In their own words, First Authors at the 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology explain their findings. Their abstracts were designated as some of the newest and most innovative research presented on Sunday, May 4 - Thursday, May 8, 2014.
#4462 - D0122. Mechanics of Optic Fissure Invagination. Benjamen Filas. May 7, 8:30am.
Coloboma (open, keyhole-shaped eye) results from malformation of the optic fissure, an embryonic structure that establishes the location of the optic nerve. Although several gene mutations have been linked to fissure malformation and coloboma, how these defects occur in the embryo is unknown.To uncover possible causes of fissure malformation, we used a combination of high resolution 3-D imaging and biomechanical modeling. Experiments and simulations suggested a novel biomechanical asymmetry exists during fissure formation in mouse, chicken, frog, and fish embryos. Specifically, we show this asymmetry results from enhanced growth on the nasal side of the fissure.This finding is interesting because approximately 90% of colobomas occur toward the nasal side of the eye where optic fissure closure normally occurs. We postulate that reduced or abnormal growth in this region may explain why colobomas preferentially occur in this location. Indeed, many of the genetic anomalies linked to coloboma play a role in maintenance of cell proliferation.With a better mechanistic understanding of how pediatric eye diseases occur, we believe possible ways to treat or prevent them will be uncovered. This work was supported by a Career Starter Award from the Knights Templar Eye Foundation.
#4590. Absence of lymphatic vessels in the developing human sclera. Barbara Neuser. May 7, 11am.
The sclera is the rigid outer membrane of the eye protecting intraocular structures and stabilizing the shape of the eye. To date only little is known about the blood vessel and especially the lymphatic vessel anatomy of the sclera. Therefore, we examined the adult human sclera and found that blood vessels were mainly located in the episclera (the outer layer of the sclera), whereas we could not find any lymphatic vessels within the sclera. This led to the question whether the human sclera is primarily alymphatic or contains lymphatic vessels during embryologic development. Consequently, we examined scleral probes from 34 fetuses and abortions by immunohistochemistry and compared the amount of blood and lymphatic vessels between three age groups from early to late pregnancy. The earliest time point where we detected blood vessels, was in week of gestation 13, mainly located in the episclera. Similar to the adult sclera, we could not detect any lymphatic vessels within the fetal sclera. This is in contrast to the conjunctiva, where the first lymphatic vessels could be detected since week of gestation 17. Therefore, the sclera is primarily alymphatic.
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#400 - C0171. The role of Decorin in ocular ageing and disease. Felicity de Cogan. May 4, 8:30am.
The incidence of ocular degenerative conditions, such as glaucoma and age-related macular degeneration, increases with age and there is no clear explanation for the increasing vulnerability of the aging eye to these diseases. We looked at a novel mechanism that naturally protects against these diseases in the vitreous, which is a clear gel that fills the back of the eye. Our hypothesis is that vitreous contains naturally occurring anti-inflammatory and anti-scarring proteins that control inflammatory signals in the eye, the levels of which decline with age, thus increasing disease susceptibility.
As an example, we show that vitreous-levels of the naturally occurring anti-inflammatory and anti-scarring protein Decorin decline with increasing age and that there is a corresponding increase in vitreous-levels of a key pro-scarring signaling molecule, TGFβ2. One action of Decorin is to trap TGFβ2 and block its scarring effects. In a secondary study we have shown that TGFβ2 is up regulated alongside other inflammatory markers in proliferative vitreoretinopathy, another disease involving scar formation. Proliferative vitreoretinopathy has very poor visual outcomes for patients. We suggest that understanding and exploiting the eye’s naturally occurring defense mechanisms will allow us to develop treatments to prevent and treat age-related ocular degenerative diseases.
#412 - C0183. A fragment of netrin-1 is implicated in the induction of permeability in diabetic retinopathy. Khalil Miloudi. May 4, 8:30am.
Diabetic retinopathy, one of the most important complications of diabetes, is the leading cause of blindness in North America. It is characterized by the deterioration of eye blood vessels, which in early disease lose their seal. This phenomenon is due to molecules produced by neurons called guidance molecules that disrupt vascular stability. Our work demonstrates that one of these guidance cues, the netrin-1, was transformed during the pathology into a second bioactive peptide VI-V massively produced, which can induce vascular permeability. In addition, our studies have also shown that UNC5B, one of the netrin-1 receptors that is associated with VI-V, is overexpressed in the blood vessels of diabetic retina. Neutralizing the VI-V peptide in diabetic eyes may represent an attractive therapeutic strategy to counter sight-threatening vascular permeability in diabetes.
#413 - C0184. Fetal hemoglobin induction by monomethylfumarate: relevance to prevention and treatment of sickle cell retinopathy (SR). Wanwisa Promsote. May 4, 8:30am.
Sickle cell disease (SCD) affects most major organs, including the eye. Sickle cell retinopathy is a common complication of SCD and a major cause of blindness among African Americans in the U.S. Pharmacologic induction of fetal hemoglobin (HbF) remains the best approach to treating complications of SCD. Hydroxyurea (HU) is the only FDA-approved drug for this purpose. However, the use of HU is limited and not currently recommended for routine use in children. Furthermore, little is known regarding the effects of HU and other HbF-inducing therapies in the eye. Our present study aims to (1) contribute to our understanding of how hemoglobin is produced in the eyes under normal conditions and in SCD, (2) present, for the first time, retinal pigment epithelial (RPE) cells, which have recently shown to be capable of producing hemoglobin in the eye, as a target for HbF induction and therapeutic management of sickle cell retinopathy, and (3) introduce a novel compound called monomethylfumarate (MMF), a compound with dual antioxidant and anti-inflammation properties, as a HbF-inducer in RPE and an alternate therapy to HU in sickle cell retinopathy. Ultimately, this study will lead to the development of a new treatment of sickle cell retinopathy worldwide.
#2355 - B0031. Targeting Galectin-3 Attenuates both Corneal Fibrosis and Retinal Gliosis. Zhiyi Cao. May 5, 3:45pm.
Most diseases that cause catastrophic loss of vision do so as a result of the growth of abnormal blood vessels in the eye and wound healing response leading to scar tissue or fibrosis. Despite the advance offered by anti-VEGF therapies, there is still clear need for significant improvement, especially in developing drugs to prevent fibrosis in tissues of the eye. Serious fibrotic eye indications with unmet needs include AMD, diabetic retinopathy, proliferative vitreoretinopathy and glaucoma. At present, there is no FDA approved drug for treatment of fibrosis in tissues of the eye. Galectin-3 is a carbohydrate-binding protein that promotes both the growth of blood vessels and scar tissue. We have previously shown that inhibiting galectin-3 by a small molecule inhibitor, TD139, inhibits growth of abnormal blood vessels in cornea. In the current study using a mouse model we demonstrate that targeting galectin-3 also attenuates the formation of fibrotic tissue in the cornea and the retina. These findings suggest a potential for development of novel, dual target drugs, for prevention of the growth of abnormal blood vessels as well as fibrosis in tissues of the eye by a single drug.
#3028. Rhodopsin binding - induced conformational changes in arrestin - 1. Sergey Vishnivetskiy. May 6, 11am.
Direct protein-protein interactions mediate cellular “decision-making” by transferring signals from one molecule to another. Conformational changes in proteins upon binding to their partners determine their signaling capabilities, ultimately telling the cell what to do. We studied the conformational changes in arrestin, a protein that terminates visual signaling in photoreceptor cells, upon its binding to the light receptor rhodopsin. We used X-ray crystallography, which yields high resolution but inherently static picture, as well as biophysical methods that reveal protein dynamics. All methods identified similar receptor binding-induced conformational rearrangements in the arrestin molecule and revealed the flexibility of bound arrestin, which likely underlies the ability of the arrestin-receptor complex to activate an amazing variety of signaling pathways.
#3475 - D0075. PSMD13 Promotes Degradation of Disease - Causing RPE65s via the Ubiquitin - Proteasome Pathway. Songhua Li. May 6, 11am.
Mutations in the retinal pigment epithelium-specific protein 65 kDa (RPE65) gene have been associated with binding disease. Many disease-causing mutations result in rapid degradation of RPE65 by an unknown mechanism. Here we show that expression levels of mutant RPE65s were 70-90% lower than that of normal RPE65 in the cells whereas the contents of mRNA encoding mutant RPE65 were similar to that of normal RPE65. Proteasome inhibitors, but not lysosome inhibitor, significantly increased expression levels of mutant RPE65s. Co-expression of the 26S proteasome non-ATPase regulatory subunit 13 (PSMD13) resulted in a further decrease in protein content of mutant RPE65s whereas knock down of PSMD13 rescued expression levels of the mutant RPE65s. WT and mutant RPE65s were ubiquitinated in ARPE19 cells. Immunocytochemistry showed that the mutant RPE65s formed aggresomes in the cells. In conclusion, our results suggest that PSMD13 regulates pathogenicity of RPE65 mutations by mediating degradation of mutant RPE65 in the proteasome.
#4992 - D0179. Expression of olfactory signaling genes in the eye. Alexey Pronin. May 7, 11am.
The surface of the eye is exposed to dry air, dust, microbes and other stressors. To advance our understanding of how the outer eye interacts with its environment, we asked whether genes involved in sensing chemical substances are expressed in the cornea. Using next-generation sequencing we identified more than 10,000 genes active there and made a surprising discovery: several olfactory receptors and other genes previously shown to be expressed in the nose and responsible for the sense of smell are also expressed in the cornea. Additional molecular and microscopic analysis confirmed these results and found expression of olfaction-related genes not only in the cornea but in other parts of the eye too, such as blood vessels supplying the retina with oxygen and nutrients. We hypothesize that olfactory system may play a role in detection of specific chemicals secreted by bacteria that appears on the ocular surface and activate the immune system, and/or monitor certain metabolites such as tear components. While the specific function of olfactory receptors in the eye remains to be established, our study identifies them as a novel potential target for therapy of ocular diseases.
#5002 - D0189. Metabolic Memory and Diabetic Retinopathy: Epigenomic and Transcriptomic Signatures. Willard Freeman. May 7, 11am.
How do events in your past affect your health today? That is a question we all have. In parallel with the many research efforts to understand how your genetics, the genes passed down to you by your parents, contribute to health and disease, a relatively new area of research, epigenetics, is seeking to answer the question of how past events in your life change your genome. Dr. Freeman’s group examines a specific type of epigenetics, DNA methylation, and how it may play a role in the development of diabetic retinopathy. In particular his group is investigating how past periods of poor diabetes management may change your epigenome and contribute to vision threating diabetic retinopathy later in life. Using new technologies they are seeking to understand how the epigenome changes in response to your environment and how to potential restore a healthy epigenome.
#5717 - B0025. Adoptive cell transfer from a glaucoma mouse model induces retinal ganglion cell loss in healthy recipient mice. Qiong Ding. May 8, 8:30am.
One goal of our research was to determine whether autoimmunity contributes to in glaucoma, a disease causing irreversible vision loss in millions of patients. After inducing glaucoma in mice we isolated their immune cells and transferred them into a second group of healthy mice. Transfer of these cells caused a number of symptoms in the recipient mice that are similar to those typical of glaucoma. These findings demonstrate that, at least in mice, glaucoma can cause an autoimmune response which then further contributes to the disease. Current glaucoma treatments do not address this mechanism of damage and it is conceivable that adding anti-inflammatory therapies could benefit patients with glaucoma.
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#165 - A0352. Visual and somatosensory contributions to Center of Pressure (COP) balance in a legally blind and normally sighted group using the Nintendo Wii Balance BoardTM. Pamela Jeter. May 4, 8:30am.
Vision is important for regulating balance. Screening for balance impairment in a cost-effective and easily accessible way is important for older people with age-related vision loss, such as glaucoma. Using the Wii Balance Board, an accessory to the popular Wii Fit Video game (Nintendo), we were able to successfully detect balance impairment among legally blind persons compared to a normal control group. This suggests that the Wii Balance Board may be useful in a clinical setting to screen visually impaired patients at risk for falls due to balance impairment.
166 - A0353. Afferent visual function in Veterans after combat blast. Glenn Cockerham. May 4, 8:30am.
Blast exposure is a frequent cause of injury in military veterans during war and civilians in terrorist events. We found abnormalities in at least one test of visual function in the majority of veterans with blast-related traumatic brain injury we tested. These abnormalities persisted in veterans retested six months later, and some were present as long as five years after the original injury. We recommend that veterans and civilians with any history of blast-related traumatic brain injury undergo a thorough examination of the eyes and vision, including at visual acuity and visual fields, even years after the injury.
#841. Effect sizes of myopia-related genes on ocular biometry in childhood and later in life. Willem Tideman. May 4, 3:15pm.
Nearsightedness (myopia) is predominantly caused by an increase in size of the eye (axial length) in childhood. Another factor in the development of nearsightedness is the corneal curvature. Family studies have shown that children whose parents are nearsighted also have an increased risk of becoming nearsighted, and several large genetic studies have found genes that are responsible for this. The goal of our research was to disentangle the onset of myopia genes. Early onset genes may point to a different mechanism and require a different therapy than later onset genes. We therefore investigated the effect of these genes in six-year-old children and in an adult population.
We examined axial length and corneal curvature in 6,690 children from the birth cohort study Generation R and 10,751 adults from the population-based Rotterdam Study in the Netherlands, and determined 42 genetic variants for myopia in all. Many genes had a significant effect in both the children and adults, implying that many myopia genes have a gradual and long-lasting effect during myopia development. However, some genes were much more significant in the children, such as genes involved in the development of retinal cells and potassium channels for signaling in the retina. These data offer further insight into the association between genes and nearsightedness, and may offer new possibilities for personalized therapy to halt progression of nearsightedness.
#1672. Costs of follow-up visit and uptake of glasses and complication treatment after cataract surgery in developing countries: PRECOG, a multi-center observational study. Mirjam Meltzer. May 5, 11am.
Cataract, the world’s leading cause of blindness, can only be treated surgically. Guidelines suggest a follow-up visit six weeks after surgery to monitor quality and to provide glasses and treatment of complications as needed. However, follow-up rates in developing countries are often low. Our study, including 2,500 cataract patients from 27 hospitals in Africa, Asia and Latin America, was set up to determine costs and benefits of such a follow-up visit. To ensure a follow-up rate of 90% at six weeks or more after surgery, data was collected either “spontaneously” at hospital, after telephone calls or transport subsidies or via home visits. Previous published results of this study showed that cataract surgical quality can be assessed with visual acuity at hospital discharge, which correlated highly with later vision. This may result in changes in recommended practice for measuring vision outcomes. Current paper shows that only 1.2% of patient had a treatable complication and the majority would accept treatment if it was either free or at minimal cost. Almost half of the patients could benefit from glasses, of which 53% would pay for them. Costs for follow-up visits and glasses showed great variation among countries. The impact of interventions to improve post-cataract surgical follow up is limited by the relative rarity of treatable complications, and costs for surgery and glasses often exceeding patients' willingness to pay.
#4579. Can the Alexander Technique improve balance and mobility in adults over 50 years of age with visual impairments? A single - blind randomized controlled trial. Lisa Keay. May 7, 11am.
At least 30% of people over the age of 65 fall each year and this can lead to serious injury. Falls are the leading cause of hip fracture but falls can also lead to loss of confidence, admission to nursing home care and decline in health status. Visual impairment is more common in older people and places them at up to 8-times greater risk of fall-related injury. While exercise programs to improve balance and strength can prevent falls in the general community, this has not been shown to be of benefit for people with visual impairment. The Alexander Technique is a novel approach to improve physical function for older people with significant vision loss. The Alexander Technique uses guided movement and verbal feedback to address habitual muscle tension and enable smooth co-ordinated movements. We conducted a 12 month randomized controlled trial to evaluate the Alexander Technique and demonstrated some benefits for physical measures of balance and gait, particularly amongst people who have fallen a number of times before the trial. Though the study only involved 120 participants, these early results suggest that the Alexander Technique is a promising strategy to reduce physical falls risk in this vulnerable population.
#6006. Better Eye Health for Aging Baby - boomers: Generational Differences in the 5 - yr Incidence of AMD. Karen Cruickshanks. May 8, 12noon.
Age-related macular degeneration (AMD) is a leading cause of vision loss in the U.S. Previous studies have reported that the risk of developing this serious eye disease declined among people born in the first half of the twentieth century. New data from the Beaver Dam Offspring Study, funded by the National Institutes of Health, suggest that this decline is continuing for baby-boomers (born 1946-1964) and generation X (born 1965-1984). Compared to their parents and grandparents, baby-boomers may be able to enjoy more years with healthier eyes. These rapid changes mean AMD is caused by exposures which are changing, and is likely to be preventable. Changes in smoking patterns, a well-known risk factor, did not explain the decline, so other factors must be involved.
#6087 - A0214. Prevalence of Near Vision Impairment in Middle - aged and Older Adults in an Urban Census Sector of Parintins, Brazilian Amazon Region. Solange Salomao. May 8, 12noon.
A progressive decrease in the ability to focus objects for near is a common symptom in the natural ageing process and it is called presbyopia. This condition usually stars around the forties and can be easily corrected by reading glasses. In this study we had the opportunity to assess near vision impairment in a sample of residents 45 years and older from an urban district of Parintins city in the heart of the Brazilian Amazon Region. In this part of the developing world there is a lack of information on the frequency of near vision impairment due to presbyopia. Our results showed that almost 90% of examined people had near vision impairment with 80% of those due to presbyopia regardless of age, gender and educational level. Only half of those in need were wearing corrective glasses and 10% of those with glasses were wearing inadequate correction. These results reinforce the need of access to basic eye care services for that population.
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#511 - A0100. Platelet Lysate as Replacement for Fetal Bovine Serum in Limbal Stem Cell Cultures: Preliminary Results. Kunal Suri. May 4, 1:30pm.
Conditions like chemical or thermal burns of the eye, multiple eye surgeries and some genetic conditions lead to blindness due to damage to the cornea, which is the transparent front part of the eye. Novel treatment aims at growing cells residing in the peripheral cornea (stem cells) in the laboratory in a medium containing various growth promoting supplements and these cells can regenerate healthy eye surface when transplanted on the diseased eye. Serum derived from bovine fetal blood has been used in the past to grow these cells but the animal products have a risk of not being accepted by human body and also carry a potential risk of transmission of diseases. Thus, in our study we used platelets derived from human blood to use as supplement to grow these stem cells in the laboratory. Human platelets are a rich source of certain factors that promote growth of stem cells. We compared this medium to fetal serum supplemented medium and found that platelet-supplemented medium can support the growth of stem cells. This medium has a potential to be used in clinical practice to grow these cells in laboratory for transplant on human eyes.
#523 - A0112. Generation of Induced Pluripotent Stem Cells from Normal and Keratoconus Corneal Fibroblasts using Viral- and Non-Viral Methods. Roy Joseph. May 4, 1:30pm.
Keratoconus is a disease of the cornea, the clear front lens of the eye (like the crystal on a watch) that occurs in one in 2,000 people. Thinning of the central corneal tissues results in a conical cornea, with visual degradation and the inability to focus a clear image on to the back of the eye. Early treatments involve substituting a contact lens for the irregular corneal surface but later the patient might require corneal transplantation. Corneal tissues are composed of collagen fibers laid in layers, sandwiching keratocyte cells. In culture keratocytes normally revert to fibroblasts (scar cells).
Our research utilizes specific factors inducing these fibroblasts into pluripotent stem cells by viral and non-viral techniques. Using a variety of agents these cells are then converted back into true corneal keratocytes. This conversion in tissue culture allows for a wealth of studies to further unravel the cellular mysteries in keratocytes from keratoconus. We believe that keratocyte abnormalities play a pivotal role in keratoconus and methods to alter this disease process might be forthcoming from these discoveries. This could be source for better understanding the disease progression and also correcting the genetic defects of this disease.
#2198. Limbal melanocytes support limbal epithelial stem cells in 2D co-culture and RAFT collagen tissue equivalents. Marc Dziasko. May 5, 3:45pm.
The cornea is the transparent tissue located at the front of the eyeball. As in other epithelial tissues, the cornea is continuously regenerated in order to maintain the vision. This regeneration relies on a population of stem cells located at the corneal periphery. These stem cells are concentrated and maintained in a specific microenvironment called the stem cell niche. We recently observed that the corneal stem cell niche containing the corneal stem cells is also populated by another kind of cell called melanocytes. Melanocytes are the cells responsible of the skin pigmentation. Within the cornea, these cells are believed to give protection against UVs to the corneal stem cells. The aim of my project was to isolate human corneal melanocytes and assess their functional involvement in the maintenance of corneal stem cells in vitro and within the native corneal stem cell niche.
#2199. Nerve induced gene expression in corneal epithelial cells during embryonic development. James Kubilus. May 5, 3:45pm.
No one likes to get poked in the eye. It hurts a lot. This is because the eye is far more sensitive to things that could damage it than other parts of the body, like the skin. The clear window at the front of the eye known as the cornea actually has one of the highest densities of nerves in the body. These nerves are specialized to sense any sort of stimulus as a sensation of pain. Our research has tried to figure out how these nerves can be responsive to all of the different things that could damage the eye and potentially cause a loss of sight. Based on our findings we believe that the nerves don’t do this on their own, but rather through cross talk with the cells of the cornea itself. Now we are trying to determine the molecules and mechanisms that make this interaction possible during early eye development. Our hope is that this information can be used to improve conditions in adults where nerves have been damaged, and thus help prevent vision loss.
#3054. A metabolome - wide study of dry eye disease. Jelle Vehof. May 6, 11am.
Dry eye disease is a common, long-term eye disease with disabling symptoms of dryness, irritation and blurred vision. It is particularly common in middle-aged and older women, and has been linked to other medical problems such as diabetes, thyroid problems, and rheumatoid arthritis. However, little is known about its exact cause and why it is so common in older women. In a large group of 1622 women, we assessed dry eye disease using validated questionnaires, and measured a wide range of 390 metabolites (small molecules produced during the body’s metabolism) in blood. We found strong and significant associations between the prevalence and incidence of dry eye disease and low androgen metabolites (e.g., dehydroepiandrosterone sulfate (DHEAS) and epiandrosterone). Androgens are sex hormones that are well known for their masculinizing effects in men, but also play a role in women and decline with age. They have been associated with tear gland function (both lacrimal and meibomian glands). This study of the metabolome suggests that androgens are an important pathway in the development of dry eye disease in females, and may also act as a biomarker of dry eye disease.
#4608. Progenitor Cells Localize to the Periphery in the Mature Cornea where they Interact with Surrounding Cells. Edgar Espana. May 7, 11am.
The cornea is the clear part of the eye that allows light into the eye. The corneal endothelium is the layer of the cornea that plays a major role in maintaining corneal transparency. Endothelial corneal transplantation is effective in restoring function in cloudy corneas by reestablishing normal transparency. This work attempts to define novel mechanisms that regulate endothelial maturation and function. Regulation of endothelial function and maturation by interactions with the surrounding environment provides new insights to establish new nonsurgical and preventive interventions that can restore corneal transparency. Our long term goal is to define the role of the surrounding structures in establishing and maintaining endothelial maturation and function.
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#814. Unmasking potential brain plasticity in amblyopic vision. Zhong-Lin Lu. May 4, 3:15pm.
People with lazy eye (“amblyopia”) often have difficulties to see fine spatial patterns. There are two possible causes for such difficulties: (1) fine spatial patterns are not represented in the visual system of people with lazy eye, or (2) they are represented but masked by high noise in neural processing. We measured the tilt aftereffects (TAE) of fine, unresolvable spatial patterns in people with lazy eye to distinguish these two possible causes. We found that although they were unresolvable to people with lazy eye, fine spatial patterns yielded considerable TAE. After looking at the unresolvable spatial patterns, their perceived orientation of a visible spatial pattern significantly changed. The results suggest that although they are not visible, fine spatial patterns are represented in the visual system of people with lazy eye. The information is most likely masked by high noise in neural processing. Reducing noise in the visual system of people with lazy eye may enable them to see fine spatial patterns.
#821. Three-Year IOP-Lowering Efficacy of Selective Laser Trabeculoplasty in Afro-Caribbeans with Open-Angle Glaucoma. Tony Realini. May 4, 3:15pm.
The prevalence of glaucoma in the Afro-Caribbean population is among the highest of any ethnicity globally. In the developing world, resources to treat glaucoma and prevent blindness are scarce. We have evaluated the role of selective laser trabeculoplasty (SLT) as a means of controlling glaucoma and preventing blindness in St. Lucia, a typical developing nation populated primarily by Afro-Caribbeans. SLT has many advantages over daily medical therapy: better reduction of intraocular pressure (IOP; the therapeutic goal of glaucoma therapy), elimination of adherence issues, and potentially less cost over the long term. The one-time minimally-invasive therapy can obviate daily eye drop therapy for three or more years based on our findings, providing greater IOP reduction than medications. This magnitude of therapeutic effect is expected to reduce or prevent glaucoma blindness.
#4546. Efficacy and Safety of New Topical Sodium Pump Inhibitor (NSPI) in Reducing Eye Oscillations in A Canine model of Infantile Nystagmus Syndrome (INS). Richard Hertle. May 7, 11am.
Knowledge obtained as a result of studying eye muscle surgery has uncovered the importance of the eye muscle’s nerves on the eye. We hypothesized that treating these nerves directly could be as effective as operating. A patient with nystagmus accidently sprayed a neurological agent in his right eye. He had initial discomfort, relieved by irrigation, after which, he reported “seeing better” and his “nystagmus was gone.” His local ophthalmologist confirmed decreased nystagmus and no serious damage from the agent, also confirmed by our later evaluation. This paper reports the results of using this new pharmacological agent topically in Briard sheep dogs with an inherited retinal disease and associated nystagmus. After safety testing and approval the drop form was tested in these animals. At 0.7% concentration there was minimal redness without other eye or body toxicity. At 0.6% eye movement recordings showed a 150-250% increase in a positive measure of nystagmus function and 30-70% decrease in intensity. Although human trials are needed, this study suggests this new class of pharmacological agents has the potential for topical treatment of infantile nystagmus. Further, this data supports the importance of the eye muscle’s sensory nerves’ contribution to eye-movement diseases and their treatments.
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#1662. Common mechanisms underlying intraocular pressure identified in functional analysis of gene lists from genome-wide association study results in IGGC cohorts. Cristina Venturini. May 5, 11am.
Raised pressure of fluid inside the eye, called the intraocular pressure, is an important risk factor for glaucoma, one of the most common causes of blindness worldwide. Genetic factors are considered to play a key role in controlling eye pressure. Recently, several genes have been identified in large genetic studies involving thousands of patients. Our research aimed to identify which biological pathways these intraocular pressure genes are involved in. This is important in order to identify potential new targets for lowering the eye pressure, the aim of current treatment for glaucoma. We performed a gene enrichment study, analyzing genome scans of over 33,000 people from studies from around the world (as part of the International Glaucoma Genetics Consortium). We found out that these genes are mainly involved in cellular adhesion, the binding of a cell to a surface or another cell, which is important in building complicated biological structures, and for communication between cells. These adhesions might be involved in the eye structures relevant for the flow of the fluid out of the eye and thus affect the control of the eye pressure. Our work provides new insights into the mechanisms involved in the eye pressure, and glaucoma.
#1664. Short-term IOP Spikes Constitute Over 11% of the IOP Energy the Eye Must Absorb During Waking Hours. J Crawford Downs. May 5, 11am.
High IOP (the pressure inside the eye) is often associated with glaucoma. IOP is typically measured once every few months in patients because it has been thought to be relatively stable over time. We use an implantable wireless pressure sensor to show that IOP is incredibly dynamic. Blinks and eye movements generate large IOP spikes that occur about 12,000 times per hour and constitute about 12% of the total IOP energy that the eye must absorb during waking hours. IOP must now be viewed as dynamic and ever-changing, and IOP fluctuations may prove to be an important contributor to glaucoma.
#2144. BioGeographical Ancestry in the African Descent and Glaucoma Evaluation Study (ADAGES): Association with corneal thickness and disc area. Christopher Girkin. May 5, 3:45pm.
This study was designed to determine if genetic ancestry is associated with differences in the structure of the eye. Differences in the optic nerve, which connects the eye to the brain, and cornea, the clear front part of the eye have been found between self-described racial groups and this may have an impact on the development of glaucoma, a blinding disease of the optic nerve that is more severe in African Americans. Rather than relying on self-description, genetic testing allows for the quantification of the contribution of continental groups of origin to an individual’s ancestry. For this study we compared the proportion of African Ancestry determined by genetic testing to several ocular structures in a cohort of people of African and European descent from a NIH-funded study focusing on glaucoma in African Americans (African Descent and Glaucoma Evaluation Study, ADAGES). We found that the structure of the optic nerve and cornea were significantly associated with genetic ancestry. This suggests that genetic ancestry can be used in place of self-describe race, which is subjective and involves many non-genetic factors.
#2170. Stiffness of the Trabecular Meshwork In Living Eyes. Larry Kagemann. May 5, 3:45pm.
Glaucoma is a blinding disease, and the only current treatment to prevent loss of vision is reduction of eye pressure. Eye pressure is regulated by a set of very specific tissues in the eye. Previous investigators have shown that the tissues through which fluid exits the eye have a direct bearing on how pressure is regulated. There was no way to study them directly in living people until we developed a non-contact, non-invasive, rapid technique that allows us to see these hidden structures. In this study, we use that technology in conjunction with gently pressing on the outside of the eye, to observe how these hidden structures change shape in response to pressure. Using this “stress test” for the eye, we present the first comparison of eyes of living people with previous studies in cadaver eyes. We found that the shape of the pressure-regulating tissues may be actively controlled by the surrounding structures to which they are anchored, suggesting a new paradigm for the regulation of pressure in the living eye; a finding impossible to achieve in cadaver tissue. This new insight into the control of eye pressure may alter our approach to the treatment of glaucoma in the future.
#5658 - D0151. Genomewide DNA methylation analysis of primary human trabecular meshwork cells with dexamethasone stimulation. Akira Matsuda. May 5, 8:30am.
Since steroid (glucocorticoid) work together with its receptor in nucleus, it affects not only gene expression but also epigenetic status (modification of DNA without changing its sequences) of the cells. The epigenetic status of the cell is determined partially by DNA methylation (chemical modification of DNA), and it affects long-term gene expression levels within the cells. To further clarify mechanism of steroid-induced glaucoma, we investigated the shift of DNA methylation status during steroid stimulation using human trabecular meshwork cells. Using genome-wide DNA methylation analysis technique, we found several genes showing constant shift of DNA methylation level in response to steroid stimulation. We also confirmed corresponding changes of gene expression for some of the genes with the alteration of DNA methylation status. Our results suggested that alteration of epigenetic machinery through steroid stimulation might affect the long-term gene expression of trabecular meshwork.
#4556. Effect of translaminar pressure modification on the rat optic nerve head. Bang Bui. May 7, 11am.
aving high eye pressure was thought to lead to vision loss from glaucoma. Paradoxically glaucoma can occur in people with what seems to be normal eye pressure. Other factors must be at play. The fluid (cerebral spinal fluid) that surrounds the brain also bathes the nerve as it leaves the eye. The pressure in this fluid thus helps to support the optic nerve and vision. Clinical evidence suggests that there is a relationship betweencerebral spinal fluid pressure and glaucoma. We show that as eye pressure goes up the nerve gradually gets pushed backwards, and the ability of the eye torespond to light decreases. When the cerebral spinal fluid pressure is higher the nerve is protected from backward bowing, as is the eyes capacity to respond to light. The converse is true when cerebral spinal fluid pressure is low, resulting in more bowing and poorer function. Thus the difference between eye pressure and cerebral spinal fluid pressure is important to vision. This line of investigation might help explain why some people with “normal eye pressure” develop glaucoma, and why people with “high IOP” never develop the condition.
#5985. Laser Induced Mouse Glaucoma Model Suitable for Studying Stem Cell - based Therapy. Yiqin Du. May 8, 12noon.
Glaucoma is a group of eye disorders leading to irreversible blindness. It is normally associated with increased pressure in the eye. Restriction in outflow of aqueous humor is thought to be a causative factor. Aqueous humor exits the eye via a complex array of channels lined with cells, including the trabecular meshwork. A decrease of trabecular meshwork cell number is thought to affect outflow. Understanding the functions of trabecular meshwork cells may hold the key to controlling glaucoma, but currently there are no suitable animal models in which the cellularity of this tissue can be controlled. This work developed a mouse model in which trabecular meshwork cells were damaged by laser photocoagulation producing cell loss and a disrupted structure. Intraocular pressure was increased for up to 6 months, and electroretinography showed reduced visual signals indicating retinal damage. We found that stem cells introduced into the damaged eyes localized in the trabecular meshwork tissue and partially repaired the tissue structure. Our work demonstrated a new model to study the effects of trabecular meshwork cellularity on control of aqueous outflow, in which we can test the potential of stem cell-based therapy as a treatment for glaucoma.
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#858. Temporal transcriptome and systems biology analysis to identify key pathways and hub genes in experimental Staphylococcus aureus endophthalmitis. Ashok Kumar. May 4, 3:15pm.
The long-term goal of this research is to prevent vision loss due to microbial infection through immunotherapy. Patients who undergo eye surgery often develop endophthalmitis, a serious bacterial infection causing swelling inside the eye. Left untreated, endophthalmitis can lead to loss of vision due to damage to the retina — a highly specialized and light-sensitive layer of cells responsible for transmitting visual signals to the brain — or even loss of the eye itself. As the aged population in the U.S. is expected to grow dramatically, the number of ocular surgeries (e.g., cataract) performed will also increase significantly, resulting in a proportional increase in the incidence of endophthalmitis. In this study, using an experimental mouse model of bacterial endophthalmitis, we have identified molecular targets to reduce inflammation (a complex biological response of cells/tissue to harmful stimuli), and protect the eye from endophthalmitis. Further testing is in progress with the goal of discovering drugs, which induce rapid resolution of inflammation in the eye.
#2493 - C0013. Suppression of experimental autoimmune uveitis (EAU) and recovery from uveitis correlate with expansion of regulatory B cells (Breg). Chengrong Yu. May 5, 3:45pm.
B cell depletion has been proposed as an effective therapy for T cell mediated autoimmune diseases and efficacy of rituximab in rheumatoid arthritis and other autoimmune diseases is partially attributable to the expansion of a rare regulatory B cell population called Bregs. The Breg cell produces the anti-inflammatory cytokine, interleukin 10 (IL-10), and is thought to play pivotal roles in restraining excessive inflammation. In this study, we show for the first time that Breg cells conferred protection of mice from experimental autoimmune uveitis (EAU) by inhibiting pathogenic Th17 and Th1 cells while promoting the expansion of regulatory T cells called Tregs. Adoptive transfer of ex-vivo generated Bregs ameliorated EAU, an animal model of human autoimmune uveitis suggesting that Bregs can be used to treat pre-existing uveitis, a potentially blinding disease that accounts for more than 10% of severe visual handicaps in the U.S.
#4062. Increased Blood CD1c(high) Myeloid Dendritic Cells with Low Antigen Uptake Enhance CD4 Helper T cell Responses in Noninfectious Uveitis. Ping Chen. May 7, 8:30am.
Patients can suffer from ocular inflammation by sources other than viral or bacterial infection. Unfortunately, the inflammatory mechanisms are often unclear. This poses significant problems, as ocular inflammation is responsible for 10% of blindness in the United States. Current common treatment involves corticosteroid use, which is accompanied by undesirable side effects if given long term. In an attempt to develop alternative treatments, immune cells and responses that are associated with the inflammatory conditions are studied. One such immune cell called dendritic cells, characterized by long arms on its surface, professionally “cleans” invaders entering the body to carry the immune surveillance. However, if dysregulated signals are received, these cells can misrecognize normal tissues as invaders, consequently producing various small molecules, which activate immune responses against themselves. Normal eye tissues can be injured in this manner, leading to blindness in some cases. We seek to understand how these cells are expanded and hyperactive in patients suffering from ocular inflammation, and have identified a subpopulation of these cells that are notably responsible for inflammation. Our goal is to develop a way to control these aberrant cells’ expansion and abnormal function, which holds great clinical potential with respect to treatment of eye inflammation.
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Multidisciplinary Ophthalmic Imaging Group
#1612 - D0027. Peek: Portable Eye Examination Kit. The Smartphone Ophthalmoscope. Iain Livingstone. May 5, 8:30am.
The Peek team are developing and testing an adapted smartphone using a bespoke app and clip-on hardware that allows comprehensive eye examination in any setting. Around 80% of blindness is curable or preventable, but most of the world’s 285 million people with visual impairment live in low-income countries, with minimal access to suitable healthcare. With the help of various partners, a team of eye surgeons, developers and engineers from the Glasgow Centre for Ophthalmic Research, London School of Hygiene & Tropical Medicine, and University of Strathclyde have developed Peek (the Portable Eye Examination Kit) - a suite that can be used by health workers lacking formal training and access to specialist equipment. The potential impact of Peek extends to high-income countries, allowing non-specialists to remotely transmit footage of eye abnormalities, expediting treatment by streamlining referrals. Peek consists of an app that measures a patient’s vision, with a clip-on adaptor enabling detailed imaging of the back of the eye, aiding diagnosis of various diseases. Data can be sent from phone to specialist anywhere in the world, allowing remote expert diagnosis. The team are currently comparing the results of comprehensive ophthalmic assessments using clinical standard equipment with examinations by community health workers using Peek.
#1634 - D0049. Optical-Sensor Guided Intelligent Micro-injector for Retinal Therapy. Peter Gehlbach. May 5, 8:30am.
This work presents a novel free hand micro-injector system that enables highly accurate positioning of a small needle tip, and injection of microliter scale fluid volumes. OCT guidance to achieve injection accuracy on the scale of 10 microns, using a handheld tool, represents progress in overcoming longstanding barriers to retinal therapy. A goal is to enable direct delivery of therapeutic agents such as nanoparticles, gene therapy vectors, stem cells and small molecules directly into the retina or other micron scale tissues.
#2173. Optical coherent tomography of intrinsic optical signal response at photoreceptor outer segments. Benquan Wang. May 5, 3:45pm.
The University of Alabama at Birmingham (UAB) investigators reports a method for functional mapping of retinal physiology at sub-cellular resolution. The retina is a delicate neural network, consisting of multiple types of cells for light sensing and visual information processing, located at the back of the eye. It is well known that different eye diseases can target different cell types, and physiological dysfunction of retinal cells may occur at early stage of eye diseases. Therefore, high resolution examination of retinal physiology is desirable for disease detection and treatment evaluation. Using a custom-designed optical coherence tomography (OCT) instrument, the UAB investigators demonstrated functional OCT mapping of transient light response correlated with physiological change at sub-cellular structures of photoreceptor cells in isolated retinas and intact animals. We anticipate that further improvement of the method will enable clinical test of retinal physiology at sub-cellular resolution, promising early detection and reliable treatment evaluation of age-related macular degeneration (AMD) and other eye diseases that can produce pathological changes of retinal cells.
#2174. Retinal Changes Associated with Hibernation Revealed by OCT Imaging. Wei Li. May 5, 3:45pm.
Imaging hibernating ground squirrel eyes helps to improve an eye examination tool The retina is a multi-layered sheet of tissue in the back of the eye that converts light into electrical signals that are relayed to the brain to form visual perceptions. Optical Coherence Tomography (OCT) is the most widely used imaging tool for evaluating the retina in patients. It provides detailed structural information about the different layers of the retina and enables clinicians to diagnose and manage various eye disorders. The separate bands seen on OCT scans correspond to different retinal layers. However, the identification of some of these layers lacks experimental evidence. To address this deficiency, we have turned to the hibernating ground squirrel as an experimental model for answers. We studied the adaptive changes of retinal structures during hibernation and these changes can be exploited to confirm or deny the correspondence of OCT signal bands to specific retinal structures. Our work with this model provided evidence for the recently proposed reclassification of OCT bands, which will improve clinical applications of OCT in eye examinations.
#2175. Single Source Fluorescence Imaging/Blue Optical Coherence Tomography in a GFP Mouse Model. Ryan McNabb. May 5, 3:45pm.
Optical coherence tomography (OCT) is a three-dimensional imaging method that has found common use both in the clinic and in basic science research. However, conventional OCT systems only detect anatomical structure and cannot detect fluorescent molecular markers that are regularly used in biological research that may provide functional information. The purpose of this project was to develop a simplified dual-modality imaging system that provided simultaneous anatomic imaging from OCT and fluorescent molecular imaging in a genetically modified mouse model. This offers scientists the potential to study both the ophthalmic anatomy and physiology of these animals as they develop.
#2176. Longitudinal In Vivo Imaging of Retinal Ganglion Cells Labeled with Cholera Toxin Subunit B. Corey Smith. May 5, 3:45pm.
The sense of vision enables us to richly experience and interact with the world around us, however eye diseases take away this experience and compromise the ability for full interaction. Age-associated vision loss is increasingly prevalent in our population consequently creating high costs to the delivery of health care. The retina is the tissue at the back of the eye that is affected in many of these diseases causing blindness and visual disability. Methods of early disease detection provide an improved prognosis and treatment, leading to greater quality of life and anticipated decrease in health care costs. The research I am presenting at ARVO consists of labeling and imaging retinal neurons (specialized cells responsible for seeing) in live animals. Imaging retinal neurons in animals is the starting point to understanding the challenges and requirements of completing the same task for patients in the clinic. The eye is a unique organ and the only part of the brain in that we can look into it and see the health of neural tissue without performing an invasive procedure. The ability to visualize single cells, particularly retinal neurons, will provide eye doctors with more information in preventing, diagnosing and treating eye diseases.
#5022. Investigating outer retinal oxygen supply using visible - light OCT. Hao Zhang. May 7, 3:45pm.
Prof. Hao Zhang from Northwestern University and colleagues developed an optical imaging technology that is able to quantitatively measure how much oxygen is being metabolized at the back of the eye; hence, this technology holds promise in better understanding, early diagnosis, and management of several significant blinding diseases including diabetic retinopathy. The novel technology is referred to as visible-light optical coherence tomography (vis-OCT). When wideband light within visible spectral range is shined to the back of eye, photons reflected by blood vessels and other ocular tissues carry different optical spectral information determined by specific tissue properties. After tomographic images of the posterior eye are reconstructed from the reflected light, blood oxygenation level, blood flow velocity, and blood vessel size are further obtained using a sophisticated algorithm. From these parameters, the research group was able to measure oxygen metabolic rate in the eye noninvasively, for the first time. The team also quantified oxygen metabolism variation in responding to various oxygen supplies. Owning to vis-OCT’s unique capabilities in measuring oxygen metabolism in the posterior eye, the researchers are aiming to make vis-OCT available for initial clinical test at the end of 2014.
#5883 - C0069. EyeArt: Advanced Image Analysis Tools for Diabetic Retinopathy Screening and Telemedicine Applications. Kaushal Solanki. May 8, 8:30am.
EyeArt is a set of advanced image analysis tools for fully-automated screening of diabetic retinopathy (DR), a blinding eye disease that can affect over 371 million diabetics worldwide, including estimated 35 million in America. Vision loss due to DR is preventable if diagnosed early, however, because the number of eye-care professionals cannot keep up with the fast-growing diabetic population, majority of diabetics do not get their recommended annual screening -- making DR the leading cause of blindness in the adult working-age population. The only realistic way to address this massive health burden is to expand DR screening to the primary care setup, and to make it much more efficient via computerized analysis. In this work, we present EyeArt, Eyenuk's patent-pending image analysis tool designed to exponentially expand DR screening by automatically analyzing retinal images, and instantly providing a refer/no-refer recommendation based on the presence or absence of lesions. These algorithms represent fundamental innovation in medical image analysis and have achieved diagnostic efficacy (sensitivity-specificity) that equals that of trained human readers. What’s more, EyeArt works on cloud-based cluster enabling analysis of hundreds and thousands of patient images in a matter of minutes. With its high diagnostic efficacy and scalable engineering, EyeArt is sure to have a high impact in managing the enormous social burden that is diabetes.
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Nanotechnology and Regenerative Medicine Group
#1435 - B0037. Measure of the intraocular pressure with three sensors during manual Perfluorocarbon Liquid injection in UV photo-crosslinkable polymer model of the human eye. Marco Dal Vecchio. May 5, 8:30am.
Introduced as a surgical technique for retinal detachment, three-port vitrectomy (TPV) has become a widespread procedure to address diseases of the vitreous and the retina. To perform TPV, the eye surgeons have to keep the eyeball pressure at a preset level to avoid damage to the delicate ocular structures. The newer surgical instruments have a control over the liquids or gases that are injected into the eye. Aim of our study was to measure the pressure into a model of eyeball during injection of fluids with manual and automated procedures. In the manual infusion the values of pressure on the inner wall of the eye is dependent on surgical experience and are much more variable than when controlled by the machine. This can potentially determine damage to the ocular structures.
#1437 - B0039. Evaluation of Bio-Immune Compatibility of Nanofibrous Scaffold for Corneal Tissue Engineering. Sahar Salehi. May 5, 8:30am.
The cornea is the most anterior and clear portion of the eye. An estimated 10 million people suffer from vision loss caused by corneal damage worldwide. For the worst cases, the only available treatment is transplantation with human donor tissue. In this context, insufficient supply of transplant material poses serious problems in numerous countries, which has stimulated the development of appropriate tissue substitutes by tissue engineering. Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences in order to develop biological substitutes that restore, maintain or improve tissue function. The present study aimed to construct corneal equivalents (scaffolds) to treat ocular surface disorders using a biomimetic concept, which constitutes the scaffold from oriented nanofibers. The fibers were spun from a biodegradable polymer and shall also be further modified for drug release in order to promote ocular surface reconstruction. The biocompatibility of the nanofibrous scaffolds was tested in vitro on human corneal cells. The scaffolds proved to be well suited for cultivation of corneal cells and did not promote cell death or trigger certain immune reactions. Further studies are under way to gain more insight into cell-scaffold interaction.
#1449 - B0051. Local Delivery of an Engineered Epithelial Monolayer by Micropatterned Polymeric Nanosheets. Hirokazu Kaji. May 5, 8:30am.
Micropatterned ultrathin films (nanosheets) are developed for local cell delivery. These biodegradable polymer nanosheets direct growth and development of a kind of eye cells, which play a central role in retinal physiology, and facilitate the injection of an engineered monolayer of cells via needle without causing the cells to die. Such ultrathin flexible carriers have the promise of minimally invasive delivery of cells into narrow tissue spaces such as the backside of the eye.
#4622 - A0190. Nanoceria with Grp78/Bip produce enhanced inhibition of retinal degeneration in tubby mice. Xue Cai. May 7, 11am.
The goal of our lab is to find an effective treatment for retina degeneration. The retina is that part of the eye which detects light and sends information to the brain for vision. Tubby mice have inherited retinal degeneration. Many eye diseases are caused by too many harmful molecules, called reactive oxygen species (ROS), which are produced in the eye. The endoplasmic reticulum (ER) is an important structure in the cell which makes proteins and folds them properly so they work. ROS cause folding problems in the ER which are called “ER stress”. We injected an AAV particle, which makes a key regulator protein of ER stress called Grp78/Bip, and unique tiny (nano) particles (nanoceria) beneath the retina in the eye of tubby mice. Our results showed that using AAV and nanoceria together produced much better effects on the regulation of ER stress, photoreceptor cell activity and the overall retinal structure than the injection of AAV or nanoceria alone. This suggests that AAV and nanoceria together may be an excellent therapy for slowing or preventing inherited blindness.
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#833. AAV-mediated gene therapy in Dystrophin-Dp71 deficient mouse leads to blood-retinal barrier permeability restoration. Ophelie Vacca. May 4, 3:15pm.
Many diseases causing impaired vision are associated to leakage of blood vessels (breakdown of the blood-retinal barrier) and liquid accumulation (edema) in the tissue responsible of vision in the eye. Ophélie VACCA and collaborators found that these symptoms can be treated in mice, by injection into the eye of particles containing dystrophin 71 gene. This finding is a major step forwards the development of new gene therapy treatments of highly frequent eye diseases such as diabetic retinopathy.
#1261. Therapeutic potential of topical ROCK inhibitor K-115 in diabetic retinopathy. Ryoichi Arita. May 5, 8:30am.
The increasing global prevalence of diabetes is a critical public health concern. In particular, diabetic retinopathy is a prevalent microvascular complication and a major cause of vision loss in diabetic patients. Vascular endothelial growth factor (VEGF) is signal protein overexpressed in the eyes of diabetics with retinopathy, and plays a central role in the development of diabetic retinopathy. Anti-VEGF therapy is widely used and effective for diabetic retinopathy. However, frequent injections into the eye are required for optimal therapy. Rho-associated protein kinase (ROCK) is a signaling molecule. Recently, we have been focusing on this molecule and investigating the therapeutic potential of the topical ROCK inhibitor K-115 in the treatment of diabetic retinopathy. K-115 can migrate from the surface to the back side of the eye significantly after topical administration. Moreover, topical administration of K-115 could improve the treatment of diabetic retinopathy. Topical K-115 treatment is expected to become a novel therapeutic strategy as “beyond VEGF” in the treatment of diabetic retinopathy.
#1937 - B0202. Generic, target-independent suppression of choroidal neovascularization by human IgG1 antibodies via Fc gamma receptor I. Tetsuhiro Yasuma. May 5, 11am.
Age-related macular degeneration (AMD) is a leading cause of blindness in the United States. In the “wet” form of AMD, blood vessels invade the retina to cause blindness. One of the most widely used and standard-of-care therapy for wet AMD is the antibody bevacizumab (Avastin), which prevents blood vessel growth in humans by specifically targeting the protein “VEGF-A.” Interestingly, bevacizumab also blocks blood vessel growth in a mouse model of wet AMD, even though it does not recognize the mouse version of VEGF-A. Therefore, we hypothesized that bevacizumab, and other antibodies, could block blood vessel growth independent of their target. We found that bevacizumab inhibited blood vessel growth in the mouse model of wet AMD via its common, non-targeted structure (IgG1-Fc), and that several other widely-used therapeutic human IgG1 antibodies also blocked blood vessel growth via their Fc domain and signaling through its receptor (Fcgr1). A major implication of this work is that IgG1 antibodies, which are used to treat millions of patients worldwide, could potentially produce unintended side effects (therapeutic or adverse) via vascular modulation. In addition, this work opens the way for the development of novel, cost-effective therapies for vascular-driven diseases (e.g. wet AMD), via next-generation IgG1-based pharmacologics.
#2888 - B0286. Role of Caveolin - 1 in Intraocular Pressure and Conventional Outflow Regulation. Michael Elliott. May 6, 8:30am.
Elevated eye pressure is the major risk factor in most types of glaucoma. Eye pressure is controlled by the rate at which fluid, called aqueous humor, is produced and the speed at which this fluid drains from the eye. In the normal eye, drainage is tightly regulated to maintain optimal pressure. The mechanisms that control fluid drainage likely involve a mechanical pressure sensor like a thermostat that causes drainage to increase if pressure increases and resists drainage if pressure is too low. The nature and cellular location of this “molecular thermostat” is unknown. Recently, human genetic studies have linked the CAV1/2 gene to increased risk of primary open angle glaucoma. This gene, which our laboratory has studied for several years, forms specialized domains in cell membranes called “caveolae.” There is emerging evidence that caveolae may be sensors for mechanical changes in cells, such as those resulting from increased eye pressure. In our ARVO 2014 presentation, we show that mice deficient in caveolae due to genetic removal of the Cav1 gene have increased eye pressure, reduced fluid drainage, and pathology associated with the drainage pathway. These findings have implications on our understanding of aqueous humor drainage and glaucoma.
#3025. Trabecular meshwork exosomes enhance cellular collagen uptake. W Michael Dismuke. May 6, 11am.
Glaucoma is a leading cause of irreversible blindness but we do not understand the underlying cause(s) of the disease. It is thought that the vision loss results from high pressure in the eye due to a problem draining a specialized fluid. We discovered that cells in the drainage area release small particles called “exosomes” that help remove a type of material found in the drain. We think the exosomes are a tool the cells use to maintain a delicate balance of support materials in the drainage area. An imbalance of these support materials can lead to high pressure in the eye and glaucoma.
#3300 - B0240. CEP290 gene addition rescues ciliogenesis in LCA patient cells. Erin Burnight. May 6, 11am.
Leber congenital amaurosis (LCA) is a term used to define a group of severe, inherited, childhood blinding disorders. Mutations in many different genes cause death of the retinal neurons that elicit vision and this degeneration leads to blindness. In this study, we aimed to determine if replacing the mutated gene, CEP290, corrects the cellular presentation of LCA. Using cells from LCA patients, we show that delivery of a functional gene does indeed correct LCA-associated cellular defects. These exciting results bring us one step closer to providing gene- and cell-based therapies to patients affected with this devastating disorder.
#3321 - B0261. RPGR gene augmentation delivered at early, mid and late stage disease in a canine model of XLRP rescues photoreceptor structure and function. William Beltran. May 6, 11am.
A consortium of investigators from the University of Pennsylvania and the University of Florida are spearheading the development of a gene therapy for an X-linked form of retinitis pigmentosa – an inherited retinal degeneration that is transmitted from mothers to sons, and is caused by a mutation in a gene called RPGR. This consortium successfully demonstrated two years ago that gene therapy delivered to dogs affected with a similar condition could prevent the onset and stop the progression of the disease if treated at an early stage. Recent work (presented at the Association for Research in Vision and Ophthalmology 2014 meeting), now shows that positive rescue of photoreceptors (the cells in the retina that capture light and transform it into an electrical signal that is subsequently sent to the brain) is persistent nearly two years after the gene therapy was delivered to dogs. In addition, animals treated at mid and advanced stages of retinal degeneration also remain responsive to the intervention. These latest findings provide hope that gene therapy may soon become a reality for patients affected with this severe and common form of inherited blindness.
#5999. Oral Delivery of ACE2 or Ang-(1 - 7) Bioencapsulated in Plant Cells Protect against Experimental Uveitis and Autoimmune Uveoretinitis. Pollob Shil. May 8, 12noon.
Inflammation of the eye is a serious condition that can cause impaired vision or even severe vision loss and is also a key underlying factor in eye diseases like age-related macular degeneration and diabetic retinopathy. Current treatment options are limited and typically relying on the use of drugs which has serious side effects. Our previous studies have identified two new anti-inflammatory protein targets. However, delivery of protein drugs to the eye has been a major challenge. This study takes advantage of an innovative technology based on the use of plant cell as highly efficient bioreactors for production and oral delivery of therapeutic proteins (named as ACE2 /Ang-(1-7)).The plant made therapeutic proteins are protected in the stomach from acids/enzymes, but are released in the gut when plant cell walls are digested by commensal microorganisms. The therapeutic protein is fused to a carrier protein, which not only facilitates the entrance into circulation, but also enhance uptake by target tissues such as eye. We showed that oral feeding with ACE2 or Ang-(1-7) produced in plant cells significantly reduced inflammation in two animal models of eye inflammation. Thus, this technology provides an efficient, cost-effective and patient-friendly approach to treat ocular diseases.
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#589 - B0116. Relationship of Posterior Vitreous Detachment to Frequency of Intravitreal Injection of Anti-Vascular Endothelial Growth Factor for Age-Related Macular Degeneration. Lisa Faia. May 4, 1:30pm.
Age-related macular degeneration (AMD) is a disease that affects the macula, the area of the retina (the film in the back of the eye) that is responsible for one’s fine and central vision. It is the leading cause of severe vision loss in industrialized countries. There are two forms of AMD: dry and wet. Though currently there is no cure for AMD, treatments are available to slow its progression. For the dry form, there are specially formulated eye vitamins and for the wet form, the mainstay of treatment involves injections of medications directly into the eye. The vitreous is the gel of the eye. As one reaches middle age, it condenses and liquefies, causing floaters and a posterior vitreous detachment (PVD). A PVD occurs when the vitreous separates from the back of the eye. Previous retrospective studies have suggested that the state of the vitreous, particularly the presence of a PVD, may influence the number of injections needed to treat wet AMD. In our prospective trial, we found the odds for getting at least one injection was 2.05 times higher for patients without a PVD. This may affect the way we counsel and treat patients with wet AMD.
#604 - B0131. Efficacy and Safety of Intravitreal Aflibercept Injection (IAI) for Treatment of Macular Edema Secondary to Branch Retinal Vein Occlusion (BRVO): 24-Week Results of the VIBRANT Study. David Boyer. May 4, 1:30pm.
The standard of care for the treatment of branch retinal vein occlusion (the second most common vascular occlusion) has been observation and/or laser. The Vibrant study clearly showed the overwhelming benefit of aflibercept in improving vision while maintaining an excellent safety profile compared to laser. This study will change the paradigm for treatment of branch retinal vein occlusions.
#1648. Gastrointestinal serious adverse events in patients treated with intraocular ranibizumab or bevacizumab for age-related choroidal neovascularisation, what do the recent trials tell us? Lauren Scott. May 5, 11am.
Adverse events involving the gastrointestinal (GI) tract have been identified as an area of concern in studies where bevacizumab was administered systemically. The purpose of this study was to synthesize the evidence on the frequency of reported GI events in head-to-head randomised controlled trials (RCTs) of ranibizumab versus bevacizumab injected into the eye for treatment of age-related choroidal neovascularisation. We collated the results from six recently conducted RCTs of ranibizumab versus bevacizumab and undertook an analysis to quantify the incidence and risk of a GI event. Data from the CATT, IVAN, GEFAL, MANTA, LUCAS and BRAMD studies were included. Collectively 1699 patients were treated with ranibizumab and 1657 with bevacizumab. CATT and IVAN followed patients for two years; one year results were available for the other trials. Pooling the results from the six studies, 74 patients (ranibizumab: 26, 1.5%; bevacizumab: 48, 2.9%) reported a GI serious adverse event (SAE). The relative risk of a GI SAE was estimated to be almost double with bevacizumab compared to ranibizumab (relative risk 1.87, 95% CI 1.17-2.98, p=0.009). However examination of these SAEs did not provide insights into the nature of abdominal pathology, as a wide variety of symptoms and diagnoses were reported.
#3066. United Kingdom Neovascular AMD Database study: Time to reactivation after a pause in treatment - outcomes from 92,000 intravitreal ranibizumab injections. Pearse Keane. May 6, 11am.
Ranibizumab is the first successful treatment for age-related macular degeneration (AMD), the commonest cause of blindness in Western Countries. Patients commonly receive three initial injections of ranibizumab, followed by further treatment only if active disease is detected at monthly assessment visits. While successful, the need for monthly medical visits over many years - sometimes seven years or longer - imposes large burdens on patients. The effectiveness of ranibizumab in AMD was demonstrated in the MARINA and ANCHOR studies; while these trials were of huge significance, they involved only approximately 1200 patients in total, followed for only a two-year time period. In this abstract, we explore the use of ranibizumab in "real-world" settings over extended time periods, and use the potential of "Big Data" - an emerging field that involves the collection of massive datasets - to provide direct improvements for patients with AMD. Using the electronic medical records (EMR) of the United Kingdom (UK) National Ophthalmology Database, we evaluate the outcomes from 92,000 ranibizumab injections over a five year time period. In particular, we examine the time to reactivation after pauses in treatment. In doing so, we hope to significantly reduce the burden of disease for patients by demonstrating that less frequent visits to the doctor's office are required for those patients whose AMD has been stable for fixed lengths of time.
#3408 - C0101. Fast Fluid Detection in 3-D Macular OCT Scans. Gwenole Quellec. May 6, 11am.
The macula is the part of our retina specialized in high acuity vision. A large proportion of older adults develop a medical condition, called age-related macular degeneration, which alters their macula: reading or recognizing faces becomes very difficult. These alterations can be temporarily attenuated or eliminated by injecting a medication into the patient’s eye. Optical Coherence Tomography (OCT) is a 3-D medical imaging modality commonly used by ophthalmologists to detect these alterations and therefore decide whether or not an injection is needed. Our research aims at detecting these alterations in OCT images automatically. Automatically detecting these alterations would allow a significant increase in the number of eye examinations. We hope this will help reduce those time intervals where patients lose their high acuity vision.
#3931 - C0233. Treat and Extend regimen versus Pro Re Nata regimen in a comparative study of ranibizumab in exudative age-related macular degeneration: 12 months results. Katja Hatz. May 6, 3:45pm.
Inhibitors of vascular endothelial growth factor (anti-VEGF), such as ranibizumab, are the gold-standard for the treatment of exudative age-related macular degeneration (AMD). However, a key factor for the efficacy of these drugs is the schedule of diagnostic evaluations and injections of the drug. While various treatment regimens are used worldwide in Europe the Pro Re Nata (PRN) regimen based on monthly optical coherence tomography (OCT) evaluations with retreatment in case of disease activity is currently favored. Applying the Treat & Extend (TE) protocol the interval of diagnostic examinations and treatments is individually determined for each patient based on disease activity. In case of disease stability the interval is extended, in case of instability it is shortened. In the study two consecutive patient groups were treated either with the TE or the PRN regimen. 140 treatment naïve patients with exudative AMD were included (70 in each group). Our results showed that the TE regimen resulted in better visual acuity (VA) outcomes and less VA oscillations during the treatment period compared to PRN treated eyes at 12 months. The number of injections in the TE treated eyes was slightly higher but the need of follow-up visits was minimized following the TE treatment regimen.
#3970 - C0272. Long - Term Visual Outcomes for a Treat and Extend Anti - VEGF Regimen in Eyes with Neovascular Age-Related Macular Degeneration. Sarah Mrejen. May 6, 3:45pm.
In industrialized countries, age-related macular degeneration (AMD) is the leading cause of severe vision loss among people aged 50 and older. Intraocular injections of anti-vascular endothelial growth factor agents have revolutionized the treatment of the wet or neovascular form of this disease by dramatically improving its visual prognosis. Clinical trials of have demonstrated the best visual results are achieved with a fixed regimen of injections given every month. We present the first long-term visual results using an alternative strategy called “Treat and Extend.” With Treat and Extend, the frequency of office visits and injections are tailored to each patient’s individual response to therapy. Over a mean follow-up period of 3.5 years, 210 eyes of 185 patients the mean number of visits and injections was reduced to 8.3 per year. Long-term visual results were similar to those previously reported with monthly therapy. We conclude that the Treat and Extend dosing regimen provides an effective alternative to monthly therapy and reduces the burdens associated with frequent anti-VEGF therapy including risk of systemic and ocular complications for patients, time invested for treatment by the patient and family, as well as the cost for patients and society.
#4534. The Progression of Hydroxychloroquine Retinopathy Depends on the Severity of Disease. Michael Marmor. May 7, 11am.
The drug Plaquenil (hydroxychloroquine) is widely used for treating rheumatoid arthritis and lupus, but becomes toxic to the retina (light-sensitive tissue inside the eye) at high doses or after years of use. Doctors used to check the retina for a “bull’s eye” lesion (ring of scarring around the center of vision), but this represents severe damage that may worsen even after stopping the drug. Earlier stages of toxicity can be detected with sensitive techniques such as automated field-of-vision tests and optical coherence tomography (OCT), a test that images retinal cell layers. However, no one has demonstrated whether early detection actually stops the progression of damage or makes a difference in outcome. We studied patients at different stages of Plaquenil toxicity when it was discovered. After stopping the drug, and they were followed for several more years. When patients had a bull’s eye lesion, the damage worsened steadily for at least 3 years and threatened vision. But when toxicity was discovered early, there was little progression and no risk to visual acuity. These results tell rheumatologists and eye doctors that proper early detection of Plaquenil toxicity, using sensitive techniques, can truly prevent a loss of eyesight.
#4941 - D0051. Prospective evaluation of Tele - Ophthalmology in initial screening and recurrence monitoring for wet Age - related Macular Degeneration (AMD). Bo Li. May 7, 11am.
Age related macular degeneration (AMD) is eye condition that disproportionally affects the older population. With the aging population, more and more people will likely be diagnosed with and require treatment for AMD. The treatment regimen of AMD requires frequent visit (as frequent as monthly) to the doctors for testing, counselling and/or treatment in the form of an injection into the eye. This strict and frequent monitoring and treatment regimen poses significant difficulties to patients, their families and incurs tremendous amount of financial cost to the society. Therefore, in our study, we looked at using remote testing centers for the screening and monitoring of AMD. With remote testing centers, patients no longer need to travel long distances to see their doctors, they are able to get tested at their nearest testing center and the testing results and images will be electronically sent to and be analysed by their doctors remotely. We demonstrated in our study that the remote testing of AMD does not result in treatment delay in term of AMD screening and it is equivalent to traditional doctor office based testing in term of AMD monitoring. It also has the benefits of reduced patient travel and physician clinic patient load.
#4977 - D0087. Morphological features and determinants of new geographic atrophy developing in participants in the IVAN trial. Frank Picton. May 7, 11am.
Injections of drugs known as VEGF inhibitors into the eye have improved the outlook for persons suffering from neovascular age related macular degeneration (nAMD). This condition arises as a consequence of the growth of abnormal blood vessels that leak fluid into the macula of the eye Since anti VEGF’s were introduced around 2008 there has been insufficient time for researchers to understand what late effects might arise that would be detrimental to the well-being of central vision. VEGF is important for the health of blood vessels and the retina. The anti VEGF drugs stop leakage from the abnormal blood vessels and cause them to shrink. However anti VEGF could block the good effects of VEGF on normal tissues. The consequence would be atrophy (a process of cell death). In AMD a type of atrophy called GA is common. Therefore we systematically examined the rate of development of GA in eyes exposed to two types of anti-VEGF and two different treatment regimens in the IVAN trial. Overall 177 persons were found to develop GA and this occurred more frequently when treatment was given every month compared to as needed. In 30 of 177, GA occurred in an area of retina that was outside the original lesion. In these > 50% also developed GA within the original lesion at a site where there was a pigment epithelial detachment. While we cannot rule out an increased risk of atrophy developing when treatment is given frequently, our findings suggest that pre-existing characteristics of the AMD lesion is a predisposing factor for GA.
#5010. High Dose Docosahexaenoic Acid (DHA) Supplementation in X - Linked Retinitis Pigmentosa (XLRP): A 4 - Year Randomized, Controlled Clinical Trial. Dennis Hoffman. May 7, 3:45pm.
Individuals with the inherited eye disease, X-linked Retinitis Pigmentosa, begin to lose night-vision within the first decade of life followed by declining visual acuity and peripheral vision (i.e., side-vision). Among the leading candidates for slowing disease progression is the omega-3 fatty acid, docosahexaenoic acid (DHA), which is found in cold water fish such as salmon and tuna and is enriched in photoreceptor cells of the retina. In a placebo-controlled clinical trial, we tested whether high daily doses of DHA could limit vision loss. After four years, we found no difference in the electrical signals reflecting cone photoreceptor function between placebo and DHA-supplemented patients. Similarly, secondary measures of night-vision and letter acuity were not different between patient groups. We did, however, find benefits in some supplemental measures such as the rate of decline of peripheral visual fields in patients receiving DHA. In conclusion, primary and secondary outcome measures failed to demonstrate that DHA supplementation slows the rate of disease progression.
#5011. Aberrant Dolichol Chain Length Distribution as Biomarkers for Retinitis Pigmentosa Associated with DHDDS Genotypes. Byron Lam. May 7, 3:45pm.
Retinitis pigmentosa is a group of inherited conditions affecting the retina, the layer inside the eye that produces biologic visual signals from light rays coming into the eye. Many different types of genetic changes can cause retinitis pigmentosa. One particular type of retinitis pigmentosa with recessive inheritance is caused by a problem with an enzyme called dehydrodolichol diphosphate synthase (DHDDS). DHDDS is involved in making a fat molecule called dolichol that is important to maintain the outer wall of every cell in the human body. DHDDS retinitis pigmentosa patients have only eye problems, because the light sensing cells in the retina are particularly vulnerable to dolichol shortage. We discovered a unique quick test to detect the altered dolichol composition in the urine and blood of DHDDS retinitis pigmentosa patients with different DHDDS mutations. The test is considered a biomarker test and can easily determine if changes in the DHDDS gene causes the retinitis pigmentosa in a patient or whether a person is a carrier of a DHDDS genetic change. The test can also detect any changes on other genes that affect the making of dolichol. The non-invasive collection of urine makes the test very clinic-friendly, especially for children.
#5874 - C0060. Evaluation Of Multicolor Spectral Reflection Imaging (488 nm, 536 nm & 786 nm) In Comparison With Color Photography, Autofluorescence And Spectral Domain OCT imaging In A Consecutive Series Of Patients With Retinal Disorders. Simone Kellner. May 8, 8:30am.
Visual communication is very important in our daily life. The retina of our eyes (the photosensitive layer, almost like the `chip´in your digital camera) detects and processes visual information. Disorders of the retina can impair our vision and may markedly interfere with our daily life. Early detection of diseases affecting the retina is therefore important to preserve our visual abilities. We have investigated a new technique evaluating the retina using blue, green and red laser light illumination either separate or combined. Compared to previous techniques of photography of the retina the advantage of this new technique are images with more details and higher resolution. The different laser lights allow to separately analyze different parts of the retina. The new technique facilitates the early detection of retinal diseases and improved screening for retinal diseases as well as earlier onset of treatment. More so, this technique needs no dye or contrast medium and so minimizes the potential risks in the diagnostic process.
#5899 - C0085. Ocular and Systemic Adverse Events Asociated with Intravitreal Bevacizumab in the Treatment of Retinopathy of Prematurity. Victoria Gonzalez. May 8, 8:30am.
in The treatment of retinopathy of prematurity, we report the adverse events associated with injections of a drug called Bevacizumab for the treatment of Children who were born prematurely and had an eye disease called Retinopathy of Prematurity. Our study was performed in 262 babies (418 eyes), inyected Bevacizumab and we found 71 local adverse events, localized in the eye that were injected, that corresponds to 16.9%. The sistemic adverse events were related to the preterm status of the babies not to the injections.
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Retinal Cell Biology
#696 - C0239. In vivo retinal development using hand held ultra-high resolution spectral domain optical coherence tomography in premature and full term infants. Samira Anwar. May 4, 1:30pm.
Premature infants are at an increased risk of having visual problems compared to term babies (born on time). Our study investigates the rate of central retinal development in premature infants using Hand Held Optical Coherence Tomography (HH SD-OCT). This is a new portable technology allowing detailed imaging of infant eyes in living subjects for the first time, particularly the retina which is a layer at the back of the eye containing light sensitive cells (photoreceptors). The retina has visual processing inner layers and visually sensitive outer layers. The central retina is called the macula. It is normally thinner than the peripheral retina and responsible for the sharpest vision.
Our results show that the macula is thicker in babies born prematurely compared to term babies, even by the time premature infants reach similar ages. Also, the visually sensitive photoreceptor outer layers appear to be less well defined using HH SD-OCT in premature babies. This may be significant with respect to vision development in childhood although this still requires further study while the babies grow and vision may be more reliably measured. Hopefully, this information and continued research will increase future understanding of retinal development and visual disease in premature infants.
#697 - C0240. Microphthalmia-associated Transcription Factor (MITF) affects optic vesicle cell proliferation and retinal pigment epithelium maturation in human ES cell (hESC) cultures. Anna Petelinsek. May 4, 1:30pm.
An understanding of early human eye development is essential for producing stem cell-derived retinal cell types for use in future therapies to combat common causes of blindness such as retinitis pigmentosa and age related macular degeneration. We have developed a human embryonic stem cell (hESC) model system that recapitulates the hallmarks of mammalian retinal development. We used molecular genetics to eliminate the function of an essential retinal gene, Microphthalmia associated transcription factor (MITF), in hESCs and used it to show that MITF plays important and distinct roles at different times during normal human eye development. These studies provide the foundation for future work on the molecular basis of retinal cell specification and may lead to improved methods for generating cells for treating retinal degenerative disorders.
#710 - C0253. Hedgehog signaling regulates cell movements underlying choroid fissure formation. Kristen Kwan. May 4, 1:30pm.
Coloboma, a birth defect and significant cause of blindness worldwide, results from errors in the formation of the proper structure of the eye. Genetic studies have identified mutations in many genes responsible for coloboma, yet we have a poor understanding of normal eye formation, as well as how the birth defect actually arises. Here, we use the small freshwater zebrafish Danio rerio as a model to study how the eye acquires its structure and how this process is disrupted in coloboma. We can watch the eye form in four dimensions in a living embryo under normal conditions, and conditions in which a gene responsible for human coloboma is mutated. In this way, we are, for the first time, determining specific cell movements that are disrupted that contribute to the structural defects in the eye in coloboma.
#1381 - A0137. Elucidating the role of FGF signaling using an iPS cell model of retinal development. Eric Clark. May 5, 8:30am.
The Gamm Laboratory has developed a protocol for making primitive human retinal structures (optic vesicles) in a dish that give rise to every major neural retina cell type. For the present study, the optic vesicles were made from stem cells reprogrammed from the blood cells of a patient with a rare form of microphthalmia (“small eyes”) caused by a mutation in the VSX2 gene. VSX2 is important for proper growth and development of the retina in the eye, perhaps by influencing the production of a group of powerful signaling molecules known as fibroblast growth factors, or FGFs. By investigating FGF expression in our stem cell-derived mutant VSX2 optic vesicles and providing FGF supplements, we sought to further elucidate the role of these factors in human retinal development. We discovered that adding FGF9 corrected many of the defects inherent to the VSX2 mutant optic vesicles. In particular, FGF9 improved cell proliferation and restored proper differentiation of the mutant optic vesicles, shedding new light on the role of this factor in human retinal development. In addition, this knowledge may prove useful for efforts to produce retinal cell types from stem cells for therapeutic purposes.
#1386 - A0142. Generation of ciliary epithelium from mouse ES and iPS cells. Hirofumi Kinoshita. May 5, 8:30am.
Recently, Eiraku et al reported a protocol for self-organizing optic-cup morphogenesis in three-dimensional culture. With this procedure, we could differentiate mouse embryonic stem (ES) cells or mouse induced pluripotent stem (iPS) cells into neural retina as well as tissue derived from neural ectoderm in the three-dimensional structure. The ciliary body (CB) of the mammalian eye is responsible for secreting aqueous humor to maintain intraocular pressure at physiological range. The CB contains the ciliary epitheliums and the stroma, the ciliary epitheliums are derived from neural ectoderm. Here, we report a possibility that ciliary epithelium could be differentiated from mouse ES/iPS cells.
#2675. Using patient - derived iPSCs to identify new drug treatments for JNCL. Luke Wiley. May 6, 8:30am.
Juvenile neuronal ceroid lipofuscinosis, also called Batten disease, is a devastating childhood disorder that causes blindness, epilepsy, decreased motor function and death by the second decade of life. Batten disease usually presents to ophthalmologists because the cells responsible for visual acuity are the first to succumb to manifesting disease. Batten disease is inherited in a recessive pattern (one copy of the mutated gene from each parent) and typically involves mutations in the gene, CLN3. There is no cure for Batten disease and treatments to slow disease progression are very limited. We have generated stem cells from affected patients to model Batten disease for the purpose of testing drug, gene replacement and gene correction strategies for the treatment of this devastating disease.
#3986 - D0045. Using stem cells to develop gene therapy for Batten Disease. Budd Tucker. May 6, 3:45pm.
Using stem cells to develop gene therapy for Batten Disease. Lay Summary: Batten disease is a devastating childhood disorder that causes blindness, epilepsy, decreased motor function and death by the second to third decade of life. Batten disease usually presents to ophthalmologists because the cells responsible for visual acuity are the first to succumb to the disease. Batten disease is inherited in a recessive pattern (one copy of the mutated gene from each parent) and typically involves mutations in the gene, CLN3. There is no cure for Batten disease and treatments to slow disease progression are limited. We have generated stem cells from affected patients to model Batten disease for the purpose gene replacement and gene correction strategies for the treatment of this devastating disease.
#5989. Analysis of the VEGFR-1,-2, and -3 distribution in the adult mouse retina and choroid and the effect of Notch activation on these receptors in laser-induced CNV. Anne Alex. May 8, 12noon.
Diseases of the back of the eye, in which uncontrolled vessel growth leads to visual impairment, such as age-related macular degeneration or diabetic retinopathy, are promoted by one main factor, so called vascular endothelial growth factor-A (VEGF-A). The current treatment of these diseases is mainly the injection of “anti-VEGF”, which blocks VEGF-A. Docking sites (receptors) are needed to transmit VEGF-A signaling. In addition to the known VEGF receptor 2, we could identify VEGF receptor 3 to be distributed over the back of the eye in the retina and the choroid. The factor Notch has the opposite role to VEGF-A and has been shown to reduce blood vessel growth. In an animal model for uncontrolled blood vessel growth, we could show reduced vascular permeability when Notch was activated. We identified two targets, VEGF receptor 3 and Notch, in which the occurrence of VEGF receptor 3 might explain a bad response to the current anti-VEGF treatment and Notch might be a new identified target in uncontrolled blood vessel growth/vascular permeability in the back of the eye.
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All abstracts accepted for presentation at the ARVO Annual Meeting represent previously unpublished data and conclusions. This research may be proprietary or may have been submitted for journal publication.
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