Despite a tremendous increase in the research efforts and progress to find treatments and cures for hereditary retinal degenerations, therapeutic options able to restore significantly vision remain to date limited. But the scenario is changing.
Alessandro Iannaccone, MD, MS, Director of the Retinal Degenerations and Ophthalmic Genetics Service and Associate Professor of Ophthalmology at the Hamilton Eye Institute of the University of Tennessee Health Science Center (UTHSC), was invited by Lancet to comment, alongside with Dr. Marco Zarbin, MD, PhD, FARVO, Professor and Chair of the Department of Ophthalmology at the Rutgers-New Jersey Medical School, on a recent Phase 1B clinical trial of a special form of retinal degeneration due to a specific enzymatic defect in the retina that reflects this changing scenario.
Dr. Iannaccone, who also serves on the Scientific Advisory Board of Foundation fighting Blindness (FFB) and is the President of the FFB Mid-South chapter of Memphis, was asked to comment on a new approach to treating Leber congenital amaurosis (LCA) with mutations in either the RPE65 or the LRAT genes. LCA is a very early onset form of a condition known better as retinitis pigmentosa (RP). These forms of LCA are characterized by enzymatic defects that cause early-onset severe visual loss and nystagmus due to a deficiency of the vitamin A metabolite, 11-cis-retinal, in photoreceptors. The 11-cis-retinal molecule is the so-called “chromophore” of the rod visual pigment, rhodopsin. “When the retina does not receive enough 11-cis-retinal or cannot recycle effectively the one it has, our night vision is greatly incapacitated”, commented Iannaccone. “In the case of these forms of LCA, the protein portion of the visual pigment, called opsin, can reach normally the outer segment of the photoreceptor, but the cells cannot use it because it is not complexed with enough 11-cis-retinal to form the actual visual pigment, rhodopsin, and night vision is very poor despite only limited degeneration of the photoreceptors themselves. The at least partial structural integrity of photoreceptors in these forms of LCA is behind the success that gene therapy has also had in the RPE65-linked form of LCA”. Patients from the UTHSC Retinal Degenerations and Ophthalmic Genetics Service at the Hamilton Eye Institute have been successful participants in such trial.
Now a pharmacological approach to bypassing the enzymatic defects in these forms of LCA has been devised and tested in a human Phase 1B trial. An orally administered synthetic retinoid, 9-cis-retinyl acetate, was used to provide an alternate form of the chromophore to photoreceptors and tested to assess its safety and its preliminary efficacy. The results have been very encouraging. “This trial is extremely encouraging and points to a rapidly changing scenario in the development of therapeutic approaches for RP, LCA and related diseases.”
But some notes of caution are warranted. “Interpreting Phase 1B clinical trials that are not designed to assess efficacy can prove tricky, so we need to be careful not to overstate the results of this otherwise very promising study,” remarked Iannaccone. “This is especially important when a largely pediatric population is treated, and visual function testing is performed on children. Some of the tests of visual function one needs to use to assess efficacy can be particularly variable, especially in children, whose attention span and comprehension of the test can be limited and can increase significantly during the trial. In these specific forms of LCA in which there is an enzymatic deficiency in the retina precluding proper provision of 11-cis-retinal to photoreceptors, there is also a very delayed ability to adapt to changes in lighting conditions. This too can impact greatly our ability to measure correctly changes in visual function in these patients, and potentially confound the outcome of such trials. Emphasis is usually placed on letting patients adjust to darkness for long enough, but not as much emphasis is placed on letting them adjust long enough to light.”
Dr. Iannaccone highlighted this important issue in the Lancet editorial, showing how increasing durations of light adaptation before running a visual field test can impact dramatically the size of a patient’s visual field and the quality of the vision measured within it. “We have to be extremely careful at controlling as precisely as possible these variables. The last thing anyone wants to do is to claim huge therapeutic successes when, in fact, the perceived benefits may have been due, at least in part, to a poorly controlled confounding variable as essential as the time spent adjusting to the light of the testing instrument before running the test. This is not as critical in normal subjects, but in patients with retinal degenerations, and especially in these specific LCA patients, it is essential.” Dr. Iannaccone noted how, in his experience, this issue is often seen in RP patients in his clinic, and especially in patients with another unique related disorder, known as choroideremia. “Since 9-cis-retinyl acetate carries also a potential risk for a neuro-ophthalmological complication known as pseudotumor cerebri, it is especially important that claims of efficacy for this treatment be made with a great deal of caution.”
There is still much appeal for treatments that can provide across-the-board help for these patients. Although hereditary retinal degenerations as a whole are estimated to affect only one in 3,500 to 4,000 people and fall in the category of the orphan diseases, there are over 200 genes that can cause these conditions. This is a huge genetic heterogeneity for such rare diseases. Thus, broad-spectrum, non-specific treatments that can favorably impact these conditions remain essential to treat these diseases. But to cure them,” remarked Iannaccone, “we now understand that a molecularly driven and genetically specific approach may be indispensable, and this Phase 1B trial with 9-cis-retinyl acetate is an excellent example of that. This is the fruit of bed-to-bench-to-bed translational research at its best, and represents the future of retinal degenerations therapeutics.” Trials and studies that Dr. Iannaccone is presently involved with at the Hamilton Eye Institute fall in the same conceptual framework. “I am very excited about the latest developments in this field. The first gene for RP was cloned just in 1990, and we have come a very long way in a short time. I have been working in this field for nearly 25 years, and the fruit of hard, at times unrewarding, work are truly coming to fruition now. It comes as no surprise to me that the National Eye Institute has also identified finding treatments and cures for retinal degenerations as one of its top programmatic priorities, and it is great to be at the forefront of this field.”
The link to the Lancet editorial in question can be found at: