for Patients with Hemoglobin Disorders (Table 5.5) 149 Summary and Recommendations 153 References 156 Chapter 6: Gene Addition Strategies for β-Thalassemia and Sickle Cell Anemia 162 Introduction 163 Oncoretroviral Vectors 164 Lentiviral Vectors 165 Addition of Non-globin Genetic Elements 169 Clinical Trials 171 Mixed Chimerism and In Vivo Selection of Transduced Cells 173 Concerns and Genome Toxicity 175 Conclusion 177 References 177 Chapter 7: Reactivation of Fetal Hemoglobin for Treating β-Thalassemia and Sickle Cell Disease 184 Introduction 185 Globin Gene Clusters 185 Hemoglobin Switching (Embryonic-Fetal-Adult) 186 Hemoglobin Variants and Hemoglobinopathies 188 Fetal γ-Globin Induction as a Therapeutic Agent for SCD and β-Thalassemia 189 Chemical Inducers of Fetal Hemoglobin 190 Hydroxyurea (HU) 190 HDAC Inhibitors 191 DNMT Inhibitors 192 MAO Inhibitors 193 DNA-Binding Drugs 194 mTOR Inhibitors 194 Transcriptional Regulation of the γ-Globin Genes 194 Summary 196 References 197 Chapter 8: Genome Editing for the β-Hemoglobinopathies 210 Genome Editing 212 Engineered Nucleases 213 Meganucleases (Homing Endonucleases) 213 Zinc Finger Nucleases (ZFNs) 213 TAL Effector Nucleases (TALENs) 214 RNA Guided Endonucleases (CRISPR/Cas9) 215 Hybrid Nuclease Platforms 215 Genetically De-Repressing γ-Globin 216 Knocking Out BCL11A As Genome Editing Approach to Increase HgbF 216 Knocking Out the Erythroid Specific Enhancer of BCL11A by Genome Editing to Increase HgbF 217 Using Genome Editing to Generate HPFH Genotypes 217 Gene Correction of Induced Pluripotent Cells 218 Gene Correction of Somatic Hematopoietic Stem Cells 219 Summary and Future Directions 221 References 221 Chapter 9: Gene and Cell Therapy for β-Thalassemia and Sickle Cell Disease with Induced Pluripotent Stem Cells (iPSCs): The Next Frontier 225 Why Use iPSCs? 225 Limitations of HSPC-Based Gene Therapy 226 iPSCs: Features and Origins 228 Proof-of-Principle Studies Using iPSCs for Gene and Cell Therapy of BT and SCD 230 Promises and Challenges of iPSCs for the Gene and Cell Therapy of BT and SCD 235 Issues Common to All Applications of iPSC-Based Cell Therapy 235 Autologous vs Histocompatible iPSCs 236 Teratoma Formation and Tumorigenicity 237 Issues Common to iPSC-Based Cell Therapy of the Hematopoietic System 237 Strategies for Genetic Correction 238 Issues Specific to iPSC-Based Cell Therapy for BT and SCD 239 Concluding Remarks 240 References 240 Index 247 Front Matter ....Pages i-xi Clinical Features of β-Thalassemia and Sickle Cell Disease (Patrick T. McGann, Alecia C. Nero, Russell E. Ware)....Pages 1-26 Genetic Basis and Genetic Modifiers of β-Thalassemia and Sickle Cell Disease (Swee Lay Thein)....Pages 27-57 Current Standards of Care and Long Term Outcomes for Thalassemia and Sickle Cell Disease (Satheesh Chonat, Charles T. Quinn)....Pages 59-87 Allogeneic/Matched Related Transplantation for β-Thalassemia and Sickle Cell Anemia (Françoise Bernaudin, Corinne Pondarré, Claire Galambrun, Isabelle Thuret)....Pages 89-122 Alternative Donor/Unrelated Donor Transplants for the β-Thalassemia and Sickle Cell Disease (Courtney D. Fitzhugh, Allistair Abraham, Matthew M. Hsieh)....Pages 123-153 Gene Addition Strategies for β-Thalassemia and Sickle Cell Anemia (Alisa C. Dong, Stefano Rivella)....Pages 155-176 Reactivation of Fetal Hemoglobin for Treating β-Thalassemia and Sickle Cell Disease (Shuaiying Cui, James Douglas Engel)....Pages 177-202 Genome Editing for the β-Hemoglobinopathies (Matthew H. Porteus)....Pages 203-217 Gene and Cell Therapy for β-Thalassemia and Sickle Cell Disease with Induced Pluripotent Stem Cells (iPSCs): The Next Frontier (Eirini P. Papapetrou)....Pages 219-240 Back Matter ....Pages 241-248 This book provides a comprehensive review of gene and cell therapy approaches for hemoglobinopathies. It covers the progress and current state of the field in hematopoietic stem cell transplantation for hemoglobinopathies and genetic correction of autologous hematopoietic stem cells. Chapters focus on such topics as the current standards of care and long term outcomes of b-thalassemias and sickle cell disease, the ability to generate autologous embryonic stem cell-like cells from primary somatic cells, and genetic strategies to reactivate fetal hemoglobin production. In addition to offering a thorough review of the field in its present state, this book also sheds light on the major changes expected in coming years. Gene and Cell Therapies for Beta-Globinopathies is part of the American Society of Gene and Cell Therapy sub-series of the highly successful Advances in Experimental Medicine and Biology series. It is essential reading for graduate students, clinicians, and researchers interested in gene and cell therapy