Retina International
A report from the 2013 ARVO Annual Meeting
Prepared by Elaine R. Richman, Ph.D.
The annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) was held in Seattle, WA, from May 5-9, 2013. More than 10,000 people attended this important international meeting of mostly vision scientists and clinician-researchers. Others in attendance were vision organization leaders, including Retina International President Christina Fasser, and industry representatives.
At each annual ARVO annual meeting, Retina International holds a summit of its scientific advisory board where the experts engage in lively discussion about the basic scientific understanding of retinal disorders and emerging trends in technology and treatment. This year was no exception.
What follows below are reports from the larger ARVO meeting that complement the RI scientific advisory board meeting discussion. Most apply directly to retinitis pigmentosa (RP). o Caution on Valproic Acid for Treating RP
Approximately 2 years ago, valproic acid (VPA) was suggested as a possible therapy for retinitis pigmentosa. Valproic acid is approved by the US Food and Drug Administration for treatment of seizure disorders and a few other neurologic conditions. Based on a retrospective study suggesting a possible slowing of visual acuity loss in patients with RP using VPA, vision researchers and clinicians began to consider prescribing it off-label for treating RP.
Researchers at ARVO 2013 pointed out the possible risk of such use on vision and liver function and recommend discontinuing VPA as an RP therapy until further safety and efficacy data is available.
They came to this recommendation based on a review of patients’ medical charts. They analyzed visual field and visual acuity changes, length of treatment, liver enzymes, and side effects: o The average length of VPA treatment was approximately 10 months. o The researchers found a trend toward a decline in both visual fields and visual acuity, although some patients report seeing less “snow” in their vision. o Over a third of patients experienced negative side effects.
Side effects were typically dose-related, which could possibly be managed with lower dosing if a true treatment effect is observed. Further, a genotype difference may exist, meaning that patients with RP caused by different gene variants may respond to VPA differently. Valproic acid is an histone deacetylase (HDAC) inhibitor and its precise function remains to be determined.
Until further preclinical studies help explain the action of VPA on photoreceptor cells and safety and efficacy data are available, the researchers recommend that VPA as a treatment for RP should be used with caution. Trials are ongoing in South Korea and the US.
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Christine N. Kay, Sheena Bhalla o Visual Function Maintenance Two Years Following UF-021 Therapy for Retinitis
Pigmentosa
Dr. Shuichi Yamamoto and his colleagues reported at ARVO 2013 on visual functioning two years after the conclusion of their 24-week clinical trial of isopropyl unoprostone (UF-021) in Japanese patients with RP. In the original study, patients were randomized to a daily high dose (2 drops/dose; 6 patients), low dose (1 drop/dose; 8 patients), or placebo dose (8 patients) of UF-
021 in eye drop form. The primary endpoint was central retinal sensitivity measured by
Humphrey Field Analyzer (HFA) microperimetry. The researchers found that UF-021 produced a statistically significant improvement in mean retinal sensitivity within the central 2° and 10° field of vision.
Here at ARVO they reported that the high dose group maintained mean retinal sensitivity at 120 months beyond the completion of the original trial, possibly indicating a highly protective effect of UF-021.
UF-021 is approved in the US and Japan for treatment of glaucoma and ocular hypertension. In eye drop form, it has been shown to increase choroidal blood flow; when given by intravitreal injection, it appears to protect photoreceptor cells from light damage; in vivo , it appears to inhibit apoptosis of photoreceptor cells. The researchers suggest that the eye drop form may also be inhibiting apoptosis (cell death).
UF-021 recently received an orphan drug designation in the US and European Union for the treatment of retinitis pigmentosa.
The researchers have launched a Phase III clinical trial in Japan where 300 patients will be randomized to receive a high or placebo dose of UF-021 for 52 weeks. This will be followed by an open-label safety study for an additional 52 weeks. Once again, the primary outcome is central retinal sensitivity measured by HFA.
Yosuke Nakamura, Akira Hagiwara, Ken Kumagai, Shuichi Yamamoto o Ciliary Neurotrophic Factor Delivered by Encapsulated Cell Technology Maintains
Cones but Not Visual Field Sensitivity in RP
Encapsulated cell technology (ECT) is a cell-based ocular implant system developed for delivering a therapeutic agent to the retina continuously. A specially engineered capsule containing proteinproducing cells is inserted into the eye via a single scleral incision. Researchers at ARVO 2013 reported on the outcome of a multicenter Phase clinical 2 study using ECT to deliver ciliary neurotrophic factor (CNTF) to the retina in patients with retinitis pigmentosa. One eye was shamtreated and the other received the protein-eluding implant.
Cone receptor density in predetermined locations was examined using adaptive optics (AO) in three patients at baseline and at select intervals up to 48 months post-implantation. In shamtreated eyes, researchers found that cone density declined by 9% to 24% in eight of nine locations; in CNTF-treated eyes they found that cone density remained stable. However, in studies of visual
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field sensitivity (VFS), treated eyes showed an opposite effect. VFS loss was greater in CNTFtreated eyes starting at 6 months. At 42 months, compared to baseline, VFS loss in CNTF eyes was significantly greater than in sham-treated eyes. Removing the ECT implant slowed the rate of VFS loss.
In a subsequent analysis, the researchers found a relationship between high- and low-dose implants and VFS loss. They plan further studies to determine the effect of dosing on preservation of cone cells and visual field sensitivity.
David G. Birch, Kirsten G. Locke, Travis Porco, Weng Tao, et al. o Depression and Retinitis Pigmentosa
A study in Singapore of 44 people with RP showed a similar rate of depression in the study participants as in the general population. Based on scores on standardized tests for anxiety and depression, only three study subjects were found to have depressive symptoms. The same three scored lowest (<30% range) on the Visual Function Questionnaire (VFQ-25) for assessing the effect of near and distance vision on daily activities and quality of life.
Study participants were recruited from a RP support group, which might have influenced the outcome of the study given that support groups help reduce isolation, a primary contributor to depression. A possible way look at this study is not so much about whether RP is associated with depression but rather that RP support groups help reduce the isolation that many people report is associated with their vision loss.
Augustinus Laude, Tock H. Lim, Adrian Koh, Fulton Wong, et al. o Electroacupuncture and Visual Function In RP
Patients often ask their health care providers about complementary medicine as a substitute or alternative to standard medical practice. Researchers from Johns Hopkins University, Acupuncture
Health Associates, and SUNY College of Optometry reported on their pilot study findings related to the use of electroacupuncture in retinitis pigmentosa.
Electroacupuncture is a form of acupuncture where a gentle electrical current is passed between acupuncture needles. In their study of 12 adults with RP they placed needles above the brow and under the eye (as well as at standard locations on the hands) in 10 half-hour sessions over a two week period. Pre- and post tests included visual acuity, contrast sensitivity, visual fields, dark adaptation, and ocular blood flow.
The researchers reported visual function improvement in eight of the 12 subjects. Three of nine subjects experienced a significant improvement in dark-adapted full-field stimulus testing that lasted several months. Three subjects had improvement in visual acuity. In several patients a significant reduction occurred in resistance in the ophthalmic artery, central retinal artery, and posterior ciliary artery. One-third of subjects reported brighter, crisper visual fields. Several reported seeing better in low light conditions.
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The NIH’s National Center for Complementary and Alternative Medicine (NCCAM) reports effective use of electroacupuncture in treating refractory pain, insomnia, stress, and postoperative pain. Mechanism of action is unknown but the researchers here propose a possible effect related to increased blood flow or possible stem cell stimulation to account for the longlasting effect. The findings suggest a need for additional research to determine efficacy and mechanism of action.
Ava K. Bittner, Jeff Gould, Collin Rozanski, Andy Rosenfarb, et al. o Ocular Inflammation Suggested in RP Pathogenesis
The pathogenesis of retinitis pigmentosa is not well-understood but recent evidence suggests a possible inflammatory component. At ARVO 2013, researchers from the University of Pittsburgh presented evidence of peripheral vascular leakage and cystoid macular edema in eyes of 25 patients with RP, indicative of an inflammatory process (vasculitis).
The researchers examined wide-field photographic and wide-field fluorescein angiography images and macular optical coherence tomography (OCT) scans for signs of vascular leakage and cystoid macular edema in 25 patients. (The analysis was based on a retrospective examination of records.) Peripheral vascular leakage was found in one or both eyes in 15 of the 25 patients.
Cystoid macular edema, a condition associated with vascular leakage, was found in 13 of the 25.
Other researchers have reported increased concentrations of pro-inflammatory proteins in aqueous humor and vitreous fluid of patients with RP compared to controls (N. Yoshida, et al.
Ophthalmology 2013) and anti-retinal antibodies in circulating blood in RP patients with cystoid macular edema (J.R. Heckenlively, et al. AJO, 1999).
Additional research is needed to characterize inflammation in the pathogenesis of RP and to develop possible therapeutic interventions based on ocular inflammation.
Matthew Kaufman, Carlos A. Medina-Mendez, Thomas R. Friberg, Andrew W. Eller o Beyond Fluorescein Angiography to Assess Blood Vessel Integrity in Macular Disease
A frequently used test for detecting fluid and blood leakage from retinal blood vessels is fluorescein angiography (FA). The test involves injecting a fluorescent dye into usually an arm vein followed by retinal photography to detect signs of fluorescein seeping from retinal vessels into the retinal tissue. The test has been standard for many years for diagnosing retinal disorders, following disease progression, and assessing treatment effects. But some patients find fluorescein angiography quite uncomfortable, plus its two-dimension image lacks details that could be helpful in clinical practice and research.
At ARVO 2013, researcher Ruikand (Ricky) Wang, Ph.D., of the University of Washington Eye
Center described a more advanced technology he and his colleagues are developing for viewing retinal blood vessels. It is called ultrahigh sensitive optical microangiography (OMAG) and is
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based on optical coherence technology—an advanced approach for visualizing anatomic structures of the eye—and Doppler technologies. OMAG requires no fluorescein and, as Dr. Wang showed, OMAG provides vastly improved views of blood vessel and in 3D.
This colorized OMAG image from Dr. Ruikand Wang shows tiny blood vessels within three discrete layers of the macula: ganglion cell layer (yellow and cyan), inner plexiform layer (green), and outer plexiform layer (red).
OMAG can be used to measure blood flow through the tiny retina vessels, too, for telling a story not just about retinal blood vessel anatomy but also about retinal physiology. We know that blood vessels transport nutrients to tissues of the body and transport waste products away.
OMAG could prove to be useful for testing the effect of therapies being developed for RP, including retinal prostheses. Eberhart Zrenner and his group, the makers of the Retina Implant AG, from
Tubingen, Germany, have found that subretinal visual implants can cause retinal vascular changes.
OMAG might be useful for addressing whether these changes signify recovery of retinal activity or an adverse effect of the implant. o Photoswitches Turn Retinal Ganglion Cells On and Off
At ARVO 2013, scientists from University of California, Berkeley, and University of Munich described their research using molecules—dubbed photoswitches—to activate retinal ganglion cells (RGCs) and restore light sensitivity to the retina of blind (rd1) mice. RGCs are normally triggered by stimuli received from rod and cone photoreceptors, which themselves are triggered by exposure to light. Axons from retinal ganglion cells travel via the optic nerve to vision centers of the brain where light is interpreted as conscious images.
In 2012, the researchers published an article in the journal Neuron reporting that intravitreal injection of a small synthetic molecule called acrylamide-azobenzene-quaternary ammonium
(AAQ) can restore pupillary light response and light avoidance behavior in mice lacking retinal photoreceptors (A. Polosukhina, et al. Neuron. 2012). AAQ is a K+ channel photoswitch that enables optical control of neuronal excitability. Before AAQ injection, 380 nm light exposure elicited no response in the mice; however, within just a few minutes of AAQ injection, nearly all
RGCs responded. At ARVO, the researchers reported on two additional photoswitches—DENAQ
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and BENAQ—that are triggered by wavelengths within the visible spectrum. Further, the photoswitches persisted for up to several weeks, were well-tolerated, showed indications that they will not interfere with healthy retinal tissue, and elicited physiologic and behavior responses to a light intensity equivalent to ordinary daylight.
The researchers envision photoswitch technology as equivalent in its likelihood of restoring visual function in the absence of photoreceptor cells to optogenetic therapy, stem cell therapy, and retinal chip technology. Advantages may be its ease of application by intravitreal injection rather than by invasive surgery or subretinal injection; its reversibility; and its long-acting potential in an extended release formulation.
Ivan Tochitsky, Aleksandra Polosukhina,, Richard Kramer, et al. o Gains in Stem Cell Research
Researchers are working on cell therapies to replace retinal cells that are defective or have died because of a retinal degenerative disease. One approach is called stem cell therapy. It is being pursued using different types of cells displaying an ability to become almost any type
(pluripotent) of mature cell and to multiple in a laboratory setting in order to produce enough identical cells to be therapeutically effective. Cells types being investigated as potential stem cells for ophthalmic use include human embryonic stem cells, human central nervous system stem cells, umbilical cord stems cells, adult stem cells, and reprogrammed fibroblasts, among others. The goal is to coax these cells into becoming retinal ganglion cells or photoreceptors.
 Scientists from the Jules Stein Eye Institute of the UCLA School of Medicine reported on clinical trials by a company called Advanced Cell Technology (ACT) where retinal pigment epithelial cells derived from human embryonic stem cells are being tested in patients with Stargardt disease and age-related macular degeneration. These are early studies and the results show safety in that the cells do not proliferate dangerously and they produce some improvement in visual acuity.
Steven Schwartz
 Other researchers are testing the feasibility of converting human umbilical cord stems
cells (hCMSC) into retinal cells. Researchers from the US and China have found that hCMSCs grown in the laboratory in a medium enriched with retinal pigment epithelial cells
(RPEs) differentiate into RPE-like or photoreceptor-like cells depending on additional properties of the growth medium. hCMSCs that are cultured in a RPE-N2-conditioned medium develop photoreceptor-like characteristics while those cultured in RPE-fetal bovine serum conditioned medium develop RPE cell-like characteristics including the capacity to clear away cell debris, an important task for maintaining cell health.
Haibin Tian, Peng Li, Li Wang, et al.
 Researchers from New York’s Neural Stem Cell Institute and Mount Sinai School of
Medicine are studying stem cells from eyes of adults who have died. Their work shows that about 3% of RPE cells from adult cadaver eyes are pluripotent and capable of proliferating and differentiating into RPE stem cells (RPESC). The cells are shown to
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express pluripotency markers (e.g., Tra-1-60, Nanog, and SSEA4) and form sheets of RPElike cells. These cells could provide an ongoing supply for studies of the retinal pigment epithelium and drug development.
Barbara Corneo, Timothy Blenkinsop, Patricia Lederman, et al.
 Another type of cell being pursued as a potential stem cell is a reprogrammed fibroblast.
Researchers from the Storm Eye Institute of the Medical College of South Carolina reported results of protein-induced pluripotent stem cells (PiPS) showing that these reprogrammed fibroblasts can become pigmented RPE-like colonies in vitro. The PiPS cells displayed RPE cell-like characteristics including ZO-1, bestrophin, CRALBP, and RPE65 proteins and phagocytosis for clearing away cell debris. The researchers plan to test the viability of the in animal models of retinal degeneration.
Jie Gong, Mark A. Fields, Lucian V. Del Priore
 Researchers who previously showed that human central nervous system stem cells
(HuCNS-SC) transplanted into the subretinal space of rats can help preserve photoreceptors and visual function, reported at ARVO 2013 that the cells do so by carrying out a phagocytotic function. This is similar to findings of others above. In other words, the transplanted cells took on an RPE cell function and removed the debris produced by normal photoreceptor cell renewal. Microscopy showed that (i) HuCNS-SCs preserve photoreceptor cells in the immediate area of cell transplant but not in untreated areas; (ii) that the HuCNS-SCs contained photoreceptor outer segments; and (iii) that the cells form synaptic connections. A Phase I/II clinical trial is underway to test the safety and preliminary efficacy of HuCNS-SC subretinal transplants in subjects with dry AMD. The study is a one year study and will be followed by an additional four years of monitoring.
Alexandra Capela, Laura Fernandez-Sanchez, Raymond Lund, et al.
 Similarly, researchers are studying ways of making photoreceptor cells from a type of cell in the eye called a retinal Müller glial cell. Müller cells provide a support function in the retina. The research, mainly in fish and amphibians, which have a known capacity to regenerate retinal neurons from glia, will help researchers understand the molecular and biochemical pathways involved in reprogramming of glia cells and regeneration of photoreceptors and other neural cells. At ARVO 2013, the researchers reported finding evidence that glia in chickens also show a potential to generate new neurons. This could possibly lead to therapies where a patient’s own retinal Müller cells would be reprogrammed, thereby avoiding potential complications like an immune reaction to cells from an outside source.
Thomas Reh o A dvances in Retinal Prostheses
Several researchers at ARVO 2013 reported on the development of visual prostheses being designed to provide some visual perception to people with RP and ultimately others with severe vision impairment.
Among the prostheses that are furthest along in their development are the Argus II, an epiretinal implant from Second Sight, a California company, and the Alpha-IMS subretinal implant from Retina Implant
AG of Germany.
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In February 2013, the Argus II became the first and only retinal prosthesis to receive FDA approval.
Specifically, it was approved for patients with RP as a humanitarian use device, a category that designates diseases affecting no more than 4,000 people in the U.S. per year. This means that Second
Sight did not have to prove the device's effectiveness but only that its benefits to users outweigh its risks and that no similar prosthesis is commercially available. The prosthesis was previously approved, in
2011, by the European CE, meaning now that clinicians in both the U.S. and the European Union can use the device to treat patients with RP.
People who are fitted with a retinal prosthesis are trained to interpret light picked on by the device as objects (e.g., a doorway, dinner plate, letter on a computer monitor).
Second Sight's report at ARVO suggests that the Argus II improves vision for its users. In the latest study, participants with RP who had received the implant were asked to read letters of varying complexity presented to them on a computer monitor. Seventy-two percent of the subjects could identify the most typographically basic letters, and as many as 52% could read the most complex letters. Those who did best in the letter-reading task moved on to smaller-sized letters, and the four participants who still performed well were tested with two, three, or four letter words. Even then, three participants could read 50% of words, suggesting that the technology is capable of providing enough vision to make everyday activities of life more accessible.
The Argus II includes a video camera mounted on a pair of glasses that captures an image of the visual field. That information is transferred to 60 microelectrodes contained in the epiretinal implant, which then stimulate cells in the retina accordingly. Unfortunately, because of the number of electrodes and the distance between them, the spatial resolution of the captured images is limited. So far, the Argus II has not allowed its users to achieve visual acuity better than 20/1200, which, though an improvement for many patients with RP, does not approach legal vision.
Acuboost™, an add-on to the Argus II described at ARVO 2013, may help compensate for the Argus
II's limits. Acuboost is a high resolution external camera that processes images before transmitting them to the implant. It comes with a wireless, hand-held remote that lets users adjust the range of the device's visual field from 0.4x to 16x that of the Argus II alone. In the study shown at ARVO, a subject was asked to identify the orientations of different gratings of bars. Using the 16x magnification, the user achieved visual acuity of 20/200, the threshold of legal blindness. The subject was also able to read short words with 2.3 cm letters at a distance of 30 cm from the notebook.
Another Argus II addition presented at ARVO was software for a face detection algorithm. The algorithm is designed to process an image only when a face appears in the visual field. In a test of feasibility, Argus II wearers were asked to locate a printed image of a face on a wall three meters away.
They also were put in a face-to-face conversation with another person and asked to report whenever that person turned away. Every Argus II wearer using the algorithm was successful in both tasks. These results and the results of the Acuboost test suggest that the capabilities of the Argus II may far exceed those that users already enjoy.
 Other visual prostheses
The other major visual prosthesis shown at ARVO, the Alpha-IMS from Retinal Implant AG, works differently from the epiretinal Argus II. As a subretinal chip, the Alpha-IMS contains
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1,500 pixels, each connected to a photodiode that analyzes luminance information. The chip stimulates bipolar cells in the visual pathway with electrical pulses varying based on the level of brightness.
The device has been in clinical trials since 2005, and promising reports on its efficacy were published in 2011 and 2013. In the most recent report, light perception, light localization, motion detection, and grating acuity measurement were restored in over 50% of participants. Visual acuity was also restored in two of the participants, one of whom reached a level of 20/546.
At ARVO, researchers discussed not only the device's effectiveness but also the procedure for implanting it. Thirty-six patients worldwide have received the implant, and clinicians want to maximize positive visual results for users while minimizing complications during surgery. An advantage of this device is that the light sensitive chips are the “camera” and so the image is picked up as the eyes scan the visual field.
Other visual prostheses under development include a suprachoroidal electrode array from
Bionic Vision of Australia; a photovoltaic retinal prosthesis from Daniel Palanker and colleagues at Stanford University in California; and another from a company in Paris called
Pixium Vision with its third generation device containing more than 5000 pixels.
This report is a snapshot of the many scientific advances reported at ARVO 2013. Some research will progress to new levels in time for the ARVO 2014 program. Retina International considers it an important part of its mission to bring news of research findings to its many constituents and hopes that we’ve succeeded in providing access to the complex science in a way that leads readers to appreciate the vast amount of work being performed in many different areas of science (basic, preclinical, translational, clinical) and follow the advances as they unfold. A “buzz” arises at every annual ARVO meeting that lets us know what attendees find the most exciting. Here we’ve offered some of the 2013 buzz and look forward to following up next year with additional outcomes from this exciting work.
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This work was prepared for Retina International by Elaine A. Richman, Ph.D., of Richman Associates, LLC, Baltimore, MD,
USA.
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