Retinal Degenerations (eBook)

PREFACE 6
CONTENTS 11
CONTRIBUTORS 14
I LIVING WITH RETINAL DEGENERATION 18
Coping With Retinal Degeneration 19
INTRODUCTION 19
CHAPTER STRUCTURE 19
COPING WITH RETINAL DEGENERATION: JAMES CAPE 20
COPING WITH RETINAL DEGENERATION: GORDON COUSINS 26
II DEGENERATIVE DISEASES OF THE RETINA 37
Epidemiology of Age-Related Macular Degeneration Early in the 21st Century 38
INTRODUCTION 38
CURRENT “GOLD-STANDARD” FOR IDENTIFYING AMD PHENOTYPES 38
PREVALENCE OF AMD Whites 39
INCIDENCE AND PROGRESSION OF AMD Whites 42
RISK FACTORS ASSOCIATED WITH AMD PREVALENCE OR INCIDENCE Genetic Influences 43
IMPACT OF AMD 54
SUMMARY 56
ACKNOWLEDGMENTS 57
REFERENCES 57
Leber Congenital Amaurosis 75
INTRODUCTION 75
DIFFERENTIAL DIAGNOSIS OF LCA 76
BIOLOGY OF THE LCA GENES AIPL1 78
CRX 81
CRB1 84
GUCY2D 87
RPE65 89
RPGRIP1 93
RDH12 96
SUMMARY 96
ACKNOWLEDGMENTS 97
REFERENCES 97
Macular Degeneration 105
INTRODUCTION 105
GROWTH FACTOR GENE THERAPY FOR AMD 106
TRANSPLANTATION OF GENETICALLY MODIFIED IRIS PIGMENT EPITHELIAL CELLS 106
ADENOVIRAL VECTORS GENE THERAPY 107
PHARMACOLOGICAL INHIBITION OF THE VEGF IN PATIENTS WITH WET AMD Background 107
VEGF AND ITS RECEPTORS 108
THE ANGIOGENESIS PROCESS: HOW DO NEW VESSELS GROW? 108
ROLE OF VEGF IN PHYSIOLOGICAL AND PATHOLOGICAL ANGIOGENESIS IN AMD 110
CLASSIFICATION OF ANGIOGENESIS INHIBITORS 111
ANTI-ANGIOGENESIS THERAPY FOR EXUDATIVE AMD 113
CONCLUSION 116
ACKNOWLEDGMENTS 116
REFERENCES 116
Stargardt Disease 118
INTRODUCTION 118
STARGARDT DISEASE 118
GENETIC PREDISPOSITION: THE ABCA4 (ABCR) GENE 120
MOLECULAR DIAGNOSIS 121
FUNCTIONAL STUDIES OF ABCA4 123
EMERGING THERAPEUTIC OPTIONS 123
OUTLOOK 126
ACKNOWLEDGMENTS 127
REFERENCES 127
X-Linked Juvenile Retinoschisis 132
INTRODUCTION 132
CLINICAL MANIFESTATION 133
CLINICAL DIAGNOSIS OF RS 134
COMPLICATIONS IN RS 135
Differential Diagnosis in RS 135
TREATMENT OPTIONS 136
ISOLATION OF THE RS1 GENE AND STRUCTURAL FEATURES OF ITS GENE PRODUCT 136
SPECTRUM AND MOLECULAR PATHOLOGY OF RS- ASSOCIATED MUTATIONS 136
FUNCTIONAL PROPERTIES OF RETINOSCHISIN The Discoidin Domain and Its Putative Role in Protein Function 139
CONCLUSIONS AND FUTURE DIRECTIONS 144
ACKNOWLEDGMENTS 145
REFERENCES 145
Retinal Degeneration in Usher Syndrome 149
INTRODUCTION 149
CLINICAL SUBTYPES AND GENETICS 149
VISUAL IMPAIRMENT IN USHER SYNDROME 150
RETINAL FUNCTION OF USHER PROTEINS 151
RETINAL PATHOGENESIS 155
SUMMARY 156
REFERENCES 156
Mouse Models of RP 161
INTRODUCTION 161
TYPES OF RETINAL DEGENERATION Retinal Degeneration 1 ( Pde6brd1) 161
SUMMARY 169
REFERENCES 169
III MECHANISMS UNDERLYING RETINAL DEGENERATIONS 174
The Impact of Diabetes on Neuronal, Glial, and Vascular Cells of the Retina 175
INTRODUCTION 175
GLIAL CELL INVOLVEMENT IN DIABETIC RETINOPATHY 176
NEURONAL CELL LOSS IN DIABETIC RETINOPATHY 178
GANGLION CELLS 179
AMACRINE, BIPOLAR, AND HORIZONTAL CELLS 182
PHOTORECEPTOR CELLS 183
RETINAL PIGMENT EPITHELIUM 183
ENDOTHELIAL CELLS 185
SUMMARY 187
ACKNOWLEDGMENT 188
REFERENCES 188
Statins and Age-Related Maculopathy 194
AGE-RELATED MACULOPATHY 194
HMG-CoA REDUCTASE INHIBITORS (STATINS) 195
BIOLOGICAL PLAUSIBILITY FOR STATINS AS BENEFICIAL FOR ARM 196
EXISTING STUDIES ON CHOLESTEROL-LOWERING MEDICATIONS AND ARM 197
SUMMARY 200
ACKNOWLEDGMENTS 201
REFERENCES 201
The Role of Drusen in Macular Degeneration and New Methods of Quantification 206
INTRODUCTION 206
DRUSEN CHARACTERISTICS AND SUBTYPES 206
DRUSEN AS A RISK FACTOR 207
DRUSEN COMPOSITION 207
DRUSEN IN OTHER DISEASES 207
PATHOPHYSIOLOGY OF DRUSEN Historical Theories 208
IMAGING 209
AUTOMATED DRUSEN MEASUREMENT BY THE MATHEMATICAL BACKGROUND MODEL The Concept 213
APPLICATION: SEGMENTATION AND CO-LOCALIZATION OF DRUSEN AND AUTOFLUORESCENCE 216
THE FUTURE OF MACULAR IMAGE ANALYSIS 216
REFERENCES 217
RPE Lipofuscin 221
INTRODUCTION 221
PACKAGING OF LIPOFUSCIN IN THE RPE 222
CHEMICAL COMPOSITION OF RPE LIPOFUSCIN 223
A2E BIOSYNTHETIC PATHWAYS AND MODULATION OF ITS FORMATION 225
SPECTROSCOPY AND FLUORESCENCE IMAGING 229
AGE-DEPENDENCE AND SPATIAL RELATIONSHIPS 230
PHOTOCHEMISTRY 231
ADVERSE EFFECTS OF LIPOFUSCIN ACCUMULATION 232
CLINICAL IMPLICATIONS OF LIPOFUSCIN ACCUMULATION 234
SUMMARY 235
REFERENCES 235
Genetic Modifiers That Affect Phenotypic Expression of Retinal Diseases 245
INTRODUCTION 245
GENETIC MODIFIERS OF RETINAL DISEASES IN HUMANS 249
GENETIC MODIFIERS OF RETINAL DISEASES IN MICE AND OTHER MODEL ORGANISMS 251
STRATEGIES AND EXAMPLES OF CLONING GENETIC MODIFIERS 254
SUMMARY AND PERSPECTIVES 258
REFERENCES 258
X-Linked Retinal Dystrophies and Microtubular Functions Within the Retina 264
INTRODUCTION 264
CLINICAL MANIFESTATIONS OF XLRP 265
RP3 TYPE X-LINKED RP AND THE RPGR GENE 266
RPGR Function 267
RP2-TYPE XLRP AND THE RP2 GENE 269
ACKNOWLEDGMENTS 271
REFERENCES 271
Synaptic Remodeling in Retinal Degeneration 275
INTRODUCTION: COMMON CONSEQUENTIAL EVENTS OF MUTATION- INDUCED ROD- CONE PHOTORECEPTOR DEGENERATION 275
SYNAPTIC ORGANIZATION IN THE OPL AND SIGNALING PATHWAYS OF MAMMALIAN RETINAS 276
RETINAL DEGENERATION IN THE RHODOPSIN P347L TRANSGENIC PIG 278
ECTOPIC SYNAPTOGENESIS IN RETINA OF RHODOPSIN P347L TRANSGENIC PIG 278
ECTOPIC SYNAPTOGENESIS IS A COMMON CONSEQUENTIAL EVENT IN ANIMAL MODELS OF MUTATION- INDUCED RP Ectopic Synaptogenesis in rd Mice 282
SYNAPTIC REMODELING IN OTHER RETINAL DEGENERATION ANIMAL MODELS AND THE UNDERLYING PRINCIPLES OF SYNAPTIC PARTNERING IN THE RETINA 287
IMPLICATIONS FOR PATHOGENESIS OF LATERAL EXTENSIONS OF ROD BIPOLAR CELL DENDRITES 289
CONCLUDING REMARKS 291
REFERENCES 292
IV DEVELOPING THERAPEUTIC STRATEGIES FOR RETINAL DEGENERATIVE DISEASES 296
On The Suppression of Photoreceptor Cell Death in Retinitis Pigmentosa 297
INTRODUCTION 297
APOPTOSIS On the Mechanism of Apoptosis 301
CALCIUM INVOLVEMENT IN APOPTOSIS 304
OXIDATIVE STRESS INVOLVEMENT IN APOPTOSIS 305
TROPHIC FACTORS AND THE POTENTIAL FOR GENE THERAPY 307
ON THE SIGNIFICANCE OF LIGHT-INDUCED RETINAL APOPTOSIS AS A MODEL OF RP 308
ON THE INFLUENCE OF GENETIC AND ENVIRONMENTAL FACTORS ON PHOTORECEPTOR CELL DEATH 309
MODIFIERS OF RP IN HUMANS 310
MODIFIERS OF RP IN MOUSE MODELS 311
CONCLUSION 312
REFERENCES 312
Cell-Based Therapies to Restrict the Progress of Photoreceptor Degeneration 322
INTRODUCTION 322
ANIMAL MODELS 323
MEASURES OF EFFICACY OF TREATMENT REGIMENS 325
EXPERIMENTAL PROTOCOL 327
DONOR CELLS Freshly Harvested RPE Cells 328
SUMMARY 337
ACKNOWLEDGMENTS 338
REFERENCES 338
Current Status of IPE Transplantation and Its Potential as a Cell- Based Therapy for Age- Related Macular Degeneration and Retinal Dystrophies 348
INTRODUCTION 348
EVIDENCE FOR RPE PROLIFERATION/MIGRATION OF RPE CELLS IN SUBRETINAL SPACE AND FUNCTIONAL RECOVERY Clinical Observations of a Case 349
COMPARISONS OF CHARACTERISTICS OF RPE AND IPE CELLS AND RESULTS OF SIMULTANEOUS SUBMACULAR SURGERY AND CULTURED AUTOLOGOUS IPE TRANSPLANTATION IN EYES WITH AMD 351
CHARACTERISTICS OF NEUROTROPHIC GENE TRANSFECTED IPE CELLS: BASIC STUDIES 359
OUR THERAPEUTIC STRATEGY FOR RETINAL DYSTROPHIES AND AMD 364
ACKNOWLEDGMENTS 364
REFERENCES 364
Recent Results in Retinal Transplantation Give Hope for Restoring Vision 368
ABSTRACT 368
INTRODUCTION Retinal Transplantation: A Hope for Incurable Retinal Diseases 368
CLINICAL TRIALS 372
ANIMAL RESEARCH WITH FETAL SHEET TRANSPLANTS Retinal Degeneration Animal Models Used for Transplantation 375
SUMMARY OF RESEARCH ACCOMPLISHMENTS BUILDING THE BASIS FOR CLINICAL TRIALS 380
FUTURE DIRECTIONS 381
ACKNOWLEDGMENTS 381
REFERENCES 382
Stem Cells and Retinal Transplantation 387
INTRODUCTION 387
RETINAL TRANSPLANTATION: FROM PAST TO PRESENT 388
STEM CELL CHARACTERISTICS 390
RETINAL TRANSPLANTATION OF CNS STEM CELLS 392
CONCLUSIONS 398
REFERENCES 399
Application of Encapsulated Cell Technology for Retinal Degenerative Diseases 402
THE ENCAPSULATED CELL TECHNOLOGY 402
THERAPEUTIC EFFICACY OF THE NT-501 DEVICE FOR PHOTORECEPTOR PROTECTION 404
PHARMACOKINETICS OF NT-501 DELIVERED CNTF 407
POTENTIAL APPLICATION OF ECT FOR OTHER RETINAL DISEASES Neuroprotection in Glaucoma 408
SUMMARY 411
REFERENCES 411
Effective Treatment for the Canine RPE65 Null Mutation, a Hereditary Retinal Dystrophy Comparable to Human Leber’s Congenital Amaurosis 415
INTRODUCTION 415
MATERIALS AND METHODS 418
RESULTS 420
DISCUSSION AND CONCLUSION 427
ACKNOWLEDGMENTS 428
REFERENCES 428
Neuroprotective Factors and Retinal Degenerations 432
INTRODUCTION 432
USING NEUROTRANSMITTERS AND THEIR RECEPTORS TO PROTECT RETINAL GANGLION CELLS FROM GLAUCOMA- ASSOCIATED DEGENERATION 433
STEROIDS AND LIPIDS AS NEUROPROTECTIVE FACTORS FOR RETINAL DEGENERATIONS 434
ANTIOXIDANTS OFFER PROTECTION TO PHOTORECEPTORS: MITOCHONDRIAL UNCOUPLING PROTEINS 435
POLYPEPTIDES THAT PROMOTE SURVIVAL OF NEURONS IN THE CNS 437
NON-NEURONAL RETINAL TARGETS FOR NEUROPROTECTIVE FACTORS 440
DELIVERY OF NEUROPROTECTIVE FACTORS Systemic Delivery 442
SUMMARY AND PROSPECTS 445
REFERENCES 446
Carbonic Anhydrase Inhibitors as a Possible Therapy for RP17, an Autosomal Dominant Retinitis Pigmentosa Associated With the R14W Mutation, Apoptosis, and the Unfolded Protein Response 454
INTRODUCTION 454
DISCUSSION 454
CONCLUSION 457
REFERENCES 457
Macular Degeneration - An Addendum 458
INDEX 462