NEWSLETTER AN UPDATE ON THE NATURAL HISTORY OBSERVATION AND REGISTRY (NHOR) STUDY AND MACTEL PROJECTS

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1 Martin Friedlander, MD, PhD, President, LMRI NEWSLETTER AN UPDATE ON THE NATURAL HISTORY OBSERVATION AND REGISTRY (NHOR) STUDY AND MACTEL PROJECTS Editor: Jennifer Trombley A MESSAGE FROM THE PRESIDENT Production: Marti Lynn Moon The Annual MacTel Meeting was held in New York City in May. This meeting brings together our benefactors, the Lowy Family, and nearly 80 investigators from the United States, Europe, Australia and Asia to discuss current projects and plan our next steps. These interactions also include young investigators who help us think critically, foster creativity and help integrate this next generation of investigators into the project. The meeting spans two days of high intensity scientific and clinical presentations that stimulate extensive discussions during question and answer periods after each lecture as well as during the meals and breaks. This year was particularly stimulating as we heard about the convergence of two entirely independent studies, one in metabolism and the other in genetics, onto a pathway involving specific amino acids which are the building blocks of proteins and other components of cells in our bodies. This work was recently published in the journal Nature Genetics, which has the highest impact factor in the field and not only provides insight into potential underlying causes of MacTel, but also gives us direction for areas to explore that may lead to new therapeutic approaches. The other tremendously exciting work we heard about were the official results of the Phase 2 clinical trial done at 11 US and Australian sites in collaboration with our partner, Neurotech. In this trial (more detailed discussion is found on page 3 in a column by Neurotech s Chief Medical Officer) we observed that the rate of disease progression, as measured by clinical imaging, could be significantly reduced in eyes treated with a factor that serves to protect photoreceptors from injury and death. We also observed maintenance of 1

2 visual function, as assessed by reading speed in treated patients when compared to untreated patients who experience significant decrease in their reading speed. The results were clinically and statistically significant and have formed the basis of our decision to go ahead with a Phase 3 clinical trial in which many more patients will be enrolled to determine whether or not the results we have observed in the Phase 2 trial can be replicated. If so, we may be able to offer a treatment for this disease. Many other exciting studies were presented and discussed and several of these are discussed below by LMRI staff scientists and collaborating scientists from other institutions. We are fortunate to have so many committed patients, clinicians, scientists, staff and sponsors; without any one of these groups we would not be able to do the work we do and we are very grateful for their efforts and support. We are particularly grateful to the Lowy family, without whose firm and continuing financial and emotional support of the MacTel/LMRI project, we would never have been able to accomplish what we have in finding a treatment and cure for MacTel. The next year promises to be just as exciting as the previous one and, hopefully, will bring us closer to understanding and finding a treatment for MacTel. NHOR REGISTRY UPDATE Jennifer Trombley, RN, MSN, Director of Global Clinical Projects, LMRI The Natural History Observation Study began in 2005 with a handful of study sites. The mission was to investigate the disorder of Macular Telangiectasia Type 2 in order to uncover the cause, define and standardize characteristics for ease of diagnosis and to explore possible preventions, treatments and/or cures. Initially, we studied people with MacTel over time, their family members who may or may not have the disorder and controls (not related and did not have MacTel). The study design has evolved over the years and currently participants are now seen one time at a study site and then contacted yearly, usually by telephone. This visit is to check on your overall state of health and make sure we have your current contact information so we can notify you of important, new information or inform you of up-coming trials that you may want to participate in. Today, the NHOR study has over 1100 active participants (affected with MacTel). There are now 25 clinics worldwide enrolling participants and new sites are added frequently. Your continued participation in this project is invaluable to us and we certainly appreciate your time, travel and cooperation. Feel free to contact us if you have any questions or information that we may find useful. And please continue with your annual phone call follow-ups. 2

3 NATURAL HISTORY OBSERVATION AND REGISTRY SITES - NHOR SITE LOCATION SITE LOCATION USA SITES Jules Stein Eye Institute (UCLA) Los Angeles, California Flaum Eye Institute Rochester, New York, USA (University of Rochester) Vitreous, Retina, Macula Consultants of New York New York City, New York Medical College of Wisconsin Milwaukee, Wisconsin, USA Retina Associates of Cleveland Cleveland, Ohio NON-US SITES Scripps Health La Jolla, California Centre for Eye Research Melbourne, Australia The New York Eye and Ear Infirmary New York City, New Hopital Lariboisiere Paris, France York The Retina Group of Washington Fairfax, Virginia Lions Eye Institute Perth, Australia Kellogg Eye Institute (University of Ann Arbor, Michigan Moorfields Eye Hospital London, UK Michigan) Scheie Eye Institute Philadelphia, Save Sight Institute Sydney, Australia Pennsylvania Moran Eye Center (University of Utah) Salt Lake City, Utah St. Franziskus Hospital Muenster, Germany Bascom Palmer Eye Institute Miami, Florida The Goldschleger Eye Tel Aviv, Israel (University of Miami) Institute Massachusetts Eye and Ear Boston, Massachusetts University of Bonn Bonn, Germany Emory University Atlanta, Georgia Oxford Eye Hospital Oxford, UK University of California at San Francisco San Francisco, California For site contact information: Call or contact us via the website CLINICAL TRIALS Charles Johnson, MD, Chief Medical Officer, Neurotech Announcement of positive data from the Phase 2 Neurotech/LMRI study of NT501 was made at this year s meeting of the MacTel/LMRI Project in New York. NT-501, is a small capsule of cells that is placed inside the eye to allow the release of CNTF directly to the retina, the light sensitive part of the eye. CNTF is a growth factor that occurs naturally in humans. It protects nerve cells, like the rods and cones and promotes their survival in disease. The loss of functional rods and cones is the cause of visual disturbance for patients with MacTel. Previously, in a Phase 1 Study, the NT-501 was implanted in 7 participants with MacTel Type 2, who were followed for 5 years with no safety issues noted. In the Phase 2 study, carried out at 8 US sites and 3 Australian sites, 67 patients with MacTel were assigned to receive either the implant or a sham procedure. About half of the patients contributed a single eye to the study and 31 contributed two eyes so that one eye had the implant and the other was the control. Since the rate of progression is quite slow when compared to other diseases the patients were observed for two years. At the end of two years it was clear that the eyes which received the implant had slowing of their disease progression by about 30% compared to the control eyes. 3

4 As we expected there was no change in vision as measured by the letter chart. At the end of two years, the control and treated eyes were no different in terms of number of letters seen on the standard eye chart. The most surprising results were from the reading test. The results from this study suggest that reading speed, measured in words read per minute, can be stabilized by treatment with NT501. The reading test is performed on each eye independently with the other eye closed or masked. In the eyes which received the implant, reading speed was unchanged over the two years of the study. In the untreated control eye, reading speed deteriorated by an average of 13 words per minute. The only noticeable side effect was a smaller pupil in the treated eye. For some, it could make adjusting to the dark a little harder. However, the presence of this condition lets us know the implant is still working. Next Steps: The patients who participated in the Phase 1 & 2 studies will be followed yearly for the next 4 years. We are now in the planning stages of a Phase 3 study which will be conducted in the US, Europe and Australia. If these larger studies confirm the exciting results of the Phase 2 study, the LMRI/Neurotech team believes that a treatment for MacTel may become generally available in a few more years. Please contact your study doctor if you are interested in participating in the Phase 3 or other up-coming trials. GENETIC STUDIES Mike Dorrell, PhD, Senior Staff Scientist, LMRI We continue to collect blood from both MacTel patients and from unaffected family members (for use as comparisons). Although we have found that there is no single gene that causes MacTel, there does appear to be a genetic component, meaning it is observed more in families than in the general public. Recently, work from both the genetic analyses, as well as from other clinical and laboratory studies, have helped steer our research focus to more closely examine serine and glycine metabolism as a potential contributor to MacTel (more information below). This is a major breakthrough and potentially represents an important step forward in understanding factors that may influence MacTel. As these leads are investigated in the lab, and further genetic information is obtained, the factors that contribute to MacTel will continue to become clearer. Hopefully new knowledge continues to bring us closer to new and better treatment options. 4

5 LABORATORY RESEARCH-METABALOMICS Mari Ganter, PhD, Staff Scientist, LMRI Several laboratories around the world are conducting basic experiments searching for possible causes of MacTel Type 2. Genetic findings suggest that the metabolism (production and usage) of serine and glycine may be altered in MacTel patients. We also found that, on average, MacTel patients have slightly lower levels of serine and glycine in their blood compared to people without MacTel. These clues have directed us to study the role of serine and glycine in retinal health. Serine and glycine are two of the amino acids used to build proteins in the body, but they also contribute to building other essential cellular components, such as cell membranes, DNA and RNA. Therefore, serine and glycine are important metabolites for every cell in the body. We are currently testing how the retina uses serine and glycine and what impact changing the levels of these amino acids has on retinal health and vision. We are also using stem cells derived from MacTel patients to discover if there is something different about serine and glycine metabolism in MacTel patient cells compared to cells from unaffected people. It is too early to recommend for or against increasing the amount of serine and/or glycine enriched foods or supplements. For more on the importance of stem cells in MacTel research, please see the Stem Cell section below. LMRI LABORATORY-STEM CELLS Kevin Eade, PhD, Staff Scientist, LMRI Recent technological advancements have allowed us to generate stem cells directly from individual patients using cells from their blood or skin. These cells, which have been converted into stem cells, are called Induced Stem Cells (ipscs). From a patient s own ipsc we can make all of the cells of the retina in the lab allowing us to create a Disease in a Dish. 5

6 With this powerful technique we can potentially determine the cause of MacTel in patients and develop therapies that are proven to work directly in human tissues. We are currently testing retinal cells that we have made from patients to see if there are differences at the cellular level that could lead to the development of MacTel in the retina. Future plans will be to test various therapies on these patient retinal cells to determine the best way to correct these cellular differences and, ultimately, the progression of MacTel. ADVANCED IMAGING PROJECTS Mina Chung, MD, Associate Professor, Department of Ophthalmology, University of Rochester School of Medicine and Dentistry Adaptive optics (AO) imaging technology enables high-resolution microscopic visualization of a person s retina. Using AO we are able to identify the cone photoreceptor cells, which are essential for visual perception, inside a person s eye. In patients affected with MacTel, AO imaging has shown that early in the disease process, the density of the cone cells is reduced. Also, in certain cases AO has demonstrated reversible changes in the cone reflectance, giving us hope that there may be potential for improvement in these early cone changes. Each AO imaging session generates a substantial dataset of cone density information. There are three AO sites in the Unites States that work together on the MacTel/LMRI Project. They are the University of Rochester (New York) Flaum Eye Institute, The Eye Institutes at the Medical College of Wisconsin (Milwaukee) and The University of California at Berkeley. We have developed standardized imaging protocols, and identified key metrics so that we can pool data across sites. Other clinical sites outside the US also have AO labs. In addition to imaging participants in the MacTel Registry, we have also looked at participants in the CNTF implant Phase 1 and Phase 2 trials for the CNTF implant. Our goal is to measure the cone cells in the treated and untreated eyes and monitor their progress over time. Because MacTel is a relatively rare condition, applying AO technology in the clinical trial setting can help to detect potential therapeutic effects in a small number of patients. ON PROGRAM 6

7 PATIENT PERSPECTIVES As many of you might understand, one of our participants felt terribly lost when he was diagnosed with MacTel and began his search for information. He also began documenting his journey. That led to a book which is being published and is expected to be released this fall. Unfortunately, specific details are not available but check the LMRI website, as we will post the information as soon as it is known ( The author, Pete Kellett PhD, attended the MacTel meeting in May and was able to share some details of what it is like to live with MacTel. The personalization of the disorder provides even more incentive for the investigators to find the cause, treatments and even a cure for this condition. And the clinicians can pass on tips to their patients. From left to right Pete Kellett, Dr. Mali Okada, Katie Litts, and Pete s wife, Hema Naidu. That s Dr. Charles Johnson photobombing. EYE DONATION PROGRAM Lea Scheppke PhD, Director of Scientific Programs and Outreach, LMRI Eye donation is critical to MacTel research. The Lowy Medical Research Institute has established an eye donation program for people with MacTel who have died. Eyes received through the Lowy Medical Research Institute s donor program are very special, and are used for specific research purposes. These eyes come with a wealth of information because the MacTel Project has archived pictures of participants retinas, medical information, and vision tests. Scientists can study the retina at a cellular level and compare what they observe to the detailed medical history that was captured through the MacTel Project. This provides an unparalleled opportunity to understand the disease. To become an eye donor, please speak with your Ophthalmologist or MacTel Project Coordinator, or visit our website 7

8 . Lea Scheppke PhD, Director of Scientific Programs and Outreach, LMRI A diagnosis of Macular Telangiectasia type 2 (MacTel) can bring up a lot of questions and emotions for patients and their family members. Finding answers is not always easy, especially because MacTel is a rare disease. In an effort to provide more information about the disease from both a clinical perspective and a patient s perspective, the Lowy Medical Research Institute updated the organization s website in The website is a MacTel-specific resource for patients and clinicians designed to offer reliable information about the disease. Here you can learn more about the diagnosis and what other people with MacTel experience in their daily lives. You can also learn about the history of the MacTel Project and opportunities to participate in clinical research beyond the registry. We encourage you to share your experience with MacTel through the LMRI website. If you are willing to be interviewed, or if you would like to recommend a patient to be interviewed, please contact us at info@lmri.net. To learn more about the Lowy Medical Research Institute and MacTel, please visit our website at: From: LMRI WEBSITE/CONTACT To: NEWSLETTER TABLE OF CONTENTS A MESSAGE FROM THE PRESIDENT. 1 NHOR REGISTRY UPDATE.. 2 CLINICAL TRIALS.. 3 GENETIC STUDIES LAB RESEARCH-METABOLOMICS 5 LMRI LABORATORY-STEM CELLS. 5 ADVANCED IMAGING PROJECTS. 6 PATIENT PERSPECTIVES EYE DONATION PROGRAM. 7 LMRI WEBSITE/CONTACT. 8 8