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Posted: 5/2/2016

Emerging trends and hot topics: Presented Monday, May 2 at the ARVO Annual Meeting

Seattle,Wash. ― In their own words, First Authors at the 2016 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 Monday, May 2.

Biochemistry/Molecular Biology

#225-1744 - D0140. Ocular parameters changes in the IRBP knockout mouse eye. Shanu Markand. May 2, 8:30am.

Myopia is an eye disease where distant objects appear out of focus. Myopia is highly prevalent worldwide and is associated with economic burden. Interphotoreceptor retinoid-binding protein (IRBP) is an important protein for normal vision. Mutations in IRBP gene in humans are linked with severe visual disorders such as retinitis pigmentosa, retinal dystrophy and myopia. We reported myopia and abnormal eye elongation in IRBP mutant mice. The purpose of this study was to test if eye size defects and myopia in IRBP mutant mice are due to selective growth of one or more internal compartments of the eye. Using a live mouse eye imaging system, we measured thickness of different eye compartments in IRBP mice compared with control mice. Our data showed a significant increase in the depth of the vitreous chamber in IRBP mutant mice.  Eye elongation contributed by selective growth of one compartment in IRBP mutant mice is similar to that observed in human myopia patients. Our data indicate the importance of IRBP in normal eye development and myopia. Future studies will aim at understanding underlying mechanisms.

#234 -1841. Ocular Gene Therapy for Choroideremia: the Alberta Experience. Ian MacDonald. May 2, 11am.

Six research participants with choroideremia, a sex-linked progressive eye disorder, were treated with an injection that delivered a gene replacement underneath the retina. One of six experienced an adverse event with apparent inflammation in the eye and a decline in vision in the post-operative period with gradual recovery. None of the other participants experienced a decline in vision. All subjects will continue to be followed for the next year.

#234 -1842. Gene augmentation therapy in a large animal model of CNGB1 retinitispigmentosa. Simon Petersen-Jones. May 2, 11am.

Retinitis pigmentosa is an important, inherited, progressive condition causing vision loss and blindnessin humans. Similar conditions also occur in dogs, mimicking the features of the human disease. In this study, gene therapy was used to introduce a normal copy of a gene, called CNGB1, into the eye of dogs going blind because they were born with a defective gene. Defects in CNGB1 in humans and dogs results in alack of vision in dim light from a very young age followed by a progressive deterioration in daytime vision. The gene therapy treatment resulted in a dramatic improvement in function of the eye, allowing the dogs to see in dimlight for the first time. The success of this therapy to reverse the effect of the gene mutation in dogs could lead the way to clinical trials for the treatment of retinitis pigmentosa in humans due to mutations in CNGB1.  

#234 -1844. In vivo reprogramming of rods to cone-like cells by Nrl-knockdown using AAV-delivered CRISPR-Cas9 rescues retinal degeneration. Wenhan Yu. May 2, 11am.

Retinitis pigmentosa(RP) is the leading cause of inherited blindness, due to gene mutations impairing the dim-light sensor rod photoreceptors in the retina. As rodsaccounts for 95 percent of total photoreceptors and provide structural and neurotrophic support to the day-light sensor cone photoreceptors, the progressive rod loss leads to secondary cone death and eventual blindness in RP patients. Preservation of cones is critical to patients’ quality of life and has been the focus of therapy development. A unique idea is to reprogram rods into cone-like cells, so that they can tolerate and survive the deleterious effects of mutations and consequently prevent cone death. To achieve this, we used state-of-the-art gene editing technology CRISPR/Cas9 to disrupt Nrl, a key factor maintaining rod features. Components of CRISPR/Cas9 were delivered to mouse retina by AAV, an efficient gene delivery tool. We demonstrated the therapeutic effects of the CRISPR-Nrl approach in three mouse models carrying different gene mutations. The treated eyes preserved significantly better retinal structure, greater number of rods and cones and better visual function than control eyes. Our study provides an efficient AAV-CRISPR/Cas9 system for retinal gene editing, and the CRISPR-Nrl approach could be developed into avialable treatment for RP.

Cornea  

#238 -1908 - A0183. A purely solid-state device for rapid reconstruction of 3D models of the anterior segment of the eye with no moving parts. Pushyami Rachapudi.May 2, 11am.

This abstract presents a purely solid-state device for rapid reconstruction of 3D models of the anterior segment of the eye with no moving parts. Routine eye exams via slit lamp are critical in detecting diseases such as cataracts and corneal injury, which affect the anterior segment of the eye. But slit lamps are complex with mechanical moving parts and can be operated by trained professionals only. Our prototype exhibits a functionality similar to that of slit lamp while lacking the complex hardware, having a portable and compact form factor with no moving parts. The capture process, which is completely automated, takes less than 2seconds enabling it to be operated by unskilled workers. It is also operated computationally to generate 3D models of the anterior segment of the eye. Making it ideal for rapid screening in resource constraint situations.  

Glaucoma

#227 -1795. Finite element analysis predicts high optic nerve head strains duringhorizontal eye movements. Xiaofei Wang. May 2, 11am.  

The eyeis connected to the brain via a thick cable known as the optic nerve. In glaucoma, the cable head (or optic nerve head) that is attached to the eye is getting damaged, which usually results in blindness (i.e. no information from the eye can reach the brain). High eye pressure is often associated with glaucoma as it could compress the nerve head and cause subsequent damages toit. However, glaucoma can occur in people with normal eye pressure. Therefore,other factors may play a role in the damage of the nerve head. During eye movements (such as when reading a book), the optic nerve is subject to a significant stretch. We hypothesize that the stretching of the optic nerve could distort the nerve head as well. To test our hypothesis, we built a computer model to simulate the eye movement. We show that the optic nerve head deforms a lot during eye movement. The magnitude of optic nerve head deformations caused by eye movement is comparable to that of caused by a high eye pressure. Our work provides new insights into the optic nerve head deformation, which is highly related to glaucoma. 

#227 -1796. Time-lapse retinal ganglion cell dendritic field degeneration imaged inorganotypic retinal explant culture. Thomas Johnson. May 2, 11am.  

Glaucoma causes vision loss by damaging the optic nerve, which delivers information from the eye to the brain.The optic nerve is made of “retinal ganglion cells (RGCs)” which have three main parts: 1) cell bodies, which function like control centers in the retina –the thin nerve tissue that lines the back of the eye; 2) axons – long filaments that transmit information through the optic nerve; and 3) dendrites – short filaments that make connections to dozens or hundreds of other retinal cells toreceive visual information.  Little is known about how glaucoma damages RGC dendrites, partly because they are small,complex, and difficult to photograph alive. We developed a new experimental system where the retina is removed from mice genetically engineered with RGC dendrites glowing yellow. The retina is kept alive in tissue culture and a specialized microscope is used to photograph dendrites of individual cells at high magnification multiple times, up to 1 week apart. Using this system, we documented early loss of individual dendrites that occurs while RGCs are still alive. We also identified compounds that protect the dendrites. This system maybe useful for better understanding how glaucoma impact RGCs and for developing new therapies to preserve vision in glaucoma.

#227 -1797. In Vivo Small Molecule Delivery to the Optic Nerve in a Rat Model.Shandiz Tehrani. May 2, 11am.

Glaucoma is a chronic degeneration of the optic nerve and is the leading cause of irreversible blindness worldwide. Our understanding of the cellular and molecular basis of glaucomatous optic nerve damage remains nascent, and current glaucoma therapiesdo not target the site of glaucoma injury at the level of the optic nerve. New research strategies to deliver small molecule drugs to the optic nerve would allow for local investigation of the pathophysiology of glaucoma, and may lead to novel therapeutic strategies. Here, we report an in vivo method for small molecule delivery to the optic nerve in a rodent model. Our approach yields reproducible delivery of small molecules to the optic nerve in vivo, as confirmed by bioanalytical testing. Further work is underway to determine the cellular and molecular effects of small molecule delivery to the optic nerve.

#227 -1793. Optic nerve and retinal ganglion cell degeneration after two weeks of intracranial pressure (ICP) elevation in mice. Guofu Shen. May 2, 11am.

Increases or decreases in brain pressure are known to cause a variety of brain, optic nerve, and eye diseases. These diseases have been difficult to study in mice because there was no way to change brain pressure experimentally. Our laboratory recently developed a new experimental model that allows us to precisely measure and change brain pressure in living, active mice. With this new model, we have found that brain pressure can be safely increased in mice for at least two weeks. After two weeks of increased brain pressure, mice have reduced numbers of specific cells of the eye and optic nerve, called retinalganglion cells. These mice see poorly and have reduced electrical activity of their eyes. Our laboratory can use this new experimental model to study what happens in response to changes in brain pressure, and use this information toimprove our ability to diagnose and treat brain, optic nerve, and eye diseases.

#278 -2540 - B0156. Inner Retina Dysfunction in Microfibril Deficient Mice with Low Tension Glaucoma. Hang-Jing Wu. May 2, 3:45pm.  

Glaucoma is a neurodegenerative disease and the leading cause of irreversible blindness worldwide.  Blindness in glaucoma is caused by the degeneration and death of retinal ganglion cells, the neurons responsible for transmitting visual information to the brain. Although glaucoma is commonly associated with high intraocular pressure,for many patients, this does not seem to be the case.  Some patients with well-controlled eye pressure still suffer from progressive vision loss.Other patients can have ocular hypertension for years with little or no effect. Currently, most basic glaucoma research relies on animal models with high eye pressure.  We have developed one of the few animal models of glaucoma with normal intraocular pressure.Strikingly, we find that although the retinal ganglion cells lose normal functioning at a young age, their cell bodies in the optic nerve persist well into advanced age.  The structural persistence of these dying, but not dead, retinal ganglion cells raises the exciting possibility that they could be rescued and restored to normal functioning.  This normal-pressureglaucoma animal model could be used to test novel neuro-restorative therapies and raises the exciting possibility that neurodegeneration in glaucoma may be reversible.

#278 -2541 - B0157. Regional and temporal patterns of retinal α-crystallinsexpression during secondary retinal ganglion cell degeneration. Jacky ManKwong.  May 2, 3:45pm.

Glaucoma is a leading cause of blindness in which initial injury to the optic nerve leads to death of retinalneurons that may be followed by secondary degeneration of neighboring cells.Adaptive molecular changes that promote neuronal survival and function a rereferred to as the cellular stress response. How expression of stress proteins relates to primary and secondary neuronal degeneration is not clearly understood. Using innovative surgical and mass spectrometry-based proteomic screening approaches, this study demonstrated novel regional and temporal differences in the stress response during initial injury and secondary neuronaldegeneration. These studies may identify new molecular targets for therapies designed to modulate the cellular stress response.

#278 -2546 - B0162. Abundance of CD163+ macrophages/microglia in the optic nerves of human post-mortem eyes with glaucoma. Milica Margeta. May 2, 3:45pm.

Glaucoma is a chronic blinding disease characterized by progressive damage to the optic nerve, the cable that connects the eye to the brain. In our study of human autopsy samples, we found an increase inCD163-positive macrophages and microglia, phagocytic cells of the immune system, in the optic nerves of eyes with glaucoma. These cells can play anti-inflammatory, reparative role in damaged tissues, and have previously been found to promote neuronal survival and regeneration. Our findings raise the exciting possibility that these cells also play a neuroprotective role in glaucoma, which could lead to development of new therapies for this blinding disease.

#278 -2542 - B0158. Is the relationship between retinal nerve fibre layer thickness and cognitive performance explained by genetic or environmental factors? A twin study. Eneh Jones-Odeh.  May 2, 3:45pm.

The eye is the window of the brain: the retina at the back of the eye contains nerve tissue similar to nerve cells in the brain. Scientists have previously shown that the nerve layer, known as the retinal nerve fibre layer (RNFL), is thinnerin people with memory loss and cognitive decline such as Alzheimers Disease.Studies of twins help separate out nature and nurture, i.e. genetic and environmental factors. The aim of this study of 823 twins aged between x and y(average z years) was to establish whether RNFL and cognition share the same underlying genetic factors, or whether the thinner RNFL is simply a marker of the loss of brain cells. All twins underwent detailed eye and cognitive testing. The results showed the RNFL was thinner in older people, and also in people who are near-sighted. Genetic factors appear to strongly influence RNFL thickness. The study confirmed the link between a thinner RNFL and worse cognitive performance, but there was no evidence that shared genetic factors influenced this relationship. We therefore conclude that the thin RNFL probably reflects loss of brain tissue with increasing age, rather than having the same underlying genetic factors.

#263 -2280. Photopic Negative Response Obtained Using a Handheld Electroretinography(ERG) Device: Repeatability and Comparison with Optical Coherence Tomography in Glaucoma. Zhichao Wu. May 2, 3:45pm.

In response to light, the cells within our eyes generate small electrical signals that can be non-invasively measured using the electroretinogram (ERG). A component of this signal is characteristically reduced in eyes with glaucoma –a major cause of irreversible blindness – as a result of damage to neurons that carry the visual information from the eye to the brain. This technique shows promise as a useful early marker of glaucoma, and could also potentially inform us about the trajectory of the disease. In this study, we used a novel handheld ERG system and observed that these signals could be measured easily and with in a short time frame (often within minutes). Although we found that state-of-the-art, high-resolution imaging of the neural tissue in glaucoma performed better than detecting glaucoma than the ERG technique, we observed that this technique was still useful for the early detection of this disease especially when access to such imaging technologies are not available. Further work is also now underway to evaluate the utility of this technique for the clinical management of glaucoma.

Lens

 

#240 -1995 - B0075. The Relationship between Insurance Coverage, Demographics, and BSCVA at the Time of Cataract Surgery. Jordan Stone. May 2, 11am.

 

How can vision help us to quantify and understand patient access to health care services? In our study, we used this question to analyze the relationship between visual acuity and demographic variables, like race,gender, and insurance status, in patients undergoing their first cataract surgery at UC San Diego’s Shiley Eye Institute. A patient’s visual acuity prior to surgery may be thought of, after controlling for other influencing variables, as a proxy for access to this sight-restoring procedure—better visual acuity reflects improved access to care, whereas worse visual acuity reflects more limited access. Following multivariate analysis, our results showed significant differences in pre-operative vision across race and insurance coverage. Namely, Hispanic race was associated with worse pre-operative vision than white race, and public insurance coverage, such asMedicaid, correlated with worse pre-operative visual acuity compared to privateinsurance coverage. These findings potentially highlight the perennialimportance of addressing health inequities within eye surgery. They alsoquantify, through visual acuity, the degree to which inequitable access to caremay unduly prolong vision losses in patients suffering from cataracts. 

MultidisciplinaryOphthalmic Imaging Group

 

#246 -2206 - D0102. Inner retinal oxygen delivery and metabolism followingischemia/reperfusion injury in rat. Michael Tan. May 2, 11am.

 

The retina is a tissue in the back of the eyethat is necessary for vision. It needs oxygen and nutrients to remain healthy.Retinal ischemia is a condition in which blood flow and consequently thetransport of oxygen and nutrients to the retina are obstructed, often resultingin vision loss. A number of conditions such as diabetes and vascular occlusionscause retinal ischemia. The effect of ischemia on the ability of the retina toconsume oxygen has not been previously reported. In the current study, changesin retinal blood flow and oxygen consumption due to retinal ischemic injurywere investigated for the first time. The findings may help reveal how reducedblood flow affects the survival of retinal tissue and causes vision loss.

Retina

 

#204-1352. Galectin-1 is an Angiogenic Factor Associated with Proliferative DiabeticRetinopathy: Novel Target for Aflibeccept. Atsuhiro Kanda. May 2, 8:30am.

 

Angiogenesisis the formation of new blood vessels from a pre-existing vascular bed andusually occurs during wound healing, organ regeneration, etc.  Numerous studies have been conducted to showthat vascular endothelial growth factor (VEGF)-A plays a central role in theproliferation of endothelial cells among a rich variety of pro-angiogenic moleculesreported so far. In the field of ophthalmology, abnormal angiogenesis driven byVEGF-A was shown to cause vision-threatening eye diseases includingproliferative diabetic retinopathy (PDR), the advanced stage of diabeticretinopathy, which is the major cause of blindness worldwide. Severalanti-VEGF-A agents, successfully developed, have so far been widely used forthe treatment of various eye diseases. Among several VEGF-A blockers clinicallyused is aflibercept, which can also target other VEGF family members (e.g.,VEGF-B) than VEGF-A. In this study, we demonstrated the blocking efficacy ofaflibercept against galectin-1, an angiogenic factor associated with PDRindependently of VEGF-A. Our findings reveal the first evidence thataflibercept binds and blocks a pro-angiogenic molecule outside of the VEGFfamily, showing an additional anti-angiogenic capability beyond its originallyprepared anti-VEGF function.

 

#223 -1663 - C0119. Correlations between retinal vessel calibers andneurodegeneration in patients with no or mild diabetic retinopathy in theEuropean Consortium for the Early Treatment of Diabetic Retinopathy(EUROCONDOR). Jakob Grauslund. May 2, 8:30am.

 

The retina is the light-sensitive layer of theeye responsible for translating the light into an electrical signal to thebrain. In order to meet this purpose, retina consists of neurogenic cells andsupportive vasculature. Diabetic retinopathy is the most common complication indiabetes and a leading cause of visual loss and blindness. Even though diabeticretinopathy has traditionally be regarded a disease of the vasculature, growingevidence has demonstrated neurogenic changes (neurodegeneration) as an earlyevent. So far, it has only been possible to treat the end-stages of diabetic retinopathy,but preventive treatment at early stages prior to visual loss would be a muchbetter option for patients.

In this paper we demonstrate the close relationbetween early vascular and neurogenic changes in diabetic retinopathy. In 440eyes with no or minimal changes, we found a close relationship between thediameters of the vessels and the thickness or the layers of neurogenic cells.In particular, we found narrower vessels in patients with loss of neurogeniccells. We believe that this could be an early event in diabetic retinopathy,and speculate that pharmacological treatment with eye drops could be used tobattle the disease at an early stage.

#229 -1809. Topline Results From Prospective, Double-masked, Placebo Controlled Phase2 Clinical Study Evaluating Luminate® (ALG-1001) in Patients with SymptomaticFocal Vitreomacular Adhesion. Baruch Kuppermann. May 2, 11am.

 

When the clear jelly(vitreous humor) that fills the eye adheres to and pulls on the delicate,light-sensitive tissue (retina) at the back of the eye, it can cause damage andvision loss. This condition is known as vitreomacular adhesion (VMA) or, as itgets worse, vitreomacular traction (VMT). Current treatment options to relievethe traction include invasive surgery or a drug that has been associated withsome serious adverse side effects. Abstract 1809 demonstrates that Luminate®(ALG-1001), a new therapy by Allegro Ophthalmics that is under clinicalevaluation and not approved by the FDA, was found to be both effective and welltolerated by the patients with VMA or VMT. By Day 90, 50% of patients treated with the 3.2 mg dose of Luminateachieved traction release, compared to 27% in the Luminate 2.5 mg group, 26% inthe Luminate 2.0 mg group, and 13% of those in the placebo control group. Therewere no serious adverse effects.

#229 -1806. Comparison of Three Non-surgical Treatments for Vitreomacular Traction(VMT). Nathan Steinle. May 2, 11am.

Oculargas injections are shown to be a very simple and very inexpensive treatment fora common eye disorder that could potentially afflict any of us. As we age,the gel in our eye can cause pulling on the middle part of our vision (a termcalled vitreomacular traction); fortunately, a simple gas injection can curethis disorder in the significant majority of patients. This gas injectioncosts less than a dollar and can be done with just local anesthesia in a clinicsetting. It saves patients from more costly procedures such as surgery orexpensive pharmacologic injections. The body simply resorbs the gas bubbleafter a few weeks and the patient is left with a lifetime of improvedvision. The potential to use this technique is particularly exciting inrural and underserved areas of the world where no other treatment optionsexist.

#228 -1802. Fully automated prediction of geographic atrophy growth usingquantitative SD-OCT imaging biomarkers. Theodore Leng. May 2, 11am.

 

Age-related macular degeneration isthe leading cause of vision loss in the developed world. Half of eyes withadvanced disease lose vision due to thinning of the nerve cells of the eye,something we call “geographic atrophy” or GA.

 

Currently, once GA forms, we do notknow which patients will get worse or where the GA will expand. Our researchsought to address this problem by taking a computerized/machine learningapproach. We analyzed a database of 118 eye scans taken over time in eyes withGA and automatically extracted information from them. This information iscalled “features” or “biomarkers.”  Usingthese scan features, we created a predictive model to guess which eyes willhave GA growth and where it would go.

 

Our model was ultimately able topredict the growth of GA (where GA will go) at a rate 81 to 87%. Thisprediction was highly correlated to the loss of certain layers of the nervecells of the eye and could have clinical application in identifying patientswho have GA that at risk for vision loss, as well as patients who wouldpotentially benefit from emerging GA therapies.

 

#282 -2694 - C0145. Cross-sectional evaluation of microperimetric fixation locationand stability in Stargardt disease in the ProgStar study. Etienne Schonbach.May 2, 3:45pm.

 

Patients with diseases of the backof the eye often lose their ability to focus a picture steadily in the centerof their vision. We found that patients with an inherited disease calledStargardt disease tend to develop a more severe form when the onset of symptomsis earlier in life. This means that their vision is less steady and moreeccentric than in patients with a later onset of disease. We also showed thatafter at least 10 years of ongoing disease, 82 % of patients have lost theability to use their central vision in either eye when focusing on a target.The extent of unsteady and eccentric vision seems to be almost identical inboth eyes of a Stargardt patient. When unsteady and non-central visiondevelops, a patient’s vision decreases rapidly at first. Once vision has becomeunsteady, further deterioration results in poorer vision only to a lesserdegree. Our results underline the importance of both steady and central vision.Although these results are from a relatively rare condition, they may serve asa model of age-related macular degeneration which is the leading cause ofcentral visual acuity loss in Americans over 50 years of age.

 

RetinalCell Biology

 

#212 -1403. Hyperhomocysteinemia Disrupts Retinal Pigment Epithelial Structure andFunction with Features of Age-Related Macular Degeneration. MacularDegeneration. Amany Tawfik. May 2, 8:30am.

 

Amino acid Homocysteine is a riskfactor for neurodegenerative and cardiovascular diseases and has been reportedto be elevated in patients with age-related macular degeneration (AMD), leadingcause of vision loss in elderly worldwide. This study is providing strongevidence and highlighting the possible role homocysteine in the development orprogression of AMD. We studied retinas (light-sensitive layer of the eye) of agenetically modified mice which have increased levels of homocysteine and alsoeyes of normal living mice injected with homocysteine. Interestingly, we foundchanges similar to the changes in patients with AMD, such as: geographicatrophy (indicative of death of photoreceptor cells, essential for vision and theirclose contacts; retinal pigmented epithelial (RPE) cells that nourish thephotoreceptor cells) and increased leakage of the retinal blood vessels. Inaddition, histologic and electron microscopic examination of the retinas,showed features of AMD, such as: RPE damage, formation of deposits calleddrusen under the retina, and choroidal neovascularization, which are abnormalblood vessels growing from their normal location in the choroid into anabnormal location beneath the retina. Enhancing homocysteine clearance, whichcould be achieved by vitamin B12 and Folic acid supplementation might be apotential therapeutic intervention in AMD.

 

#284 -2737 - D0271. Long-term photoreceptor rescue in two rodent models of retinitispigmentosa by adeno-associated virus delivery of Stanniocalcin-1. Gavin Roddy.May 2, 3:45pm.

 

Retinal degenerations, including age-relatedmacular degeneration and the retinitis pigmentosa family of diseases, are theleading causes of legal blindness in the United States. We recently identifiedStanniocalcin-1 (STC-1) as a novel treatment for retinal degeneration.Following intraocular injection of STC-1, we previously observed molecular,histologic, and functional rescue of retinal degeneration in two different ratmodels of retinitis pigmentosa. The results were attributed in part to areduction in oxidative damage. To achieve sustained delivery, we elected todeliver STC-1 by utilizing a viral vector. Delay of photoreceptor degenerationwith this treatment was observed in two rodent models, and gene survey analysishas identified several potential candidate genes acting downstream.  This is proof of principle that long-termdelivery of STC-1 is effective in reducing retinal degeneration and may be apotential treatment for patients with currently incurable diseases of theretina.

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