- •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
General discussion I
Farber: Earlier I was talking to Paul Sieving and he described some interesting data on treating patients with Accutane (isotretinoin). Paul, could you describe these?
Sieving: Yes. We have tried an Accutane experiment with two subjects, to learn whether we could alter the rate of rhodopsin regeneration as measured by dark adaptation time course. Once we had found that in rodents that treatment with cis-retinoic acid was slowing rhodopsin degeneration, we tried this in people using dark adaptation psychophysics and also in monkeys by recording the electroretinogram (ERG). While I cannot be positive that we performed the experiment correctly in the two subjects, we did not ¢nd an e¡ect on dark adaptation after 5 mg/kg Accutane. The only e¡ect was that both subjects acquired substantial headaches that persisted for a couple of days. In the case of the monkeys, I believe that we did do the experiment correctly, as we applied the same technique as we had developed for mouse and rat. With 5 mg/kg subcutaneous dose in monkey, we did not observe any perceptible slowing of ERG recovery following a bleaching light exposure that could be attributed to a rhodopsin cycling e¡ect.
I am curious whether this might work for Stargardt’s: I would like to think it would. We had found that slowing of retinoid cycling and rhodopsin regeneration diminished the extent of retinal damage from acute light exposure in rats. We also studied the e¡ect on retinal degeneration in the RCS rat and in Matt LaVail’s Pro23 rhodopsin rat, but we did not see a generalized protection in either case that extended beyond light-damage protection. We then thought that other genetic models in which rhodopsin cycling was critical might be appropriate targets, such as Abcr4. With Gabe Travis there are now preliminary data that look really hopeful on this model.
We were also curious about whether Accutane was the only retinoid compound that had an e¡ect on retinoid cycling. Part of our motivation was that we were in the process of ¢ling a patent application at the University of Michigan for this idea in 2000. We tried a large range of retinoid analogues, and we found that many of them had a comparable e¡ect on the ERG recovery from bleaching light, which was interpreted as a slowing of rhodopsin regeneration and retinoid cycling. Does the e¡ect of retinal light compounds extend beyond Accutane alone? Does anyone know of other diseases that might involve retinoid cycling?
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GENERAL DISCUSSION I |
Bok: Certainly, RPE65 mutation is an example where reduced retinoid can be bene¢cial under certain circumstances. The C2J mouse is an example where less retinoid can be better.
Sieving: Has the Abcr4 mutant been crossed onto one of these backgrounds? Bok: Gabriel Travis has looked at his Abcr4 knockouts in the context of whether
C2J is present or not.
Travis: We moved it onto an albino background, and we wanted to make sure we had the so-called wild-type RPE65, the sensitizing mutation. We do.
Thompson: Another disease involving retinoid cycling would be retinal degeneration resulting from mutations in the LRAT gene. Mutations in LRAT would be expected to result in decreased levels of 11-cis-retinal, as in the case of mutations in RPE65. On the other hand, Jack Saari suggested to me that LRAT mutations might also result in high concentrations of free vitamin A in the retina and retinal pigment epithelium (RPE), and that this could produce toxic e¡ects. This is what he felt he was seeing in his own work with the CRBP knockout mouse. If it does turn out that absence of 11-cis-retinal is the main problem resulting from LRAT mutations, then strategies that work for RPE65 mutations may work equally well for patients with mutations in LRAT. However, mutations in LRAT appear to occur with much lower frequency than mutations in RPE65, and therefore the number of LRAT patients available for treatment could be low.
Bird: We talked to dermatologists and they took the view that it would be bad to give Accutane to people over a long period, just because of the side e¡ects. Will the other compounds known to interfere with vitamin A metabolism inevitably have the same side e¡ects?
Sieving: I do not have an answer for that.
Bird: I would say that any condition where there is elevated auto£uorescence at the level of the pigment epithelium might conceivably be a disorder that would bene¢t from such an approach. This would include Stargardt disease, the cone dystrophies, the macular disorders associated with retinitis pigmentosa (RP), and even geographic atrophy with ageing. In all of these there is increased auto£uorescence that accompanies cell death. It might have a much wider application than Stargardt disease.