Retinal Dystrophies: Functional Genomics to Gene Therapy (Novartis Foundation Symposium 255)

Retinal dystrophies are the major causes of incurable blindness in the Western world. Our insight into their aetiology has improved remarkably over the past decade and a number of key genes have been identified. Together with a more detailed understanding of disease processes, this knowledge is stimulating new approaches to therapeutic strategies involving gene therapy, growth factors and retinal cell transplantation. Molecular genetic studies have provided detailed information on the pathogenesis of retinal dystrophies. An important proof of principle that gene therapy holds great promise for the treatment of these conditions was demonstrated in the rds mouse: introduction of a functional copy of the peripherin gene subretinally resulted in complete rescue of rod outer segment structure. Novel approaches are being developed based on the manipulation of biochemical pathways that previously were not considered relevant to these diseases. For example, renewed interest in retinal dystrophy pathogenesis led to the successful use of high dose vitamin A treatment in Sorsby fundus dystrophy. This important new book covers all aspects of retinal dystrophies from the molecular and developmental biology of these disorders to possible therapeutic approaches, with special reference to gene therapy. Specific chapters deal with the molecular genetics of gene therapies, clinical genetic studies, molecular and cellular mechanisms of the development of the disease, functional genomics of retinal diseases, animal models of retinal dystrophies, and finally with studies on gene therapeutic approaches to correcting the disorder. With contributions by many of the leading researchers worldwide, this book is likely to be an important milestone in this rapidly developing field.

Retinal dystrophies are the major causes of incurable blindness in the Western world.Our insight into their aetiology has improved remarkably over the past decade and a number of key genes have been identified. Together with a more detailed understanding of disease processes, this knowledge is stimulating new approaches to therapeutic strategies involving gene therapy, growth factors and retinal cell transplantation.

Molecular genetic studies have provided detailed information on the pathogenesis of retinal dystrophies.An important proof of principle that gene therapy holds great promise for the treatment of these conditions was demonstrated in the rds mouse: introduction of a functional copy of the peripherin gene subretinally resulted in complete rescue of rod outer segment structure. Novel approaches are being developed based on the manipulation of biochemical pathways that previously were not considered relevant to these diseases.For example, renewed interest in retinal dystrophy pathogenesis led to the successful use of high dose vitamin A treatment in Sorsby fundus dystrophy.

This important new book covers all aspects of retinal dystrophies from the molecular and developmental biology of these disorders to possible therapeutic approaches, with special reference to gene therapy. Specific chapters deal with the molecular genetics of gene therapies, clinical genetic studies, molecular and cellular mechanisms of the development of the disease, functional genomics of retinal diseases, animal models of retinal dystrophies, and finally with studies on gene therapeutic approaches to correcting the disorder. With contributions by many of the leading researchers worldwide, this book is likely to be an important milestone in this rapidly developing field.

RETINAL DYSTROPHIES: FUNCTIONAL GENOMICS TO GENE THERAPY......Page 3 Contents......Page 7 Participants......Page 9 Chair’s introduction......Page 13 Gene therapy of retinal dystrophies: achievements, challenges and prospects......Page 16 Discussion......Page 24 Identifying retinal disease genes: how far have we come, how far do we have to go?......Page 29 Discussion......Page 39 Dominant cone and cone-rod dystrophies: functional analysis of mutations in retGC1 and GCAP1......Page 49 Discussion......Page 61 Isotretinoin treatment inhibits lipofuscin accumulation in a mouse model of recessive Stargardt’s macular degeneration......Page 63 Discussion......Page 75 The expanding roles of ABCA4 and CRB1 in inherited blindness......Page 80 Discussion......Page 91 What should a clinician know to be prepared for the advent of treatment of retinal dystrophies?......Page 97 Discussion......Page 102 Role of subunit assembly in autosomal dominant retinitis pigmentosa linked to mutations in peripherin 2......Page 107 Discussion......Page 125 The search for rod-dependent cone viability factors, secreted factors promoting cone viability......Page 129 Discussion......Page 139 Studies on retinal and retinal pigment epithelial gene expression......Page 143 Discussion......Page 157 From disease genes to cellular pathways: a progress report......Page 159 Discussion......Page 172 Prospects for gene therapy......Page 177 Discussion......Page 185 General discussion I......Page 189 Range of retinal diseases potentially treatable by AAV-vectored gene therapy......Page 191 Discussion......Page 200 Gene therapy for Leber congenital amaurosis......Page 207 Discussion......Page 214 Index of contributors......Page 220 Subject index......Page 222 Covers all aspects of retinal dystrophies from the molecular and developmental biology of these disorders to possible therapeutic approaches, with special reference to gene therapy. Specific chapters deal with the molecular genetics of gene therapies, clinical genetic studies, molecular and cellular mechanisms of the development of the disease, functional genomics of retinal diseases, animal models of retinal dystrophies and studies on gene therapy approaches to correcting the disorder.