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Book Details
Abstract
Sight loss and blindness is a very prevalent cause of disability. Retinal diseases leading to visual loss affect many people worldwide and the search for adequate drugs remains a challenge and an important area of interest in the drug discovery field. This book addresses approaches to the treatment of retinal diseases, targeting common processes and components. Despite their causative origins, which comprise genetic dystrophies, age-related degenerations, as well as pathologies associated with other diseases, a neurodegenerative component appears, sooner or later, in the course of the disease. As is the case for most neurodegenerative diseases, the available treatments are far from satisfactory. The aim of this book is to highlight research and drug development efforts in targeting such common processes as a potential path to provide treatments to the millions of affected people.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Therapies for Retinal Degeneration: Targeting Common Processes | i | ||
| Preface | vii | ||
| Contents | ix | ||
| Chapter 1 - The Cellular Course of Retinal Degenerative Conditions | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 Alterations in Retinal Homeostasis | 1 | ||
| 1.2.1 Oxidative Stress | 2 | ||
| 1.2.2 Neuroinflammation | 3 | ||
| 1.2.3 Apoptosis, Autophagy, Necroptosis and Necrosis | 3 | ||
| 1.3 Morphological Impairments in Retinal Degeneration: Neurons and Circuitries, Microglia, Astrocytes, Müller Cells and Retinal V... | 7 | ||
| 1.3.1 Retinal Morphology | 7 | ||
| 1.3.2 Early Onset of Rod Photoreceptors Degeneration | 7 | ||
| 1.3.3 Modifications of Second-order Neurons in the Retina | 9 | ||
| 1.3.4 Cell Connectivity in the OPL at Late Stages of Retinal Degeneration | 11 | ||
| 1.3.5 Modifications in the Inner Plexiform Layer | 11 | ||
| 1.3.6 Modifications in Glia: Microglia, Astrocytes and Müller Cells | 14 | ||
| 1.3.7 Alterations of Retinal Vascularization | 16 | ||
| 1.4 Physiological Degeneration of the Retina | 17 | ||
| 1.4.1 Electroretinogram | 17 | ||
| 1.4.2 Visual Evoked Potentials | 18 | ||
| 1.4.3 Visual Acuity | 19 | ||
| 1.5 Retinal Remodeling | 20 | ||
| Acknowledgements | 21 | ||
| References | 21 | ||
| Chapter 2 - Immune Response of the Retina | 31 | ||
| 2.1 Introduction | 31 | ||
| 2.2 The Immune System and Inflammation | 31 | ||
| 2.2.1 The Immune System | 31 | ||
| 2.2.2 Inflammation | 34 | ||
| 2.3 Immune Defence System of the Retina | 34 | ||
| 2.3.1 Immune Privilege of the Eye | 34 | ||
| 2.3.2 Retinal Resident Immune Cells | 35 | ||
| 2.3.2.1 Microglia | 35 | ||
| 2.3.2.2 Perivascular Macrophages | 37 | ||
| 2.3.2.3 Dendritic Cells | 37 | ||
| 2.3.3 The Complement System in the Retina | 38 | ||
| 2.4 Immune Response in Retinal Degenerative Conditions | 39 | ||
| 2.4.1 Parainflammation in the Ageing Retina | 39 | ||
| 2.4.2 Inherited Retinal Degeneration | 40 | ||
| 2.4.3 Age-related Macular Degeneration | 40 | ||
| 2.4.4 Diabetic Retinopathy | 41 | ||
| 2.4.5 Glaucoma | 42 | ||
| 2.5 Conclusions | 43 | ||
| References | 43 | ||
| Chapter 3 - Modulation of Calcium Overload and Calpain Activity | 48 | ||
| 3.1 Overview | 48 | ||
| 3.2 Targeting Calcium Overload | 49 | ||
| 3.3 Targeting Calpains | 53 | ||
| 3.4 Conclusions | 54 | ||
| Acknowledgements | 55 | ||
| References | 55 | ||
| Chapter 4 - CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy | 61 | ||
| 4.1 Introduction | 61 | ||
| 4.2 Retinal Alterations in Neurodegenerative Conditions of the Brain and Spinal Cord | 63 | ||
| 4.3 Neurodegenerative Conditions of the Brain and Retina Share Common Pathological Mechanisms | 65 | ||
| 4.4 GSK-3 as an Example of a Common Therapeutic Target for Neurodegenerative Conditions of the Brain and Retina | 67 | ||
| 4.5 Proinsulin, a Candidate Drug for Neurodegenerative Conditions of the Brain and Retina | 70 | ||
| 4.6 Conclusions | 72 | ||
| Acknowledgements | 72 | ||
| References | 72 | ||
| Chapter 5 - Modulation of p75NTR/Pro-NGF as a Therapeutic Approach for Degenerative Retinopathies | 76 | ||
| 5.1 Mature NGF, Pro-NGF, and Their Receptors | 76 | ||
| 5.2 Localization of Mature NGF, Pro-NGF, and Their Receptors in the Retina | 77 | ||
| 5.3 Role of NGF, Pro-NGF, and Their Receptors in Retinal Degeneration Disease | 79 | ||
| 5.3.1 Retinitis Pigmentosa | 79 | ||
| 5.3.2 Glaucoma | 80 | ||
| 5.4 Optic Nerve Axotomy and Retinal Ischemia | 81 | ||
| 5.4.1 Diabetic Retinopathy | 81 | ||
| 5.5 Clinical Application of Pro-NGF Antibody and p75NTR Inhibitor | 83 | ||
| References | 84 | ||
| Chapter 6 - Modulation of cGMP-signalling to Prevent Retinal Degeneration | 88 | ||
| 6.1 Photoreceptor Cell Death and Hereditary Retinal Degeneration | 88 | ||
| 6.2 Defining a Common Target for Genetically Heterogeneous Forms of Retinal Degeneration | 89 | ||
| 6.3 cGMP Analogues as Drugs to Prevent Retinal Degeneration | 90 | ||
| 6.4 The Problem of Retinal Drug Delivery | 91 | ||
| 6.5 Efficacy Testing of cGMP Analogues and Liposomal Drug Delivery | 92 | ||
| 6.6 The “Drugs for Retinal Degeneration” (DRUGSFORD) Project | 93 | ||
| 6.7 Concluding Remarks | 95 | ||
| Acknowledgements | 95 | ||
| References | 95 | ||
| Chapter 7 - PEDF Peptides in Retinal Degenerations | 99 | ||
| 7.1 Introduction | 99 | ||
| 7.2 A Member of the Serpin Superfamily | 100 | ||
| 7.3 Mechanism of Action | 102 | ||
| 7.4 PEDF Isoforms | 103 | ||
| 7.5 Mapping of Active Domains | 104 | ||
| 7.6 Biomimetic Peptides as Drugs | 105 | ||
| 7.7 Conclusions | 108 | ||
| Acknowledgements | 109 | ||
| References | 109 | ||
| Chapter 8 - Beyond Anti-inflammation: Steroid-induced Neuroprotection in the Retina | 113 | ||
| 8.1 Introduction | 113 | ||
| 8.2 Glucocorticoids | 115 | ||
| 8.2.1 Evidence for Protection | 115 | ||
| 8.2.2 Mechanism of Action | 118 | ||
| 8.3 Sex Steroids | 121 | ||
| 8.3.1 Evidence for Protection | 121 | ||
| 8.3.1.1 Oestrogen-specific Neuroprotection | 122 | ||
| 8.3.1.2 Progesterone-specific Neuroprotection | 123 | ||
| 8.3.2 Mechanism of Action | 124 | ||
| 8.3.2.1 Oestrogen-specific Mechanism of Action | 124 | ||
| 8.3.2.2 Progesterone-specific Mechanism of Action | 128 | ||
| 8.4 Discussion | 130 | ||
| Acknowledgements | 131 | ||
| References | 131 | ||
| Chapter 9 - Alternative Experimental Models of Ciliary Trafficking and Dysfunction in the Retina | 144 | ||
| 9.1 Introduction | 144 | ||
| 9.1.1 Cilia and Retinal Biology | 144 | ||
| 9.1.2 Ciliopathies | 146 | ||
| 9.2 Rodent Models | 149 | ||
| 9.3 Induced Pluripotent Stem Cell-derived Retinal Organoids | 149 | ||
| 9.3.1 Introduction | 149 | ||
| 9.3.2 iPSC Ciliopathy Models | 150 | ||
| 9.3.3 Future Prospects | 152 | ||
| 9.4 Zebrafish | 152 | ||
| 9.4.1 Introduction | 152 | ||
| 9.4.2 Zebrafish Ciliopathy Models | 154 | ||
| 9.4.3 Future Prospects | 155 | ||
| 9.5 Caenorhabditis elegans | 155 | ||
| 9.5.1 Introduction | 155 | ||
| 9.5.2 C. elegans Ciliopathy Models | 156 | ||
| 9.5.3 Future Prospects | 157 | ||
| 9.6 Conclusion | 157 | ||
| Acknowledgements | 157 | ||
| References | 157 | ||
| Chapter 10 - Drug Delivery Systems for the Treatment of Diseases Affecting the Retina and Optic Nerve | 164 | ||
| 10.1 Introduction | 164 | ||
| 10.2 Drug Delivery Systems | 166 | ||
| 10.2.1 Implants | 166 | ||
| 10.2.2 Microtechnologies | 170 | ||
| 10.2.3 Nanotechnologies | 172 | ||
| 10.3 Conclusion | 175 | ||
| Acknowledgements | 175 | ||
| References | 175 | ||
| Chapter 11 - Gene Therapies for Retinal Degenerations | 179 | ||
| 11.1 The Goals of Gene Therapy | 179 | ||
| 11.2 Vectors and Gene Delivery in Retinal Gene Therapy | 180 | ||
| 11.3 Clinical Applications of Retinal Gene Therapy | 181 | ||
| 11.3.1 Gene Addition Therapy for RPE65-Leber Congenital Amaurosis | 181 | ||
| 11.3.2 AAV2-Based Gene Therapy for Other Forms of Retinal Degeneration | 182 | ||
| 11.3.3 Clinical Trials with Different Vectors for Improved Targeting or Delivery of Larger Genes | 183 | ||
| 11.4 Where Do We Go from Here | 184 | ||
| 11.4.1 Maximizing Retinal Cell Transduction | 184 | ||
| 11.4.2 Expanding the Number of Indications | 186 | ||
| 11.5 Conclusions | 187 | ||
| Acknowledgements | 187 | ||
| References | 188 | ||
| Chapter 12 - Stem Cell Therapies for Retinal Repair and Regeneration | 196 | ||
| 12.1 Introduction | 196 | ||
| 12.1.1 Retinal Degeneration as a Cause of Visual Impairment and Blindness | 197 | ||
| 12.2 Stem Cell Potential for Retina Regenerative Therapies | 198 | ||
| 12.2.1 Embryonic Stem Cells | 199 | ||
| 12.2.2 Induced Pluripotent Stem Cells | 199 | ||
| 12.2.3 Adult Stem Cells | 199 | ||
| 12.3 Neural Stem Cells during Retinal Development and Adult Life | 200 | ||
| 12.3.1 Embryonic Development of the Retina | 200 | ||
| 12.3.2 Retinal Organoids Formed by ESCs and iPSCs in vitro | 202 | ||
| 12.4 Prospects for Retinal Repair and Regeneration Using Stem Cells | 203 | ||
| 12.4.1 Stem Cell Transplantation | 203 | ||
| 12.5 Endogenous Regeneration – Targeting Factors with Potential to Induce Regeneration | 205 | ||
| 12.6 Stem Cells as a Source of Neuroprotective Factors to Promote Neural Survival and Regeneration | 208 | ||
| 12.7 Conclusions and Future Trends | 209 | ||
| References | 209 | ||
| Chapter 13 - The Application of Lipid Nanoparticles for Retinal Degenerative Diseases | 216 | ||
| 13.1 Introduction | 216 | ||
| 13.2 Application of LPD for Ocular Diseases | 218 | ||
| 13.3 Cell-specific Promoters Enable LPD to Deliver Cargo to Specific Cells of the Retina In Vivo | 221 | ||
| 13.4 Conclusions | 224 | ||
| Acknowledgements | 224 | ||
| References | 225 | ||
| Chapter 14 - Biologicals in Retinal Therapy | 230 | ||
| 14.1 Introduction | 230 | ||
| 14.2 Biologics for Treatment of Neovascular Retinal Disease | 232 | ||
| 14.2.1 Age-related Macular Degeneration | 232 | ||
| 14.2.2 Diabetic Retinopathy | 233 | ||
| 14.2.3 Retinopathy of Prematurity | 233 | ||
| 14.2.4 Anti-VEGF Therapies | 235 | ||
| 14.2.4.1 Ranibizumab | 236 | ||
| 14.2.4.2 Bevacizumab | 237 | ||
| 14.2.4.3 Aflibercept | 239 | ||
| 14.2.4.4 Disadvantages of Anti-VEGF Therapy in Retinal Disease | 240 | ||
| 14.2.5 New Horizons in Biologics for Neovascular Retinal Disease | 241 | ||
| 14.3 Biologics for Non-infectious Inflammatory Retinal Disease | 243 | ||
| 14.3.1 Anti-TNFα Therapies | 243 | ||
| 14.3.1.1 Anti-TNFα for Non-infectious Uveitis | 245 | ||
| 14.3.1.2 Disadvantages of Systemic Anti-TNFα Therapy | 245 | ||
| 14.3.1.3 Anti-TNFα Utility for Diabetic Retinopathy, DME and AMD | 245 | ||
| 14.3.2 Other Anti-inflammatory Biologics in Retinal Disease | 246 | ||
| 14.4 Biological Agents for Treatment of Geographic Atrophy End Stage of AMD | 247 | ||
| 14.5 Conclusions | 250 | ||
| References | 250 | ||
| Subject Index | 256 |