- •Contents
- •Participants
- •Chair’s introduction
- •Gene therapy of retinal dystrophies: achievements, challenges and prospects
- •Discussion
- •Identifying retinal disease genes: how far have we come, how far do we have to go?
- •Discussion
- •Dominant cone and cone-rod dystrophies: functional analysis of mutations in retGC1 and GCAP1
- •Discussion
- •Isotretinoin treatment inhibits lipofuscin accumulation in a mouse model of recessive Stargardt’s macular degeneration
- •Discussion
- •The expanding roles of ABCA4 and CRB1 in inherited blindness
- •Discussion
- •What should a clinician know to be prepared for the advent of treatment of retinal dystrophies?
- •Discussion
- •Role of subunit assembly in autosomal dominant retinitis pigmentosa linked to mutations in peripherin 2
- •Discussion
- •The search for rod-dependent cone viability factors, secreted factors promoting cone viability
- •Discussion
- •Studies on retinal and retinal pigment epithelial gene expression
- •Discussion
- •From disease genes to cellular pathways: a progress report
- •Discussion
- •Prospects for gene therapy
- •Discussion
- •General discussion I
- •Range of retinal diseases potentially treatable by AAV-vectored gene therapy
- •Discussion
- •Gene therapy for Leber congenital amaurosis
- •Discussion
- •Index of contributors
- •Subject index
Chair’s introduction
Shomi Bhattacharya
Department of Molecular Genetics, Institute of Ophthalmology, 11^43 Bath Street, London EC1V 9EL, UK
In introducing this symposium, I’d like to begin by looking at where we stand in relation to genes and loci associated with retinal dystrophies. Stephen Daiger has a helpful diagram charting the numbers of mapped and cloned retinal disease genes on his website, RetNet (http://www.sph.uth.tmc.edu/RetNet/; see Fig. 1 on page 19).
This graph shows that there are more than 135 genetic loci now mapped for retinal dystrophies, and something in the region of 80 genes that have been cloned and characterized. The types of dystrophies that we are familiar with can be broken down into three broad categories, namely retinitis pigmentosa, cone/ rod dystrophies and macular diseases. We will hear in detail about the clinical aspects from Alan Bird at this meeting. The number of genes that have been associated with retinal dystrophies tells us a lot in relation to how the cell functions and its characteristics, and when there are mutations in these genes how this leads to dysfunction and cell death. How cells are actually killed by mutations is still debatable. Some of the potential therapies that are currently being developed would rely on this critical information about how the cell reacts to the mutation and eventually how it succumbs.
The key issues which face us are in the following four areas. First genetics, because practically all these conditions are inherited so we assume that there is a genetic mutation that results in the phenotype. Clearly, genetics has a major role. Then, if we know the gene, what are the functional consequences of the gene mutation? This can be understood through functional genomics. As you all know, a great deal of work is underway in this area. Third, there is the issue of animal models: when we know the gene, can we generate an animal model to mimic the disease situation? This will be extremely helpful. Of course, the development of animal models would also play an important role in the fourth topic we will be considering, which is developing gene therapy approaches for human patients. I recognize that in relation to therapy there are various possibilities that are being considered at the moment, including self transplantation, pharmacogenomics, or augmenting or removing the faulty gene in the appropriate cell type.
1
2 |
BHATTACHARYA |
Under the ‘heading’ genetics, what are the key issues? Steve Daiger’s compilation shows us 135 loci with retinal pigment genes isolated. I have no doubt that there are still many more genes to identify. Steve will be addressing this in his paper. We will be addressing the extent of genetic heterogeneity, how many more genes remain to be identi¢ed, and then the approaches for novel gene identi¢cation. The proportion of patients with mutations that have been identi¢ed is also an issue. Again, I would like to think that a signi¢cant proportion of patients with retinal dystrophies now know what mutations they have, but clearly there are many patients out there in whom the gene hasn’t been identi¢ed and the mutation is not known.
The human genome has been more-or-less sequenced, and a large number of novel genes have been identi¢ed. We need to know whether a proportion of these genes are expressed in the eye in the appropriate cell types in the retina: some could be appropriate candidates for these types of retinal dystrophies. The contribution of the human genome project to our endeavour needs to be elucidated.
Bioinformatics is a major issue. Now we can do a lot of gene identi¢cation and characterization in silico. This will play a key role in developing our understanding of the retinal dystrophy genes and mutations.
For clinicians and scientists involved in this endeavour, the understanding of the interrelationship of genotype and phenotype will be a key issue. Given the extent of heterogeneity seen in patients, it is important to be able to correlate phenotype and genotype, which will help improve the clinical diagnosis and management of patients.
In functional genomics we will discuss the identi¢cation of novel genes with novel function. The biochemical basis of disease will be discussed later when David Hunt talks about the retGC/GCAP mutation and its role in how the disease might develop. Of course, as we know more about the genes we will understand the biochemical basis of the disease, and this is a key issue. Then on the subject of the progression from genes to cellular pathways there will be papers by Anand Swaroop and Don Zack. These are based on a functional genomics approach. Once again, the key issue in our understanding may develop from this kind of functional genomics work, looking at the progression from genes to cellular pathways. Microarrays will be one of the key items in our discussions. Don Zack and Anand Swaroop will both present data on these. Will observed alterations in gene expression help in our understanding of the disease pathways? I have no doubt that microarray analyses will make a major contribution, telling us a great deal about the disease biology. This same technology will also enable us to identify suitable candidate genes. The most recent success is the cloning of the dominant RP locus on chromosome 7q. This was on the basis of microarray SAGE analysis where candidate genes have been
CHAIR’S INTRODUCTION |
3 |
identi¢ed and one of these genes mapped in the same locus as the 7q dominant RP locus.
A key issue regarding animal models is how we can generate them. Do they truly represent human diseases, and will our understanding of the disease process come from studying these models? Is an animal model necessary for each gene implicated in retinal degeneration? Are there going to be some generic lessons that will help in developing therapy or understanding the disease process?
The ¢nal area is gene therapy. There are other methods that are being developed for therapy, but for this meeting we are concentrating on gene therapy. The key issues here are the choice of vectors, pathogenicity of the vectors and the delivery system. Also, are large animal trials necessary before clinical trials can begin? In this regard we are going to hear a talk from Jean Bennett who will talk about the RP65 dog model. There are clear issues about e⁄cacy and safety. Another question concerns whether some diseases are more amenable to gene therapy. Which disease gene should be the ¢rst target for gene therapy? And what assessment criteria should we use? We need to know whether we have made some objective improvement in the patient, so good criteria are needed for evaluating therapy. Finally, and very importantly, there are issues of consent and ethical approval.
These are the challenges that I see facing us during this meeting. I hope that we will ¢nd answers to many of these questions and raise other important issues for future investigation.