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Katrina Norfleet
Posted: 5/7/2017


Emerging trends and hot topics: Presented Sunday, May 7 at the ARVO Annual Meeting


Baltimore, Md. ― In their own words, First Authors at the 2017 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 7, 2017.

Anatomy and Pathology/Oncology
#161 - 1107 - B0527. Choroidal Structure and Relation to Responses to Imposed Defocus in Young Guinea Pigs. 3:15pm.
With changes in our life styles, myopia (near-sightedness) is becoming an increasing problem, with half of the world’s population likely to be affected by 2050. Because myopia is a product of eyes growing too long, there is much interest in understanding how eye growth is controlled and so excessive growth can be prevented. Our group has found that just like people, some strains of guinea pigs are more susceptible to myopia than others. In my study, I found strain-related differences in the thickness and structure of the choroid, a layer of blood vessels in the wall of the eye. This layer provides nutrients to the eye and also warms it in cold weather. It is now also believed to have an important role in controlling eye growth. My results suggest that having a thicker choroid may offer some protection against from over growing and thus myopia.

#161 - 1097 - B0517. Towards elucidation of the myopia signaling cascade: association of human cone system electrophysiological response parameters with a myopia susceptibility polymorphism. 3:15pm.
Short sightedness (myopia) is becoming more and more common worldwide. Not only does it mean needing glasses, but it also increases the risk of other problems that can cause blindness.

Myopia is usually caused by the eye growing too long so that light is not focused correctly on the layer at the back of the eye called the retina. The retina detects light and turns it into an electrical signal that is sent to the brain. We know that signals from the retina control eye growth, but we do not know what these signals are. We also know that certain versions of certain genes make people more likely to develop myopia, but we do not know how.

In our study we recorded electrical responses from the retina in over 150 volunteers. These volunteers had blood tests to see which versions they had of a gene that has been linked to myopia. We found that the electrical responses generated by certain nerve cells in the retina were different depending on which version of the gene the volunteers had. This means that the electrical activity of these nerve cells may be important in causing myopia. This could help us understand how short-sightedness develops.


#161 - 1115 - B0535. Morphological changes of scleral fibroblasts in a murine lens-induced myopia model. 3:15pm.
Human eye is ball-like shape tissue. Recently, people who has a deformation of the eye shape (extend back to forth length resulting to fusiform shape) have been increasing especially in Asian country. This deformation is cause of nearsightedness. Several report estimated more than 80% people has nearsightedness in Asian country and dramatically increased in other countries including America. As was the case with the development of treatment for many diseases, to conquer the nearsightedness boom in worldwide, we have to know what biological changes occur in eyeball and how eyeball is deformed during nearsightedness development. In the conference, our group will answer what biological changes occur in eyeball during nearsightedness development using mouse model.

Clinical/Epidemiologic Research
#108 - 181 - B0125. Newly identified genes for refractive error and risk of myopia. 8:30am.
Myopia (shortsightedness) is a disorder caused by a complex interplay between genetic and environmental factors. Up to now, more than 100 genetic factors have been identified. We studied whether we could distinguish persons with myopia from persons with hyperopia based on their genetic background. For 10,792 participants of the Rotterdam Study, we calculated an individual genetic risk score; the higher the score, the higher the chance of being myopic. Our study showed that we still have not identified all myopia genes. Nevertheless, based on currently known genes, we were able to discriminate well between persons with low and high risk of myopia. Persons with the highest genetic risk had an almost 10x higher risk of myopia.

Eye Movements/Strabismus/Amblyopia/Neuro-Ophthalmology
#140 - 762 - B0601. Stepping into the virtual unknown: feasibility study of a virtual reality-based test of ocular misalignment. 1:30pm.
Strabismus, or squint, describes any misalignment of the eyes, and can affect both children and adults. It can have significant impact on visual function, and its appearance has substantial psychological and social ramifications. In order to determine the best treatment, tests of strabismus are performed in eye clinics. However, these tests require specialized equipment and training to perform, and are very operator dependent.

Our case series describes the first use of a virtual reality headset in assessing eye misalignment, and demonstrates that it is a feasible test of strabismus. Comparison of results with traditional tests of strabismus indicate good agreement across a range of common pathologies.

The low cost of virtual reality headsets opens exciting possibilities for clinical testing and automated diagnosis of patients outside of the eye clinic. Optometrists could make diagnoses prior to referral, while neurologists could assess patients in their own clinic or at the bedside. As the technology matures, we believe a complete assessment of squint could be performed by non-specialists using only a virtual reality headset.

#152 – 866. Out of the blue: Effects of blue-filtering lenses on EEG and eye movements during reading. 4:45pm.
The increasing use of computer and mobile devices screens also means that our eyes are exposed to larger amounts of blue light than in normal environments. Previous studies have shown that this may lead to sleep problems and may also adversely affect concentration. Solutions to this issue include dimming the blue light in computer screens or wearing glasses that filter out the blue light. In our study, we test how such glasses affect both eye movements and brain activity during a simple reading task. We show that even a brief period of 30 minutes of wearing the glasses leads to changes in brain activity that are consistent with a more relaxed brain state, as well as to more efficient eye movements during reading. Overall, our results provide further validation for the effectiveness of blue-light filtering lenses.

#104 - 13 - A0001. Effect of Sildenafil Citrate on Choroidal Thickness in Age-Related Macular Degeneration. 8:30am.
Age related macular degeneration (AMD) is a common eye condition and a leading cause of vision loss among the elderly. AMD damages the retina, the light-sensitive tissue that allows us to see. Despite intensive research, the pathogenesis of AMD remains unclear. The choroid is a layer of blood vessels that supply part of the retina. Our team is interested in studying how blood flow to the choroid affects the development and progression of AMD.

There are two forms of AMD. The dry form involves deposits of waste products called drusen, which can eventually lead to retinal atrophy. In the wet form of AMD, new blood vessels grow in the choroid and can bleed and form scar tissue.

Sildenafil citrate is a drug that dilates blood vessels and is most commonly used to treat erectile dysfunction. Previously, it has been shown that the choroid dilates in response to sildenafil citrate in healthy young subjects. In our study, we measured thickness of choroidal vessels before and after oral administration of sildenafil citrate in subjects with both wet and dry AMD. We found that sildenafil citrate increases choroidal thickness in both forms of AMD. However, eyes with dry AMD demonstrated a slower rate of increase, particularly in patients with end-stage disease called geographic atrophy. This suggests that stiffening of choroidal vessels may play a role in the pathogenesis of some forms of AMD.

#104 - 15 - A0003. Personalized Prognosis in Early/Intermediate Age-Related Macular Degeneration based on Drusen Regression. 8:30am.
Age-related macular degeneration (AMD) is a devastating disease of the back of the eye (retina) that affects elderly people. The retina produces metabolic waste during visual function. This is normally disposed, but in AMD deposits called drusen start to accumulate under the retina. However, at some point they can suddenly disappear and often a more severe form of AMD develops precisely at that location. The challenge is that it currently unknown when and where such event will occur in a given individual. In this work, we automatically analyzed high-resolution scans of the retina and measured a number of parameters inside and around the drusen. From this set of measurements, artificial intelligence (AI) was trained to recognize which of these drusen will disappear and in which time-frame. At the same time, we can inspect which measurements were used by the AI, obtaining insight into their predictive value. The results are expected to advance our understanding of AMD, help identify patients at greater risk of progression and thus adjust their personalized screening schedule. Finally, they may help develop therapies for early treatment before AMD advances into severe forms, which is currently a large unmet clinical and social need.

#153 - 871 - A0050. The Real World Effect of Anti-VEGF Injections on IOP Using the IRIS Registry. 3:15pm.
This study examined whether anti-VEGF drugs, a type of treatment used for diseases with abnormal blood vessel growth in the retina, are related to sustained intraocular pressure (IOP) increases, which are a risk factor for glaucoma. Over 23,000 patients were followed for at least 1 year by using a large database called the IRIS Registry maintained by the American Academy of Ophthalmology. Three groups were examined: all patients, those patients with web age related macular degeneration and those who had not been treated with these drugs for a year before the study started. There was an overall trend for a small decrease in eye pressure over time. However, a small subset of patients (2-3%) had a clinically significant pressure rise. Interestingly, those who received over 25 injections of one of the drugs, bevacizumab, had an increased risk of clinically significant IOP rise, with a risk of almost 10%. This indicates that, although these drugs are overall associated with a low rate of clinically significant higher IOP, those who receive many bevacizumab injections have an increased risk of a sustained IOP rise.

#104 - 19 - A0007. Automated 3D Choroidal Segmentation Using Multimodal Complementary Information. 8:30am.
Choroidal changes have been suggested to be of relevance to the appearance and progression of geographic atrophy (GA). GA is a manifestation of late-stage age-related macular degeneration - the leading cause of blindness in people over 65. Techniques to rapidly and precisely quantify choroidal changes would appear to be of great value in advancing the understanding of GA pathogenesis and the effectiveness of emerging potential agents.

Recent advances in 3D spectral-domain optical coherence tomography (SD-OCT) have enabled enhanced depth imaging to better visualize the choroid. Although automated choroidal detection algorithms in 3D OCT images (including ours) have been developed, they were prone to detection failure in the regions with GA. Fundus autofluorescence (FAF) - a 2D imaging technique, provides a high contrast for the identification of GA. We thus developed a novel 3D OCT choroidal detection approach which utilized the GA information from companion FAF images. To validate the algorithm performance, we automatically detected the 3D OCT choroid in 43 eyes using the approaches with and without FAF information respectively, and compared the results to manual delineation from masked certified OCT graders. With FAF information, the accuracy of the automated 3D OCT choroidal detection was significantly improved.

#104 - 29 - A0017. Effect of Human Central Nervous System Stem Cells Subretinal Transplantation on Progression of Geographic Atrophy Secondary to Non Neovascular Age-Related Macular Degeneration. 8:30am.

Age-related macular degeneration is an important cause of blindness worldwide. Even with the development of effective anti-angiogenic therapies for the neovascular form, many patients eventually lose vision due to atrophy of the retinal photoreceptors.

Thus far there have been no effective approaches to arrest the progression of geographic atrophy or improve vision. Stem cells have been explored as a possible therapeutic approach and are being evaluated in early phase trials.

Eleven patients with geographic atrophy in both eyes participated in this IRB-approved pilot study (NCT: CL-N01-AMD) of stem cell therapy. Each patient received a subretinal injection of human central nervous system stem cells to one quadrant of one eye. The growth of geographic atrophy was measured over the next year. At 12 months, the average rate of lesion progression was slower towards the quadrant in which the stem cells were injected, compared to the remote quadrants, as well as all quadrants of the fellow eye. Of note, a reduction in enlargement rate was not observed if only the total lesion (as opposed to specific quadrants) was considered.

To our knowledge, this is the first study to show localized reduction of GA enlargement at the site of stem cell therapy. Larger confirmatory studies are necessary, but these results emphasize the importance of considering regional lesion growth rates when assessing stem cell therapies.

#104 - 32 - A0020. Imaging Hydoxyapatite in sub-RPE Deposits by Fluorescence Lifetime Imaging Microscopy (FLIM). 8:30am.
Recently, we discovered that within the eye deposits of age-related macular degeneration (AMD) called drusen, there are microscopic bone mineral particles. We proposed that proteins and fats stick to these particles and start the growth of drusen, and so finding these particles in the eye may be predictive of AMD at a very early stage. If we identified the mineral particles early, perhaps the drusen formation process could be stopped well before irreversible sight loss occurs. The technical problem was how to detect these microscopic particles in the patient’s eye. We found some widely-used drugs that label the particles with luminescence which can be visualized in the eye. The labeled particles exhibit a characteristic luminescence property called fluorescence lifetime that we can detect using a technique abbreviated as FLIM. The FLIM technique has already been used to study eyes, and is fast, painless, and very sensitive. The advantages of these drugs as labels are that they are quite safe, widely used, and well understood; usually, they are taken orally as a pill. The long clinical experience with these drugs not only enhances safety but should speed their introduction to find persons who might develop AMD, before vision is affected.

#104 - 42 - A0030. Expeditious bilateral murine fundus fluorescein angiography (FFA): Maximizing optical imagery with a transportable digital camera. 8:30am.
Age-related macular degeneration is a medical disorder that destroys the macula, which is the central region of the back of the eye, the retina that controls clarity of vision. Age-related macular degeneration is also the leading cause of severe and irreversible blindness world-wide. We improvised the use of a lightweight and cost-effective digital camera to register the delicate images of macular degeneration from the tiny eyes of mice, all of which is being presented at the May 2017 Annual ARVO Meeting in Baltimore, Maryland. This seamless, handheld and flexible recording method utilizes a customized acrylic platform that allows maximal stability and comfort for the mouse, to allow precise optical imagery that can efficiently compare the effects of new drugs in reversing the blinding process of age-related macular degeneration. As a result of the above promising findings, the Benny Laboratory hopes to bring mankind a step closer to a final and effective cure for age-related macular degeneration.

#131 - 372 - A0238. Automated Case-Adaptive Slab Configuration for Visualization of Choroidal Neovascularization in Swept-Source OCT Angiography. 1:30pm.
Age-related macular degeneration is the leading cause of vision loss among people aged 50 and older. This disease causes noticeable visual changes in an advanced stage due to the growth of abnormal blood vessels, a pathology known as choroidal neovascularization (CNV), below and in the deep layers of the retina, a light-sensitive layer of tissue in the eye. It is important to find possible first indications of CNV and monitor its changes over time to start and monitor response to treatment. Swept-source OCT angiography (SS-OCTA) is a non-invasive imaging technology that allows the visualization of retinal vessels with impressive detail in three dimensions. However, the extent of CNV is often difficult to visualize and quantify in SS-OCTA images due to the presence of other surrounding asymptomatic blood vessels. We have developed a prototype method to automatically isolate the volumetric region corresponding to CNV within these images and created visualizations where the CNV vessels are either 1) combined in a color-coded image together within the rest of the retinal vessels or 2) in an additional color configuration where different colors relate to different CNV depth relative to the retina. The resulting images can be used to easily evaluate CNV over time.

#145 – 820. Early detection of choriodal neovascularization with OCT Angiography. 4:15pm.
Optical coherence tomography angiography is a new technology that can image blood vessels in the eye. Scans are acquired in less than five seconds and do not require an intravenous dye injection. This new technology can detect the abnormal blood vessels that cause wet macular degeneration earlier than traditional imaging techniques. The very early stages of these abnormal vessels do not affect vision but they are at high risk for progression and vision loss. However, some have been shown to remain benign. These vessels should be monitored closely so appropriate and timely treatment can be administered.

Retinal Cell Biology
#130 - 356 - A0198. Utilization of Super Resolution Nanoscopy to Localize CEP290 within the Connecting Cilium of Rod Photoreceptor Cells. 3:15pm.
My research centers on a protein named CEP290. People who inherit defects in CEP290 suffer many symptoms, often including blindness. To understand how blindness occurs and what might be done to stop it, we need to know what CEP290 does, and to understand that, we need to know precisely where it is and what structures it forms. CEP290 in our eye is found in a tiny cylinder-shaped compartment called the cilium, which is part of the light-sensing rod and cone cells, and which is 200 times thinner than a human hair. The structures within it are too small to be visualized by ordinary light microscopes. I have used a new technology, “superresolution fluorescence microscopy”, that allows us to make out different regions within the cilium and visualize CEP290 within them. I have discovered that CEP290 is in an outer ring portion of the cilium, so its function must be linked to processes in that region. I have also found it is located along the length of the cilium, and is not restricted to the unique structures found only at the cilium base. I am now asking what happens to CEP290 in mouse model of human blinding diseases.

#111 - 291 - B0344. Intravitreal transduction profile of recombinant adeno-associated virus in murine and human retina. 8:30am.
A large percentage of people worldwide are born with genetic mutations that cause their photoreceptors, the light sensitive cells at the back of the eye, to function incorrectly and die. This leads to severe visual impairment and in the worse cases, total blindness, dramatically reducing patient quality of life. Using a technique called gene therapy, it is possible to make a photoreceptor cell function normally and stay alive longer by replacing its faulty genetic material with new, non-mutated DNA. As the ability of a person to see is correlated directly to the number of photoreceptors they have remaining, it is vitally important to correct the genetic mutation and preserve as many cells as possible. Currently, the most effective method of delivering new DNA to photoreceptors is to package it within the shell of a virus, which is subsequently injected into the eye. We show that modifying the structure of the virus shell improves the efficiency with which the virus reaches and enters photoreceptor cells, using live mice and post-mortem human tissue as a model. Our overall aim is to increase the effectiveness and safety of virus-based gene therapy treatments intended to prevent photoreceptor loss in patients with genetic eye diseases.

#143 – 804. The insulin receptor substrate-1 (IRS-1) regulates Kir4.1 expression in retinal Müller cells. 3:45pm.
Circadian rhythms regulate a variety of physiological and behavioral processes of our bodies such as feeding, body temperature, hormone release, and sleep-wake cycle.

Disturbance in circadian rhythms as observed in shift workers can lead to diabetes. The retina, a light-sensitive tissue at the back of the eye exhibits a circadian clock independent of clock controlled by the brain. Müller cells which cover a large portion of the retina, play a critical role in regulating potassium ion levels of the retina through tiny pores on its surface called as Kir4.1 ion channels. In our laboratory, we discovered that the Kir4.1 channels display a circadian clock and the natural rhythm of Kir4.1 is lost in diabetes. In this study, we asked a question whether an insulin, a hormone with a natural circadian rhythm possess a regulatory role in Kir4.1 channels in the retina. Our studies demonstrate that a target protein of insulin, insulin receptor substrate (IRS) possess a circadian rhythm in the retina and loss of IRS results in a decrease in Kir4.1 expression. We believe that in future therapies targeted towards maintaining IRS expression will help in correcting Kir4.1 levels in diabetes and in protection from ocular complications of diabetes.

#158 - 1045 - B0301. Connexin 43 translocation in retinal pigment epithelium during phagocytosis of photoreceptor outer segments. 3:15pm.
Specialized neurons in the eye that are responsible for light sensation undergo continuous renewal by shedding parts of their membrane. Scientists found that the cells (retinal pigment epithelium, RPE) responsible for the necessary breakdown of these membrane fragments modify their cellular junctions when the process is ongoing.
The study finds that when the membrane renewal is not ongoing, special connections between the cells known as gap junctions are mainly found in the cell-cell junctions. However, once the shedding starts the gap junctions move to the sites where the breakdown occurs. The research also shows that this process is dramatically enhanced once the gap junctions are blocked. Building on previous indications, the scientists now believe that the gap junction structures are required for the particle breakdown.