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Minutes of the 2009 Meeting of the Scientific and Medical Advisory Board of Retina International Date: Monday, 4 May 2009 Venue: ARVO annual meeting, Ft. Lauderdale, FL USA Attendees: President: Ms. Christina Fasser SMAB co-chairman: Drs. Eberhart Zrenner and Joe Hollyfield SMAB Secretary: Dr. Jerry Chader Invited Speakers: Dr. Jean Bennett Dr. Emily Chew Dr. Mark Humayun Dr. Daniel Martin Dr. Javier Romero Dr. Bernhard Weber Dr. Eberhart Zrenner Other Invited Participants: Dr. Robin Ali Dr. Sten Andriasson Dr. A. Ciccodicola Dr. Francoise Assimasopoulos Dr. To Chi-ho Dr. Patrick Corley Dr. A. T. Moore Dr. Ragnheiour Bragadottir Dr. Nicolas Cuenca Dr. John Flannery Dr. Andreas Gal Dr. Fredrik Ghosh Dr. Christian Grimm Dr. Elise Heon Mr. Tom Hoglund Dr. Peter Humphries Dr. Artur Cideciyan Dr. Frans Cremers Dr. Nathan Mata Dr. Weng Tao (Ms. K. Dickinson) Dr. Theo van Veen Dr. Scott Whitcup Dr. Ruth Reese Dr. Birgit Lorenz Dr. Jean-Michel Rozer Dr. Jose Sahel Dr. Mike Michaelides Dr. Diane Sharp Dr. Andrea Vincent Dr. Francis Munier Dr. Isabelle Pinilla Dr. Markus Preisig Dr. F. Javier Romero Dr. Sirkka-Liisa Rudanko Dr. Eeva-Marja Sankila Dr. Daniel Schorderet Dr. Paul Sieving Dr. Santa Tumminia Dr. Marian Humphries Dr. Reetta Jalkanen Dr. Josselyn Kaplan Dr. Caroline Klaver Dr. Matthew LaVail Dr. Elizabeth Mc Kennen Dr. Robert Molday Dr. Erica Strettoi Dr. Bart Leroy Dr. Miltiadis Tsilimbaris Dr. Alan Laties Dr. Eric Pierce Dr. Anthony Moore Agenda Items A) Introduction Ms. Fasser opened the meeting with a hearty greeting to all the participants and thanks to all the speakers. After some other opening remarks, she turned over the meeting to Drs. Zrenner and Hollyfield to begin the scientific presentations. B) Scientific Program Clinical Trials Note: Specifics about most clinical trials can be found at “clinicaltrials.gov” on your computer search engine Gene Replacement Clinical Trials UPenn Trial on LCA- RPE65 Gene Therapy – Dr. A. Cideciyan, University of Pennsylvania, Philadelphia, PA USA Preclinical studies on gene replacement therapy in animal models of Leber Congenital Amaurosis (LCA) were very successful. Specifically, the RPE65 gene was replaced in these cases using an AAV viral vector with excellent safety and efficacy that has restored a measure of sight in animals for a number of years. Based on this work, a Phase I clinical trial began in 2007 in LCA subjects with the RPE65 mutation with the approval of the FDA and support of the National Institutes of Health. The trial is led by Dr. Samuel Jacobson at the University of Pennsylvania in Philadelphia where the patients are first entered into the trial and examined before and after surgery. Surgery and gene-vector production occurs at the University of Florida under the leadership of Drs. William Hauswirth and Barry Bryne. Dr. Artur Cideciyan gave an update on this trial. The primary outcome of the trial is safety; secondary outcomes include changes in vision. The trial was initially planned for 3 cohorts (groups) of patients, each with three individual subjects, The first cohort consisted of 3 young adults between 21 and 24 years of age. These patients received subretinal injections of the AAV2 vector with the normal RPE65 gene. The results available through the first 90 days post-treatment have been published and were encouraging. In terms of safety, there were no vector-related Serious Adverse Events (SAEs) and no systemic toxicities. All patients selfreported and increase in visual sensitivity in their treated study eye compared with their control eye. This was especially noticeable under reduced ambient light conditions. Using a full-field stimulus test under dark-adapted conditions, the study eye showed significant sensitivity increases. Specialized methods of vision testing corroborated that there were significant improvements in sensitivity localized to the area of treatment in the injected eye. The gene therapy procedure improved both day vision originating in cone photoreceptors as well as night vision originating in rod photoreceptors of the LCA patients. Day vision could be improved up to 50fold and night vision up to 63,000-fold compared to pretreatment levels. Dr. Cideciyan stated that the first cohort of patients has passed the 1-year time point and continue to do well. Specifically, there are no vector-related serious adverse events and the intervention appears to be safe. Based on the positive results in the first cohort, the Data Safety and Monitoring Committee has allowed the study to continue to the second cohort which includes adults injected with a higher dose of vector and to the third cohort which includes children. CHOP Trial on LCA- RPE65 Gene Therapy – Dr. J. Bennett, University of Pennsylvania, Philadelphia, PA USA Dr. Bennet reported that at the Children’s Hospital of Philadelphia (CHOP) as well as in Naples, Italy and Ghent, Belgium, work continues on investigating the effects of RPE65 gene replacement in LCA subjects. The first subject received a single unilateral subretinal injection of AAV2.hRPE65v2 in October of 2007 and, since that time, 10 additional individuals have been enrolled and received injections. Baseline testing, surgery and follow-up testing are carried out at CHOP. CLIA testing for the RPE65 mutation was done by Dr. E. Stone at the Univ. of Iowa. The first 3 subjects enrolled (Naples, Italy) are young adults (19-26 yrs at the time of injection) and are now 15 months post-injection. They continue to do well as to both safety and efficacy. Duplicate baseline testing is now done at CHOP and in Naples serving to generate a robust data set. Individuals enrolled over the last year include 4 children. All have recovered visual function with improvement in their nystagmus. They are reading without aids. The upper age limit (72 yr) was eliminated in the protocol since a therapeutic effect was observed in the 26 yr old individuals in the first cohort. The oldest individual enrolled to date is 44 yr old. All the juvenile and adult subjects are doing well. Two of these patients are from Ghent, Belgium so a third follow-up site is planned for this location. In conclusion, Dr. Bennett said that the program in on target and the patients are happy with the results – all asking to have their second eye injected. Question: Are there plans for gene therapy in other RD diseases Answer (Dr. Bennett): Yes, we have a list of others such as Stargardt and Usher but funding is needed.. Question: was improvement in nystagmus observed in the other 2 clinical trials? Answer (Drs. Cideciyan and Dr. Ali): No improvement was noted. Retina Prosthesis Clinical Trials Subretinal Implant - Retina Implant AG – Dr. Eberhart Zrenner, University of Tuebingen, Tuebingen, Germany Dr. Zrenner reported on progress in the clinical study of the SUBRET consortium. In the current studies, subretinal implants were placed near the macula using a transchoroidal approach in 11 patients. The electronic array is 3 x 3 mm in size and carries 1500 photodiodes, amplifiers and electrodes. It is powered by a subdermal cable. Dr. Zrenner stated that, using this device, “Proof of Principle” has been established in that blind RP patients could recognize unknown objects. From data obtained from the most recently implanted 3 patients, it can be concluded that the active subretinal multielectrode implants with currents close to recognition threshold (10 and 27 nC/electrode) produce retinotopically correct patters.Stripe patterns of moderate luminance can be resolved by the implanted patients up to 0.35 cycles/deg. Visual acuity measured by use of Landolt rings reached levels of 1/50. VA = 20/2000. Standard tests include object recognition (e.g., apple vs. banana) and letter recognition (4 cm height at 40 cm distance) presented on a table in front of the subject. Dr. Zrenner concluded that, again, he considers this as Proof of Principle that light-sensitive subretinal multi-electrode devices are suited for restoration of useful visual percepts in blind patients. He noted that this is the first time worldwidr that such high resolution has been achieved by an implant in blind persons. This experience and calculations by various groups indicate that at least 1000 electrodes are needed to achieve spatial resolution of this kind. He added though that any prosthesis-mediated vision is yet very limited and further technical developments and clinical studies will be necessary to arrive at a device that will allow for such recognition abilities in daily living for blind RP patients. Epiretinal Implant - Second Sight Medical Products (SSMP): Dr. Mark Humayun, USC School of Medicine, Los Angeles, CA USA Dr. Humayun and his collaborators including SSMP have taken an epiretinal approach to implantation of their prosthetic array, i.e., on the vitreal side of the retina juxtaposed to retinal ganglion cells. Phase 1 of an FDA-approved clinical trial with 6 patients has been completed (2002-2004) although patient testing continues. This device, the Argus I, had 16 electrodes in the retinal array. More recently, an Investigational Device Exemption (IDE) has been obtained from the US FDA to continue the implant studies using a 60 electrode array (Argus II). To date, over 20subjects have been implanted at 8 centers around the world. All subjects had bare light perception or worse due to advanced Retinitis Pigmentosa. The average age of the subjects is 60 + 9 years. Currently, the age limitation for enrollment has been dropped to age 25. Surgically, the Argus II electronics were sutured episcleraly and a vitrectomy was performed. Then, the electrode array was inserted through the pars plana and tacked to the retina in the macular region. To date in this ongoing trial, the safety of the device has been acceptable. Most of the adverse events occurred around the time of surgery, i.e., within one month of the procedure. All resolved and/or were successfully treated by the end of 6 months. There were no device failures and no explants. Concerning efficacy, all of the subjects can now perceive phosphenes. Significant improvement has also been seen in spatial localization, motion detection, orientation and mobility as well as in other specialized tasks. A logMAR value of 2.2 has been determined in one of the subjects. All subjects have been able to take the Argus II system (including glasses and battery-operated video processing unit) home for use outside the clinic. Question: What are the target groups of patients? Answer (Dr. Zrenner): Currently, all groups apply such devices in patients with hereditary retinal degenerations. Others disease conditions could be considered but only after safety and efficacy are established for the electronic retinal prostheses. Antioxidant Clinical Trials Age-Related Eye Disease Study 2 (AREDS2) – Dr. Emily Chew, National Eye Institute, NIH, Bethesda, MD USA With the successful conclusion of AREDS1, the AREDS 2 study is now designed to see if a modified combination of vitamins, minerals and fish oil can further slow the course of AMD. AREDS2 is designed to evaluate the usefulness of omega-3 long chain polyunsaturated fatty acids (PUFAs) and lutein in the treatment of AMD and cataract. The study will also examine the effects of the elimination of beta-carotene from the AREDS1 supplement and decreasing the dose of zinc on the treatment of AMD. Lutein and zeaxanthin are yellow pigments derived from plant sources that accumulate near the macula of the retina and are thought to provide antioxidant protection to the central retina. Fatty acids such as DHA and EPA are derived from fish oils and are also thought to have antioxidant properties. As of September of 2008, the study had enrolled 4,203 participants of ages 50 to 85 in 82 clinical centers both at academic institutions and at community practices. The dietary supplements are taken by mouth. They include a tablet containing 10 mg lutein and 2 mg zeaxanthin as well as 2 soft-gel capsules containing the DHA and EPA. In addition, all participants are offered the possibility of being randomized into treatment with the original AREDS formulation (“standard of care”) and 3 variations of this formula. These are 1) no beta-carotene 2) lower zinc content and 2) no beta-carotene and lower zinc. The primary goal (outcome) of the study will be to determine if the formulation changes the progression to advanced AMD in patients at moderate to high risk for progression. Secondary outcomes include progression to moderate vision loss, the occurrence of adverse events, progression of lens opacities and the effect of the supplements on cognitive function and cardiovascular health.. Dr Chew said that she and her coworkers plan to have 5 years of follow-up in the trial on the ocular effects of the supplements. In collaboration with other NIH institutes, effects on both cognitive function and cardiovascular function will also be carefully examined. Question: Do you still recommend beta-carotene? Answer (Dr. Chew): There is a very good risk:benefit ratio with beta-carotene in persons who are not currently smoking. We found no increased mortality in participants randomly assigned to antioxidant vitamins, including beta-carotene. Moreover, there is actually reduced mortality seen with zinc supplementation although this is yet a question with lutein. RetinaComplex Clinical Study in Retinitis Pigmentosa Patients – Drs. Javier Romero and Theo van Veen, University CEU Cardenal Herrera and Mediterranean Ophthalmology Foundation, Valencia, Spain and University of Tuebingen, Tuebingen, Germany Previous work by Prof. van Veen established the efficacy of using a combination of potent antioxidants called RetinaComplex in slowing the progression of retinal degeneration in animal models of RP. Please see the minutes from last year’s SMAB meeting for a position paper by Retina International on safety and efficacy issues in such use. In the absence of Dr. Romero, Professor van Veen described the current clinical study. This is a hospital-based prospective, randomized double-blind clinical study with an appropriate control group being performed in Valencia, Spain. The first 12 months of the study have now been concluded with a total of 44 subjects with Retinitis Pigmentosa. 23 subjects received RetinaComplex and 21 subjects received placebo for 12 months. Written consent was obtained from the participants after they were given a reasonable explanation of the study details. A complete history of each participant with respect to age, gender, clinical symptoms, etc. was collected using a questionnaire. Blood samples are collected to check for 1) glycosylated hemoglobin (a marker for metabolic control and possible diabetes) 2) zinc and vitamin E (to check for possible patient selfsupplementation) and 3) malondialdehyde (a lipid peroxidation product that is a marker for oxidative stress).The fundus of each participant was exampled with an ophthalmoscope and macular OCT performed. Miltifocal ERG as well as other functional studies such as automated perimetry was performed and a general health evaluation questionnaire was obtained. All these baseline parameters are being compared with the same parameters obtained after 12 month RetinaComplex intake using appropriate statistical analysis. From the intermediate data collected so far, no difference could be established between paired data, except for the amplitude of the multifocal erg. The placebo group showed a statistical difference between the data collected at the beginning of the study and the end of the first 12 month period. Of importance though, the patients receiving RetinaComplex showed no statistically significant difference between the two sets of data. This confirmsthat there is a slower progression of disease in the treated subjects compared with those getting only placebo. Although this study was initially planned for only 1 year, the promising results obtained makes it worthwhile to continue the study for a longer period if proper funding can be obtained. The results of the first two years of the study will be available in autumn of this year. Neuroprotection Clinical Trials Brimonidine Study – Dr. S. Whitcup, Allergan Inc. Irvine, CA USA Brimonidine is an alpha-2 agonist that is approved for use in lowering Intraocular Pressure (IOP) in patients with glaucoma and ocular hypertension. It has also been shown to be neuroprotective in animal models of glaucoma and retinal disease. Dr. Whitcup reported that, this year at the ARVO meeting, investigators have shown that brimonidine, delivered in a bioerodable intravitreal sustained-release implant enhances visual-evoked responses in preclinical studies. In these studies, normal rabbits were used to study the effect of the drug on sweep Visually Evoked Potential (sVEP). Animal were given doses of 66 ug, 200 ug or 600 ug in the left eye with the right eye receiving placebo. With different concentrations of brimonidine, statistical differences were observed in acuities compared with baseline with high statistical significance. No abnormalities were observed in retinal histology in the treated eye as well no abnormalities detected with color fundus photography. Currently, intravitreal sustained-release brimonidine implants are being studied in clinical trials on patients with retinal disease including atrophic AMD and Retinitis Pigmentosa. The trial is sponsored by Allergan, Inc. Two different concentrations of the drug are being studied. For the AMD trial, the primary outcome is a change from baseline in size of geographic atrophy on stereoscopic color fundus photography and with fluoroscein angiograqphy. CNTF-ECT Clinical Trials – Ms. Kathleen Dickinson – Neurotech, Lincoln, RI USA CNTF is a natural compound found in the body that helps to protect neuronal cells from damage, hence is a “neuron-survival” and “neurotrophic” agent. It has been shown to slow the course of retinal degeneration in a number of RD animal models. A problem with neurotrophic agents though is in the method of delivery to the retina. However, Neurotech has devised an ingenious capsule that is implanted within the vitreous cavity of the eye that delivers a sustained and safe dose of CNTF to the retina. This is called “Encapsulated Cell Technology” or NT-501-ECT. Preclinical experiments were successful using this device, showing relative safety as well as efficacy. Phase I of an FDA-approved trial also has successfully been completed. Dr. Dickinson first apologized that Dr. Weng Tao, who was initially scheduled to give the Neurotech update was, at the last minute, unable to attend. She then proceeded to inform the group as to the current advanced-phase trials on subjects with RP and on those with Geographic Atrophy (GA). The trials are as follows: CNTF2 for dry AMD/GA; CNTF3 for late stage RP; CNTF4 for early stage RP. For example, 51 patients with dry AMD are being studied in the GA trial. To date in this ongoing work, the safety results are good in that Neurotech has encountered no significant treatment-related Serious Adverse Events (SAEs). No serum antibodies have developed against CNTF or the encapsulated cells that produce it. Dr. Dickinson reported that the biological effect of NT-501 has been identified. OCT images have demonstrated that there is improved definition of the Outer Nuclear Layer (ONL) of the retina in treated subjects at 12 months, compared to baseline images. A significant increase in retinal thickness, measured as total macular volume was determined by OCT. This was a dose dependent effect and observed in all three CNTF protocols. These results are consistent with published reports from preclinical observations. Retinal thickness was determined by the Duke Reading Center to not to be due to cystoid macular edema, epiretinal membrane formation, vitreoretinal traction or choroidal neovascularization. Thus, the results appear to be encouraging such that CNTF-ECT might be the first treatment generally available to both RP and dry AMD patients. Fenretinide Trial – Dr. Nathan Mata – Sirion Therapeutics,, Tampa Fl, USA In the retina, vitamin A is certainly needed for vision through the visual cycle. However, in some retinal degenerative diseases, toxic byproducts of vitamin A can form, causing damage and cell death. Thus, theoretically, somewhat lowering the vitamin A level in the retina could slow the accumulation of the toxic byproducts and thus slow the degeneration. Fenretinide is a low molecular weight drug that is a member of the retinoid (vitamin A) family of compounds. As with vitamin A (retinol), fenretinide can bind to Retinol-Binding Protein (RBP), a protein that transports retinol in the blood (serum) and delivers it to its target tissues and cells such as Retinal Pigment Epithelium (RPE) cells. Fenretinide thus competes with vitamin A for such binding on the RPB molecule and ultimately reduces the amount of serum vitamin A available for entry into the RPE. In this way, the accumulation of toxic byproducts should be reduced and the process of retinal degeneration also slowed. Dr. Mata reported that, in January of 2008, Sirion Therapeutics began a two-year, doseranging phase II trial to investigate the efficacy of fenretinide in preventing or slowing the growth of retinal lesions in patients with geographic atrophy secondary to AMD. The drug is given orally at concentrations of 100 or 300 mg/day. A 1-year interim analysis was performed in March of 2009 and the results were positive. Among the subpopulation of patients who reached the 18 month visit, 78% of the subjects in the 300 mg group had lesions less than the median of those receiving only placebo. A similar treatment effect was observed in the subjects receiving the 100 mg dose, specifically in subjects who had smaller lesions at baseline. This suggests that early intervention may result in improved outcomes. Concerning safety, most side effects were similar in occurrence in placebo and treated groups. Importantly, despite a significant reduction in circulating retinol, the incidence of delayed dark-adaption was comparable among placebo and treatment arms of the trial. Concerning efficacy, the results look good to date in that over twice as many patients in the group receiving only placebo developed neovascularization as in the fenretinide-treated group. Question: Genetically, a defect in the serum RBP gene can lead to retinal degeneration. Could fenretinide thus cause a retinal degeneration? Answer (Dr. Mata): The RBP level in patients is carefully monitored. The decrease in serum RBL level is approximately 60%. Question: Could fenretinide be used in Stargardt disease? Answer (Dr. Mata): Currently, this use is not planned since fenretinide, as with other retinoids, is a teratogenic agent and is therefore not appropriate for use in the young. Question: Is there a change in the hyperfluorescence in the retinas of the treated subjects? Answer (Dr. Mata): Data are being collected on this question. Antineovascular Clinical Trial Leucentis vs. AvastinTrial – Dr. Daniel Martin – Cleveland Clinic Foundation, Cleveland, OH USA In wet AMD, VEGF is a primary factor in neovascular development. Thus, inhibitors of the action of VEGF can slow or stop the formation of the abnormal new vessels. One of these, Lucentis, has been shown by Genentech to be particularly effective in treating wet AMD. Lucentis (ranibizumab) is a human antibody fragment that functions as an anti-VEGF agent. Similarly, Avastin (bevacizumab) is an antibody that acts against VEGF-like compounds and has been extensively used in cancer therapy. With similar mechanisms of action but with Avastin much less expensive than Lucentis, several studies around the world have started to test the two agents “head to head” in the same study to determine if there are differences in safety or efficacy between them. Dr. Martin summarized these studies giving as an example the trial sponsored by the National Eye Institute - “Comparison of AMD Treatments Trials: Lucentis vs. Avastin Trial”. Current enrollment is 800-1200. Although the trial is proceeding well, he cited several problems in trials such as this. For example, there is a large difference in US government copayment in the drug use and thus difficulty in masking the bill so the type of drug remains hidden. He felt that there is a need for government intervention (Congressional amendment) for NIH-sponsored clinical trials such that appropriate masking can be done. He said that investigators were now looking at the genetic background of the trial subjects to see if there is any correlation between genotype and trial outcomes. Final results should be available in 2010/2011. Question: In patients with compromised blood-retinal barriers, what is the effect of antibodies in the periphery? Answer (Dr. Martin): A study has been started to measure systemic antibody levels. Preclinical Science RD Genotyping – Dr. Bernard Weber – University of Regensburg, Regensburg, Germany RD genotyping is important in giving the patient information about their disease and its probable prognosis (progression). It is also important in some clinical trials and absolutely necessary before gene replacement therapy can be done. Several laboratories, commercial and academic, now perform RD genotyping, at least on selected genes known to cause RD. Dr. Weber spoke about the 300 kb Affymetrix re-sequencing array that is now available in his laboratory at the University of Regensburg. This array allows for the testing of 72 genes associated with retinal dystrophies including the 3 genetic types of Retinitis Pigmentosa – autosomal dominant, autosomal recessive and X-linked. It also can be used for testing of macular dystrophy, Stargardt disease (dominant and recessive). Usher syndrome and Bardet Biedl syndrome. The “Retchip” will be available for routine testing after May, 2009. Question: What are the costs of this array if only 1 patient is tested? Answer (Dr. Weber): The total costs would amount to EUR 1.5.000-04.000 per patient but, if mutation analysis is combined from different patients with different phenotypes, costs can be lower. AMD Genetics – Dr. Bernhard Weber – University of Regensburg, Regensburg, Germany In 2000, no genes were known whose mutations increased the risk for AMD. Today, several gene mutations have been uncovered that together, account for a large percentage of the risk in developing AMD. Interestingly, several of these mutations are in genes involved in immune regulation. Dr. Weber stated that there are two major genetic risk factors associated with AMD. These are polymorphic variants in the CFH and ARMS2/HTRA1 genes. Case/control association studies have also suggested several other risk factors with minor contributions to disease such as Complement Component 2, Factor B, Complement Component 3 and APOE. Yet others have been reported in single studies but have not been independently replicated so far. Continuation of this line of work will greatly aid our understanding of the molecular pathogenesis of AMD and will allow the design of targeted therapies. Dr. Weber said that an international consortium of investigators is needed to further this work since new genes represent only a smaller percentage of unknown mutations in AMD patients and that 45,000 (and possibly up to 10,000) patients will probably be needed in the studies. LCA Preclinical Therapy Studies – Dr. Frans Cremers – Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Dr. Cremers updated the group on preclinical studies that should lead to a clinical trial on gene replacement therapy of the LCA5 gene (lebercilin). After the identification of the LCA5 gene in 2007, research groups from Bar Harbor (Dr. P. Nishina), Montreal (Dr. R. Koenekoop), Nijmegen (Drs. F. Cremers, A. den Hollander, R. Roepman) and Philadelphia (Dr. J. Bennett) as well as other members of these groups started a collaboration to develop a gene therapy protocol for LCA patients with mutations in the LCA5 gene. The core of this work is funded by the Foundation for Retinal Research as well as additional funding by the Foundation Fighting Blindness, USA, FFB Canada and the FRSQ and CIHR. There are 4 important goals of the consortium: To develop a mouse model that mimics human LCA5-associated vision loss. Using sophisticated molecular techniques, homologous recombination was performed generating homozygous Lca5 (-/-) mutant mice. The mutants show early-onset retinal degeneration. In the next 2 years, these mice will be used to test gene-replacement therapy using the lebercilin gene. To perform gene replacement therapy in the LCA5 KO mice. This work is now ongoing. The human LCA5 cDNA, driven by a constitutive promoter, was cloned into adeno-associated virus construct and expression of the lebercilin protein was confirmed in vitro by Western blot analysis. To identify a sizable group of patients with LCA5 mutations. Since the LCA5 mutation is so rare, the group has to date sequenced 400 patients with LCA and 100 with arRP without detecting additional mutations in LCA. Worldwide, about 1400 probands have been analyzed which identify 28 individuals with LCA5 mutations in 13 families. To understand the role of the lebercilin protein in retinal function. Dr. Cremers explained that the group aims to understand the function of lebercilin through deciphering its protein network. Using protein-protein interaction experiments, interacting proteins have been identified including microtubule-associated proteins, ciliary transport proteins and other proteins of unknown function. Importantly, lebercillin was found to interact with a ninein-like protein that also interacts with the USH2A protein. All three proteins localize to the basal bodies of photoreceptor connecting cilia. Thus, lebercilin probably forms a link between Usher syndrome and LCA caused by mutations in ciliary proteins. In summary, Dr. Cremers said that the work is on target to begin a clinical trial on gene replacement therapy by 2011. To accomplish this though, extra efforts are needed to identify enough patients with LCA5 mutations. New Business, Announcements and Conclusion Stem Cell Treatments – Dr. Robin Ali Ms. Fasser asked Dr. Ali to say a few words about the potential of stem cell therapy in sight restoration and current “treatments” in a number of countries. As discussed last year at the SMAB meeting, advertisements in places such as the internet for several indications such as blindness are now common. However, there are serious questions as to both safety and efficacy of such applications. Dr. Ali cited several examples of purported treatments in different countries that are delivered for different forms of blindness. He feels that it is the “unmet” needs” of the patient that stimulates these types of treatment and that there is an inability of the lay public to distinguish between a true, scientific “trial” and an unsubstantiated “treatment”. He mentioned that grave consequences can occur from such uncontrolled treatment including the potential for tumor development. Ms. Fasser asked Dr. Ali if he would write a draft of a position paper for consideration by Retina International as to the current and future use of stem cells in treating retinal degeneration. Dr. Ali agreed to do this. European Vision Institute – EuroVisionNet.eu – Dr. Eberhart Zrenner – University of Tuebingen, Tuebingen, Germany Dr. Zrenner wished to bring to the attention of the SMAB meeting participants that the “Vision Research Gateway” is a new web-based portal service for vision researchers in Europe as well as others who are interested in basic and clinical progress in vision. The website is meant to bring researchers together and stimulate communication as well as to give vision research a higher profile and visibility in the general community. The website can be accessed at www.vision-research.eu. Rod-derived Cone Viability Factor (RdVF) – Dr. J.A. Sahel - Institut de la Vision, Inserm, Paris, France Ms. Fasser asked Dr. Sahel to summarize the work of his group on RdCVF. RdCVF and RdVCVF2 are novel neurotrophic factors that promote the survival of cone photoreceptor cells. They belong to the family of thioredoxin proteins that play an important role in redox signaling in photoreceptor cells and are involved in protection from oxidative stress. Dr. Sahel said that the RdCVF signaling links oxidative stress in photoreceptors to neuroprotective responses. This is especially true in rodents with light-induced damage. Essentially, the relevant genes, Nxn11 and Nxn12, are part of a signaling pathway that couples oxidative stress and cone photoreceptor cell survival. There are now good animal model data demonstrating better ERG function after RdCVF treatment. In the future, this could allow for treatment of RD patients, protecting cone photoreceptors and preventing central vision loss. Future Meetings XVI World Congress of Retina International – Dr. A. Ciccodicola – University of Naples, Naples, Italy Dr. Ciccodicola reminded RI members to hold the dates of 26-27June 2010 for the next RI World Congress. It will be held in Stresa, Italy at Lago Maggiore, a beautiful lake-side venue in northern Italy. The theme of the meeting will be “Change our Vision – Bridging the Gap from the Lab to the Patients”. XIV International Symposium on Retinal Degeneration – Dr. Matthew LaVail – University of California, San Francisco, CA, USA Dr. LaVail announced that the next RD Symposium, RD 2010, would be held on July 13-17, 2010 in Mt.-Tremblant, Canada. Conclusion Ms. Fasser closed the meeting by thanking all the speakers for their presentations. She felt that this was an excellent update of advances in moving towards treatments and cures for the retinal degenerative diseases. She wished all would have a productive ARVO meeting and looked forward to seeing everyone again at next year’s SMAB meeting in Ft. Lauderdale and then at the RI Congress in Italy. For the minutes: Dr. Gerald J. Chader Doheny Retina Institute Los Angeles, CA USA