RetinaReview A newsletter from the Wilmer Eye Institute at Johns Hopkins Fall 2014 Bright Spot on Geographic Atrophy Map

ver 200,000 people worsening can be different among in the U.S. each year individuals, in a preliminary, develop the “wet” or company-conducted study of this Oneovascular form of agent known as lampalizumab AMD in which growth factors (Roche/Genentech), investigators cause scar tissue to replace the found that this agent, compared center of the retina, the light- with no treatment, slowed visual sensitive tissue lining the inside loss more often than might be back of the eye. Unlike their wet expected by chance variation AMD counterparts, whose vision Dr. Bressler, left, and Dr. Campochiaro among individuals. “The average loss often can be stopped with deterioration that occurred in the periodic injections of anti-growth involving over 300 sites worldwide people who received the injection factor agents into the middle including Johns Hopkins University, of the anti-complement factor, cavity of the eye, patients with investigators at Wilmer are taking their loss of tissue, was slower than geographic atrophy, the “dry” form part in a landmark trial with a in those who got no treatment at of AMD associated with vision loss, treatment that appears promising all,” Dr. Bressler says. “However, traditionally have been left without for slowing the worsening of the study was not designed to be any treatment options. geographic atrophy. definitive, and it’s still possible that With geographic atrophy, patients “One of theories behind the the difference noted was due to may lose vision when abnormal degeneration is that it’s related to an chance alone.” yellowish material, termed drusen, inflammatory pathway in the body Now, Wilmer investigators accumulates below the center of known as the complement pathway,” are collaborating with Roche/ the retina for years if not decades, Dr. Bressler says. So, the hope is Genentech on a definitive study to ultimately causing the overlying that an anti-complement factor, determine if the lampalizumab is retina to disintegrate. Since retina injected periodically into the middle really effective and safe to warrant tissue does not replace itself once cavity of the eye might slow down its use as part of standard care for lost, dry AMD can cause irreversible this rate of atrophy, he explains. this dry form of AMD. The study blank spots in the vision to While the pace of atrophy will also tap the expertise of, Peter interfere with reading, driving, and Campochiaro, MD, the George S. recognizing faces. and Dolores Dor Eccles Professor This blinding condition can Investigators at of Ophthalmology, who will be cause substantial vision loss for at Wilmer are taking the principal investigator of the least 20,000 additional people each part in a landmark trial clinical site at Wilmer, one of the year, according to Neil Bressler, with a treatment that sites worldwide participating in the MD, the James P. Gills Professor appears promising for study. of Ophthalmology and Chief of After the lampalizumab has been slowing the worsening the Retina Division. Now, with injected into the eye, much of it of geographic atrophy. Dr. Bressler chairing the Executive may be gone in about 30 days. It Advisory Committee of two studies (continued on page 4)

Eye Tumors May Hold a Key to Fluid Treatment Boundaries for Conquering Retinal INSIDE 2 Better Understanding Cancer 3 Central Serous Chorioretinopathy 6 Degeneration 1 Eye Tumors May Hold a Key to Better Understanding Cancer

Each year, patients travel from eye, we do not have good therapies,” she says, adding all over the world to be treated at that better adjuvant therapies for individuals with high Wilmer for vision-threatening and risk uveal melanoma are needed. In recent years, many life-threatening forms of eye cancer. centers have implemented adjuvant treatment trials. “I Mary Beth Aronow, MD, Assistant would like to see Johns Hopkins be among these,” Dr. Professor of Ophthalmology, has Aronow says. been interested in the field of Retinoblastoma is the most common primary ophthalmic oncology since attending intraocular tumor in children. Johns Hopkins is one of medical school at Yale University. “The eye is one of just a few institutions worldwide that offers intra-arterial the only places where you can see a tumor in its near chemotherapy, a highly localized form of treatment, to entirety,” she says. “This provides a unique opportunity children with this to visualize tumors as they are responding to therapy.” life-threatening Eye tumors are an excellent model for studying the condition. Dr. clinical behavior of cancer and for developing improved Aronow is pleased treatment strategies for patients. to have access to Dr. Aronow came to Wilmer from the Cleveland this approach. With Clinic where she trained in ophthalmic oncology and excellent available most recently from the National Eye Institute, National therapies, nearly all Institutes of Health, where she pursued fellowship children in the US training in medical retina. with retinoblastoma At Wilmer, Dr. Aronow is treating the spectrum survive and retain of intraocular tumors. She has instituted a research good vision in many Choroidal melanoma with n program to advance our understanding of uveal characteristic orange pigment and cases. melanoma. “Once this tumor metastasizes outside of the subretinal fluid.

Dry AMD under the Microscope oxidative stress magnifies the Handa says. If this Nrf2 system fails, immune response and leads to too great an immune response may macular deterioration. “When there’s create some tissue damage. too much oxidative stress in the eye So, he is trying to determine or in other areas of the body, the where in the cell the damage is immune response converts from a arising by comparing tissue damage protective one to being overactive,” in genetically-modified mice with Dr. Handa says. Or, this response Nrf2 to those without this. After can fail altogether, causing tissue exposing the mice to a cigarette- injury and leading to macular smoke stressor, he will determine if degeneration, he explains. macular degeneration is magnified Also, he is examining how the when the Nrf2 system is failing While there’s currently no way to Nrf2 system, which is a factor in our and test whether some drugs can head off dry AMD, a common cells (a “transcription” factor) that rejuvenate the system. cause of blindness in Western protects cells and in this case turns In other work, he is considering cultures, James T. Handa, MD, on a system of antioxidant genes, whether complement, which is Robert Bond Welch Professor of may be involved. “In our macular part of the immune system, when Ophthalmology, is hard at work degeneration samples, as well as in genetically impaired, may be trying to understand how the disease our animal model, we find that the contributing to AMD. Complement- develops. Nrf2 response gets blunted with too factor H is known to help regulate His team is studying how much oxygen or with aging,” Dr. (continued on back page)

2 Home-field Advantage Found for Monitoring Patients with AMD

or those over age 50, the by the process of “wet” or choroidal neovascular randomization, like a form of age-related macular flip of the coin, were Fdegeneration is the leading asked to use the device cause of blindness throughout daily in conjunction with most of the developed world. If traditional monocular this disease is left untreated, the vision function testing, vast majority of eyes will become such as use of an Amsler legally blind. Yet, when appropriate grid, while the other treatment is given, vision can be half used traditional maintained at the presenting level in testing alone. Both 90% of cases for at least several years, groups also received with about 30% of these patients pre-scheduled office visits even able to improve somewhat from to monitor for AMD the level of vision at which they progression following present to the eye doctor. the usual practice A patient is pleased with the ease of monitoring her “Since we have a therapy that recommendations own vision from home using the ForeseeHome device can maintain vision in 90% of of their individual (pictured with Dr. Susan Bressler, left). people affected by neovascular physician. (wet) AMD, the critical issue shifts “When study participants home device, a substantial difference. to early diagnosis of this aspect developed wet macular degeneration, Dr. Bressler terms this difference of the disease,” stresses Susan B. the event, worsening of their AMD, clinically meaningful since the Bressler, MD, the Julia G. Levy appeared to be picked up earlier device allowed most patients to PhD Professor of Ophthalmology at if they were using the device plus maintain vision of 20/40 or better Wilmer. standard care as compared to at the time their neovascular AMD Dr. Bressler has been one of the standard care alone,” Dr. Bressler was diagnosed, a level that is not leaders in a clinical trial evaluating says. Those assigned to the device associated with driving restrictions the efficacy of a home monitoring group had a median loss of 4 letters and is consistent with the absence of strategy that uses the ForeseeHome on the eye chart when their AMD any substantial visual impairment. (Notal Vision, Inc.) device, which progressed to the neovascular phase With prompt initiation of wet AMD was developed with initial tests as compared with a median loss of treatment in these eyes, there is a at Wilmer several years ago to try 9 letters for those individuals using high probability these patients will to identify when eyes with AMD traditional monitoring without the avoid meaningful compromise in have progressed to wet macular their everyday life functions. degeneration as early as possible. Dr. Bressler views the results here This device can monitor the “This is the only home as having great import. “This is central field of vision in each monitoring system the only home monitoring system patient’s eyes and transmit these that really has been that really has been demonstrated results via tele-monitoring to a demonstrated to to make a difference in picking up remote monitoring center. Regular make a difference in neovascular AMD early,” she says. test results are monitored for picking up neovascular The ForeseeHome system is already changes that may signify the start AMD early.” FDA-approved and Dr. Bressler is of wet AMD. In a recent study of hopeful that it ultimately will be the ForeseeHome strategy, half covered by all medical insurance of the trial participants chosen companies. n

5 Fluid Treatment Boundaries for Central Serous Chorioretinopathy

Deciding when to treating these patients. provides blood vessel support to initiate treatment Catherine B. Meyerle, the rods and cones, but the retinal for patients with MD, Assistant Professor of pigment epithelium, a layer of cells central serous Ophthalmology at Wilmer, is now supporting the rods and cones, plays chorioretinopathy investigating the ideal timing of an important role too, she points is a vexing photodynamic therapy (PDT) here. out. “Treatment designed to promote issue. With PDT targets the increased choroidal better retinal pigment epithelial this condition, hyper-permeability that can allow function also might be valuable,” she subretinal fluid collects and stresses fluid to collect, she explains. The says. the photoreceptor cells, the rods original PDT parameters were In Dr. Meyerle’s view, central and cones, in the retina lining the adapted from studies in age-related serous chorioretinopathy remains inside back of the eye and which are macular degeneration. “There undertreated. In 30% to 50% of critical to creating the image which have been multiple central serous cases, fluid recurs and may lead we see. Patients typically have some chorioretinopathy studies refining to damage with every episode, decreased visual acuity. But even these parameters, looking at reduced she points out. “While patient’s when this is not compromised, they dose and reduced fluence. However, visual acuity may be reasonable on may experience distortion and have the ideal time to treat is still not standard testing with a high contrast reduced retinal sensitivity making known,” Dr. Meyerle says. “Perhaps eye chart, I think these people have dark objects look somewhat faded earlier intervention would be more issues with sensitivity to subtle or gray. Indeed, some such eyes have appropriate for these people.” changes in contrast and distortion been shown to have decreased cone Dr. Meyerle is also looking into of vision, where images have a wavy density. Since most episodes resolve possible new treatments. Most novel appearance,” she says. “I think within 6 months, the standard care treatments today focus on targeting earlier intervention would help these is to wait up to 6 months before the choroid, the layer of tissue that patients.” n

Part of the new crowd: Christopher J. Brady For Christopher J. Brady, MD, a With this, he explains, individuals do small Internet- new face on the Wilmer faculty as of based tasks for minimal compensation, making it August 1st, but returning to Hopkins affordable to communities world-wide to have screening where he received his M.D. degree, for damage to the retina from diabetes. the idea of bringing the wisdom of Dr. Brady started out by recruiting 10 anonymous many to interpretation of potential people per selected fundus photograph to render diabetic retinopathy fundus photos their interpretation and compared this to an expert’s is appealing. Dr. Brady, who recently findings. “People did much better than I expected,” he finished his retina fellowship including state-of-the- says. “If they made a mistake, typically it was that they art retinal surgical training at Wills Eye Hospital in overestimated level of retinopathy.” Later, with a larger, Philadelphia, worked on a pilot telemedicine project more subtle data set, the crowd still reliably detected there involving “crowdsourcing.” This screening project higher levels of disease, but did struggle with more is one he hopes to expand on at the two clinics where subtle diabetic retinopathy cases. His work already has he will be working, Wilmer within the Johns Hopkins been recognized as award-winning research within the Hospital and the Wilmer Bethesda satellite office. specialty society of retina physicians in the U.S. and The premise of his research is to try to figure out published in the peer-reviewed literature. within mass public screening whether it’s possible to Now at Wilmer, Dr. Brady would like to broaden the decentralize the interpretation of photographs of the scope of this work. He hopes to get access to additional retina, the light-sensitive tissue of the back of the eye, data sets which allow him to try out this approach and harness the power of many through the Internet. on real patients (continued on back page)

3 Sights on New Diabetic Treatment Target

For patients with diabetic eye inducible factor (HIF), a transcriptional enhancer disease, the threat of blindness is activated by low oxygen, which raises the levels of ever present. However, research “HIF-target” genes. “One of those genes is VEGF and being conducted by Akrit Sodhi, this unfortunately has some negative consequences MD, PhD, Assistant Professor of in the retina including the growth of leaky blood Ophthalmology, seeks to change vessels that promotes both macular edema and also this. One of the major focuses of neovascularization,” Dr. Sodhi explains. Dr. Sodhi’s work at the Wilmer Eye Likewise, Dr. Sodhi’s group has shown that Institute is on looking for novel treatment targets for increased expression of ANGPTL4 can have similar patients with diabetic eye disease. consequences. Dr. Sodhi theorizes that the reason Already he has helped identify an important new that many diabetic patients don’t respond adequately gene known as Angiopoietin-like 4 (ANGPTL4). Dr. to anti-VEGF treatment alone may be because Sodhi and fellow investigators are honing in on this ANGPTL4 also plays an important role in diabetic eye factor, which is increased in diabetic ocular conditions. disease. “We’re currently looking at the possibility of inhibiting Dr. Sodhi and fellow investigators are studying other this target to treat both diabetic macular edema and factors as well, looking for potential new diagnostic diabetic retinopathy,” Dr. Sodhi says. and treatment approaches revolving around HIF, and Findings have shown that expression of the considering potential therapies to block these new ANGPTL4 gene increases for the same reason targets. “Our hope is that this will allow for more safe that VEGF (Vascular Endothelial Growth Factor) and effective treatment of patients with diabetic eye becomes elevated. Both are increased by the hypoxia- disease,” Dr. Sodhi concludes. n

Bright spot continued from page 1 currently is unknown how long the same effect from the drug. Some now we have a hint that complement anti-complement factor needs to be who have a variation in the gene is involved. Then on top of that given. So, to determine how often for complement factor I may we have data from an early phase this agent might be needed, in the be predisposed to damage from trial that has provided the first definitive trial, some patients will geographic atrophy, he points proof of concept in humans that receive the drug every 4 weeks, while out. “Such people may be more suppressing the complement pathway others will get this every six weeks susceptible to complement-induced with Lampalizumab may slow instead, he explains. If both intervals damage, including disease processes progression,” Dr. Campochiaro says. are found to work, even longer like AMD where complement may “All of this makes us quite excited periods between injections might be be involved in the death of RPE about this trial, which I think offers warranted in future studies. cells,” he says. Such patients might the first glimmer of hope for patients Besides potentially confirming be more likely to benefit from who have geographic atrophy.” the preliminary results seen in the injections of Lampalizumab. To recently completed preliminary investigate this hypothesis, patients Those at Wilmer interested in trial, investigators at Wilmer and will be have testing to determine participating in the geographic elsewhere also will look at other whether they have variations in the atrophy study can contact Dr. parameters such as the impact of the complement factor I gene. Campochiaro ([email protected]) treatment on reading, Dr. Bressler While patients are just beginning or Dr. Gulnar Hafiz (ghafiz@jhmi. notes. to be recruited, Dr. Campochiaro edu), head coordinator of many Dr. Campochiaro emphasizes is already optimistic. “For so long retina clinical trials in the Retina that not all patients may get the we haven’t had any treatment and Division. n

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Conquering Retinal Degeneration Dry AMD continued from page 2 the strength of the immune Retinal is excited to join forces of one of the response. However, Dr. Handa degeneration largest groups in this field of clinical hypothesizes that impairment of from retinitis care and research. 2 regulators, which control the pigmentosa to Dr. Scholl is looking forward activity of complement, may be Stargardt disease to this as well. He says the pair is needed before the system becomes and more, slated to work on several ground- overactive. Using mice with genetic threatens the sight breaking trials. “One will be the first mutations, he is testing whether of millions of gene therapy at Wilmer for retinal impairing other complement vulnerable patients around the world. degeneration called the StarGen regulators with cigarette smoke may The Wilmer Eye Institute is now project,” Dr. Scholl says. This will cause something that looks like welcoming back Syed Mahmood entail treatment for Stargardt disease macular degeneration. Shah, MD, who will be working while a second trial, UshStat, will If his results substantiate this, together with Hendrik Scholl, MD, focus on Usher syndrome. “So, prevention may come down to the Dr. Frieda Derdeyn Bambas we would establish gene therapy trying to reduce the oxidative-stress Professor of Ophthalmology, to help at Wilmer to treat those two load. Also, if there are found to be tackle such conditions. Dr. Shah conditions,” Dr. Scholl says. “Another multiple complement regulators is not new to Wilmer and started program that we are working on impaired in AMD, this would give his career here as part of pioneering together is the first pharmacotherapy investigators a better idea what to research on developing anti-VEGF for Stargardt disease.” target for treatment involving the treatment for both age-related Meanwhile, Dr. Shah notes that complement system. n macular degeneration and diabetic the pair will also be focusing on macular edema. developing outcome measures to He has now returned to help look detect the progression of diseases New Crowd continued from page 3 for answers on the genetic aspects which will allow investigators to being screened and more. “I’d like of retinal degeneration. “I believe evaluate efficacy of new treatments in to figure out how I can teach the the genes hold the key to not only the shortest possible time. Ultimately, crowd new things and ask them the origins of the diseases but the Dr. Shah is also excited about honing new questions,” he says, adding treatments as well,” Dr. Shah says. in on treatment here, which he is that from there he hopes to find a During his fellowship, he had the hopeful can one day be tailored to way to garner FDA approval in this opportunity to work with Dr. Scholl individual patients based on their uncharted territory. n who he describes as a foremost expert genetic profile. n on retinal degeneration, and now he