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Dispatches from ARVO 2014, Day 4 - Between Prevention and Cure: Life Support for a Dying Cell

May 8, 2014

by Jennifer Phillips, Ph.D.

Preventing or slowing the rate of retinal cell degeneration in the various forms of RP has been a well-covered topic at the past few ARVO meetings, and this year is no exception. Following are some summaries of the main factors being explored for the role of retinal neuroprotection:

Valproic Acid If you’ve been reading this blog for longer than a year, you know that Valproic Acid (VPA) and I have a long and not-so-illustrious history. The published data as of ARVO 2013 (detailed in the link) suggests that while VPA might have some protective effect (usually assessed by visual field testing) in some RP patients, it has a neutral or damaging effect in others. The affected gene, and even the exact mutation in the same gene, make a huge difference in the type of effect VPA will have on an RP patient.

This year I saw two reports that were characteristic of the state of the VPA research to date. The first was from a research group in Kobe, Japan who conducted a trial where 29 RP patients between 30 and 70 years of age were put on the same dose of VPA for 6 months. The genetic causes of the RP weren’t disclosed, but they ranged from autosomal dominant (5 patients), autosomal recessive (11), and ‘sporadic’ (13), meaning that the family history didn’t point to any particular inheritance pattern for the disease. In other words, a heterogeneous group, with no control group. The researchers reported small but measurable improvements in the visual fields for all patients, although the data presented did not allow for independent analysis of this finding. Hopefully the peer-reviewed publication, when it appears, will contain the raw numbers, but the work I’ve seen thus far was not overwhelmingly convincing, especially in light of the inconsistent and conflicting studies reported previously.

The second report did not involve human subjects, but instead used four different frog models of RP, each with a different mutation in the rhodopsin gene, which encodes the light-sensitive protein in rod photoreceptors. Each of these mutations is also found in humans with Autosomal Dominant RP, and all involve amino acid substitutions that cause the rhodopsin protein to misfold (see yesterday’s post for a bit more on that whole business). These researchers, from the University of British Columbia, found that rod degeneration in one mutant decreased with VPA treatment, but that degeneration was accelerated in the other three mutants. Remember, again, these are four different mutations in the same gene. All cause protein folding problems. We heard about the same thing last year when mouse models of two different mutations in the same gene had opposite responses to VPA treatment. So what’s the difference between these mutations? No one knows. It may have something to do with the exact way that the cell’s misfolded protein detection and disposal system deals with the bad products, but at this point we don’t have a specific hypothesis for how VPA behaves inside a photoreceptor at all, let alone how that behavior might have different consequences for cell survival depending upon the genetic background. From a scientific point of view it’s an interesting question, but I feel I should point out again that no USH patients have taken part in any of these reported studies, so we have zero information on what kinds of responses (yes, I’m using the plural on purpose) we might see in retinas that have problems due to Usher gene mutations.

TUDCA We first heard about this a few years ago when Mark attended the Usher Symposium in Valencia, Spain. This compound (tauroursodeoxycholic acid, for those of you playing Jargon Bingo at home) first came on the scene half a dozen years ago or so, and was originally isolated from bear bile. It had been noted anecdotally that the compound seemed to improve visual function, and indeed, in many cases it has been shown to preserve cell viability in several animal models of retinal degeneration and also in retinal cell cultures. In fact, two presentations I saw using retinal cell cultures had used TUDCA not as the main focus of their experiment but as a means of countering the toxic effect of the particular gene therapy they were trying to test. Like VPA, the effect of TUDCA is variable depending on the mutation in question. Unlike VPA, there has not yet been a report of accelerated cell death with TUDCA treatment, only a lack of effect in some cases. TUDCA is currently not FDA approved, but I talked to a few people about what it would take to make that happen, and there may be enough experimental and clinical interest to begin that process in the near future. Again, no testing of the effects of TUDCA specifically on Usher syndrome patients has been reported.

DHA The omega-3 fatty acid Docosahexaenoic acid (Bingo!!!) has been on our radar for a while as a molecule that is clearly important for retinal and brain health. DHA is highly enriched in retina, brain and a few other tissues, and lower than normal levels of DHA in those tissues have been correlated with the presence of degenerative disease. Thus, it is characterized as a neuroprotective substance.

Researchers at the University of Texas Southwest Medical Center reported on a clinical trial for X-linked Retinitis Pigmentosa patients. This was an impressively well designed trial. The researchers followed a control group and a group treated with high doses of DHA for the full four years. Each group had close to thirty patients to start, and although a few dropped out along the way, they still had over 20 per group to follow for the duration of the study, which was four years. The average patient age was 15 (placebo) or 16 (DHA treatment) at the start of the trial. In addition to monitoring changes in vision, the researchers also tested the levels of DHA in the blood and confirmed that it remained steady throughout the four years of testing. The dosage was determined based on the preclinical and phase I clinical trials that preceded this study, and it was really a large amount to consume as a supplement, although it was still a bit lower than what the researchers wanted. The researchers reported on a number of clinical tests tracked over the four years of the study, and unfortunately concluded that overall there was no significant difference between the patients taking DHA and those taking a placebo. The presenter suggested that the blood levels of DHA might not have been sufficient to see an effect, in spite of the very large dose these patients were consuming. Another observation was that the neuroprotective effects of DHA are often perceived when it is consumed with other compounds in fish oil, rather than as an isolated molecule, so recapitulating this combination in future trials may be necessary. The presenter noted that he tended to advise his patients, especially teens, to focus on a healthy diet rather than supplementation, as the benefits of these isolated supplements have been generally unimpressive in clinical trials.

Tomorrow is the last day of the ARVO meeting, but I’ve got one more story to tell and it’s a good one.

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