Advanced Dry Age-related Macular Degeneration Research Articles

Rescue of cone and rod photoreceptor function in a CDHR1-model of age-related retinal degeneration

Age-related macular degeneration is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of age-related macular degeneration that has the appearance the ‘dry’ form, or geographic atrophy. Biallelic variants in CDHR1 – a specialised protocadherin highly expressed in cone and rod photoreceptors - result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional and behavioural rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months post-injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy appears to be near complete – with morphological findings of the rescued retina not obviously different to wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry age-related macular degeneration. Accurate clinical classification is now critical as their pathogenesis and treatment are distinct.

Complement Inhibitors for Advanced Dry Age-Related Macular Degeneration (Geographic Atrophy): Some Light at the End of the Tunnel?

Geographic atrophy (GA) affects around 5 million individuals worldwide. Genome-wide, histopathologic, in vitro and animal studies have implicated the activation of the complement system and chronic local inflammation in the pathogenesis of GA. Recently, clinical trials have demonstrated that an intravitreal injection of pegcetacoplan, a C3 inhibitor, and avacincaptad pegol, a C5 inhibitor, both statistically significantly reduce the growth of GA up to 20% in a dose-dependent fashion. Furthermore, the protective effect of both pegcetacoplan and avacincaptad appear to increase with time. However, despite these anatomic outcomes, visual function has not improved as these drugs appear to only slow down the degenerative process. Unexpected adverse events included conversion to exudative NV-AMD with both drugs. Occlusive retinal vasculitis and anterior ischemic optic neuropathy have been reported in pegcetacoplan-treated eyes.

Empowerment-Based Physical Activity Intervention for People with Advanced Dry Age-Related Macular Degeneration: Mixed-Methods Protocol.

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment and impacts daily life. These impacts include loss of social activities, decreased functional independence, and reduced physical activity. This protocol aims to describe a prospective, mixed-methodology for studying a population with AMD before, during, and after an empowerment-based physical activity intervention (EPI). A study framework was also developed for EPI. The intervention will include 20 older individuals (age 65+ years) with AMD recruited in Sweden. The intervention period is six months and comprises adapted physical activity and social activities in a group twice a week and individual health coaching on three occasions. The quantitative pre-test and three follow-ups include physical functional tests, an accelerometer that monitors physical activity continuously for one week, and questionnaires. Individual and focus-group interviews and ethnographic observations will explore the experience of living with AMD and what it means to participate in the EPI for individuals with AMD. The chosen methodology offers a structured way for researchers to explore the experiences and factors that may provide insights into the potential of creative supervised, adapted physical activity in groups, health coaching, and socialising that are significant to enable well-being among older individuals with AMD.

Optimising image quality with EyeMax Mono lens in dry age-related macular degeneration.

To investigate clinical outcomes in patients with dry age-related macular degeneration (AMD) after intracapsular implantation of a novel EyeMax Mono macular lens. In this study, 22 phakic eyes of 19 moderate to advanced dry AMD patients with macular disciform scar and/or macular atrophy who were followed up for ≥ 3months after surgery were studied. A thorough pre-operative ophthalmological examination was performed, including measurement of corrected distance visual acuity in logMAR and ETDR. Following phacoemulsification, the EyeMax Mono lens was implanted intracapsularly via a 2.2-mm clear corneal incision to improve retinal image quality in all areas of the macula ≤ 10° from the central fovea. Main outcome measures included optimisation of corrected distance visual acuity and surgical safety. Male-to-female ratio was 13:6. Mean age at surgery was 68.37 ± 10.23years. The mean duration of post-operative follow-up was 7.91 ± 3.42months. The mean post-operative refractive spherical equivalent improved to + 2.31 ± 1.56 D with significant visual improvement as early as 3months post-operatively. Post-operative corrected distance visual acuity improved significantly from 1.05 ± 0.45 to 0.72 ± 0.43 logMAR (P < 0.001), equivalent to mean ETDRS of 49.55 ± 20.05 (P < 0.001). There were no major surgical complications, either intra- or post-operatively, except in two patients who experienced intra-operative haptic rupture. Extended macular vision lenses appear to have a comparable safety profile as standard IOLs in the short to medium term. It could be the preferred lens for improving and preserving visual acuity in moderate to advanced dry AMD patients.

A Surgical Kit for Stem Cell-Derived Retinal Pigment Epithelium Transplants: Collection, Transportation, and Subretinal Delivery.

Transplantation of stem cell-derived retinal pigment epithelium (RPE) cells is a promising potential therapy for currently incurable retinal degenerative diseases like advanced dry age-related macular degeneration. In this study, we designed a set of clinically applicable devices for subretinal implantation of RPE grafts, towards the overarching goal of establishing enabling technologies for cell-based therapeutic approaches to regenerate RPE cells. This RPE transplant kit includes a custom-designed trephine for the production of RPE transplants, a carrier for storage and transportation, and a surgical device for subretinal delivery of RPE transplants. Cell viability assay confirmed biocompatibility of the transplant carrier and high preservation of RPE transplants upon storage and transportation. The transplant surgical device combines foldable technology that minimizes incision size, controlled delivery speed, no fluid reflux, curved translucent tip, usability of loading and in vivo reloading, and ergonomic handle. Furthermore, the complementary design of the transplant carrier and the delivery device resulted in proper grasping, loading, and orientation of the RPE transplants into the delivery device. Proof-of-concept transplantation studies in a porcine model demonstrated no damage or structural change in RPE transplants during surgical manipulation and subretinal deployment. Post-operative assessment confirmed that RPE transplants were delivered precisely, with no damage to the host retina or choroid, and no significant structural change to the RPE transplants. Our novel surgical kit provides a comprehensive set of tools encompassing RPE graft manufacturing to surgical implantation rendering key enabling technologies for pre-clinical and clinical phases of stem cell-derived RPE regenerative therapies.

Imaging and artificial intelligence for progression of age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of severe vision loss. With our aging population, it may affect 288 million people globally by the year 2040. AMD progresses from an early and intermediate dry form to an advanced one, which manifests as choroidal neovascularization and geographic atrophy. Conversion to AMD-related exudation is known as progression to neovascular AMD, and presence of geographic atrophy is known as progression to advanced dry AMD. AMD progression predictions could enable timely monitoring, earlier detection and treatment, improving vision outcomes. Machine learning approaches, a subset of artificial intelligence applications, applied on imaging data are showing promising results in predicting progression. Extracted biomarkers, specifically from optical coherence tomography scans, are informative in predicting progression events. The purpose of this mini review is to provide an overview about current machine learning applications in artificial intelligence for predicting AMD progression, and describe the various methods, data-input types, and imaging modalities used to identify high-risk patients. With advances in computational capabilities, artificial intelligence applications are likely to transform patient care and management in AMD. External validation studies that improve generalizability to populations and devices, as well as evaluating systems in real-world clinical settings are needed to improve the clinical translations of artificial intelligence AMD applications.

A column-based deep learning method for the detection and quantification of atrophy associated with AMD in OCT scans.

The objective quantification of retinal atrophy associated with age-related macular degeneration (AMD) is required for clinical diagnosis, follow-up, treatment efficacy evaluation, and clinical research. Spectral Domain Optical Coherence Tomography (OCT) has become an essential imaging technology to evaluate the macula. This paper describes a novel automatic method for the identification and quantification of atrophy associated with AMD in OCT scans and its visualization in the corresponding infrared imaging (IR) image. The method is based on the classification of light scattering patterns in vertical pixel-wide columns (A-scans) in OCT slices (B-scans) in which atrophy appears with a custom column-based convolutional neural network (CNN). The network classifies individual columns with 3D column patches formed by adjacent neighboring columns from the volumetric OCT scan. Subsequent atrophy columns form atrophy segments which are then projected onto the IR image and are used to identify and segment atrophy lesions in the IR image and to measure their areas and distances from the fovea. Experimental results on 106 clinical OCT scans (5,207 slices) in which cRORA atrophy (the end point of advanced dry AMD) was identified in 2,952 atrophy segments and 1,046 atrophy lesions yield a mean F1 score of 0.78 (std 0.06) and an AUC of 0.937, both close to the observer variability. Automated computer-based detection and quantification of atrophy associated with AMD using a column-based CNN classification in OCT scans can be performed at expert level and may be a useful clinical decision support and research tool for the diagnosis, follow-up and treatment of retinal degenerations and dystrophies.

Deep learning-based classification of retinal atrophy using fundus autofluorescence imaging

PurposeTo automatically classify retinal atrophy according to its etiology, using fundus autofluorescence (FAF) images, using a deep learning model. MethodsIn this study, FAF images of patients with advanced dry age-related macular degeneration (AMD), also called geographic atrophy (GA), and genetically confirmed inherited retinal diseases (IRDs) in late atrophic stages [Stargardt disease (STGD1) and Pseudo-Stargardt Pattern Dystrophy (PSPD)] were included. The FAF images were used to train a multi-layer deep convolutional neural network (CNN) to differentiate on FAF between atrophy in the context of AMD (GA) and atrophy secondary to IRDs. Three-hundred fourteen FAF images were included, of which 110 images were of GA eyes and 204 were eyes with genetically confirmed STGD1 or PSPD. In the first approach, the CNN was trained and validated with 251 FAF images. Established augmentation techniques were used and an Adam optimizer was used for training. For the subsequent testing, the built classifiers were then tested with 63 untrained FAF images. The visualization method was integrated gradient visualization. In the second approach, 10-fold cross-validation was used to determine the model's performance. ResultsIn the first approach, the best performance of the model was obtained using 10 epochs, with an accuracy of 0.92 and an area under the curve for Receiver Operating Characteristic (AUC-ROC) of 0.981. Mean accuracy was 87.30 ± 2.96. In the second approach, a mean accuracy of 0.79 ± 0.06 was obtained. ConclusionThis study describes the use of a deep learning-based algorithm to automatically classify atrophy on FAF imaging according to its etiology. Accurate differential diagnosis between GA and late-onset IRDs masquerading as GA on FAF can be performed with good accuracy and AUC-ROC values.

The posterior eye with age-related macular degeneration has isotropic and nonlinear viscoelastic properties

Here we characterize and compare the anisotropic and nonlinear viscoelastic properties of the posterior eye of advanced dry age-related macular degeneration (AMD) patients and age-matched normal subjects. Ten normal horizontal, ten normal vertical, ten AMD horizontal, and ten AMD vertical strips of the macular retina and the underlying choroid and sclera were preloaded, preconditioned, and subjected to incremental stress-relaxation tests in body-temperature saline. The stress-relaxation response was characterized by a fully nonlinear viscoelastic formulation in which the relaxation modulus was approximated by a Prony series and a second-order polynomial using the comprehensive viscoelastic characterization method. Normal retina, choroid, and sclera were found to be anisotropic, whereas AMD tissues were isotropic. AMD retina and choroid showed greater stress-relaxation response than normal tissues (p < 0.05), whereas AMD sclera had smaller stress-relaxation response than normal tissue (p < 0.05). The nonlinear viscoelastic stress-strain relationship of the posterior eye is hence describable for the first time.

Global Analysis of Macular Choriocapillaris Perfusion in Dry Age-Related Macular Degeneration using Swept-Source Optical Coherence Tomography Angiography.

PurposeSwept-source optical coherence tomography angiography (SS-OCTA) was used to investigate if the clinical stage of dry age-related macular degeneration (AMD) was correlated with global and regional macular choriocapillaris (CC) perfusion.MethodsIn this retrospective, cross-sectional study, 6 × 6-mm SS-OCTA images from eyes with early, intermediate, and advanced dry AMD (56 eyes, 41 patients) were analyzed using algorithms described in the literature to assess regional flow deficit percentage (FD%) and average flow deficit size. Regions were defined by concentric areas centered on the fovea: a 1-mm-diameter area, 3-mm-diameter ring, 5-mm-diameter area, 5-mm-diameter ring, and 6 × 6-mm whole image. Data were modeled using the generalized estimating equations approach.ResultsThe relationship between age and CC FD% and average flow deficit size was statistically significant (P ≤ 0.05) in all regions of analysis by linear modeling. The relationship between dry AMD stage and FD% was statistically significant by linear modeling in the 5-mm ring, and between dry AMD stage and average flow deficit size in the 3-mm ring, 5-mm area, 5-mm ring, and 6 × 6-mm whole image.ConclusionsLinear modeling suggests a statistically significant relationship between dry AMD stage and CC perfusion, most prominent in the more peripheral regions of the macula.

Eyes on New Product Development.

Journal of Ocular Pharmacology and TherapeuticsVol. 35, No. 10 Featured ColumnFree AccessEyes on New Product DevelopmentGary D. NovackGary D. NovackAddress for correspondence: Dr. Gary D. Novack, PharmaLogic Development, Inc., 17 Bridgegate Drive, San Rafael, CA 94903 E-mail Address: gary_novack@pharmalogic.comPharmaLogic Development, Inc., San Rafael, California.Department of Ophthalmology, School of Medicine, University of California, Davis, Sacramento, California.Search for more papers by this authorPublished Online:6 Dec 2019https://doi.org/10.1089/jop.2019.29060.gdnAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail In this period, 2 new products are in late stage evaluation for the treatment of allergic conjunctivitis, and data were reported on a controlled study of a new device for use in glaucoma surgery. Legislative and regulatory actions continue including reorganization within the Food and Drug Administration (FDA) and efforts to manage the affordability of medications. Several gene and cell therapies are in clinical development for the treatment of retinal diseases. A formulation of bevacizumab designed for use in ophthalmology is in late stage clinical trials.Ophthalmic Pharmaceuticals and BiologicsAerie announced that the European Medicines Agency (EMA) recommended marketing authorization approval for its Rhokiinsa™ (netarsudil, sold as Rhopressa® in the United states) for the reduction of intraocular pressure in primary open-angle glaucoma or ocular hypertension (September 2019).Aldeyra presented results of its ALLEVIATE phase 3 clinical trial of reproxalap in patients with allergic conjunctivitis (September 2019).Allergan and Molecular Partners announced that the EMA has accepted for review a biologics license application for abicipar pegol, an investigational DARPin therapy for wet age-related macular degeneration (AMD) (September 2019).Clearside Biomedical announced that FDA requested additional chemical stability data on the new drug application (NDA) for its Xipere™ (triamcinolone acetonide suprachoroidal injectable suspension) currently under review (August 2019).Ocular Therapeutix commenced enrollment in a phase 3 clinical trial of its Dextenza™ (dexamethasone intraocular implant) for the treatment of allergic conjunctivitis (September 2019).Outlook Therapeutics commenced enrollment in a phase 3 clinical trial of its ONS-5010, a proprietary ophthalmic bevacizumab product candidate for the treatment of wet AMD (July 2019).Oxurion presented results from a phase 1 study of its THR-149, a plasma kallikrein inhibitor, in patients with diabetic macular edema (September 2019).ProQR received orphan designation from the FDA for its QR-1123, an investigational antisense oligonucleotide for the treatment of autosomal dominant retinitis pigmentosa due to the P23H mutation in the rhodopsin gene (September 2019).Regenxbio and Clearside Biomedical announced an option and license agreement that will give Regenxbio exclusive worldwide rights to Clearside's SCS Microinjector for the delivery of RGX-314 to the suprachoroidal space (September 2019).Tarsius Pharma submitted an investigational new drug (IND) application with the FDA for its TRS01, an immune-based treatment, for the treatment of ocular diseases (September 2019).Vertical Pharmaceuticals, a subsidiary of Osmotica Pharmaceuticals, submitted a NDA to the FDA for RVL-1201, oxymetazoline, for acquired blepharoptosis treatment candidate (September 2019).Gene and Cell TherapyAdverum reported results on the OPTIC phase 1 trial of its ADVM-022 gene therapy designed for long-term vasoactive endothelial growth factor (VEGF) suppression through the expression of aflibercept (September 2019).Lineage Cell Therapeutics presented results of the safety and tolerability of OpRegen (Retinal Pigment Epithelial cells) in a dose-escalating phase 1/2a clinical trial in patients with advanced dry AMD accompanied by geographic atrophy (September 2019).Ocugen's OCU400, a gene therapy candidate, received a second orphan drug designation from the FDA for the treatment of CEP290 mutation-associated retinal disease (September 2019).Wize Pharma entered into an exclusive license agreement to develop and commercialize products based on nonviral gene therapy technology from Copernicus Therapeutics. WP-REP1, Wize's gene therapy product based on Copernicus' technology, will comprise DNA-compromised nanoparticles and designed to treat choroideremia (September 2019).Medical DevicesSanten presented results on its DE-128 microshunt in its INN-005 controlled trial in patients with primary open-angle glaucoma not controlled with maximum tolerated glaucoma medications (August 2019),Regulatory, Government, and Pharmaceutical IndustrySandoz voluntarily recalled all generic forms of Zantac® (ranitidine) in the United States after confirmed contamination with N-nitrosodimethylamine, a possible human carcinogen (September 2019).The Economist presented an analysis that the pressure to reduce the prices of generic medicines has led to an increasingly fragmented and globalized production process, which reduces the number of manufacturers, increasing the risk for drug shortages.1According to a reorganizational plan for the FDA, new ophthalmic drugs, currently reviewed by the Division of Transplant and Ophthalmic Products would be in a new Division of Ophthalmology in the Office of Specialty Medicines (September 2019).U.K.'s National Health Service Department of Health Research Authority provided guidance on the impact of a “no-deal” Brexit on clinical trials of medicinal products medical devices (August 2019).U.S. House Speaker Pelosi proposed legislation that would allow the federal government to negotiate the prices of prescription drugs for Medicare health care beneficiaries (September 2019).Author Disclosure StatementThe author consults for numerous ophthalmic pharmaceutical and medical device firms.Funding InformationNo funding received for this article.Reference1. Anonymous. A dire scarcity of drugs is worsening, in part, because they are so cheap. Economist. 2019. Google ScholarFiguresReferencesRelatedDetails Volume 35Issue 10Dec 2019 InformationCopyright 2019, Mary Ann Liebert, Inc., publishersTo cite this article:Gary D. Novack.Eyes on New Product Development.Journal of Ocular Pharmacology and Therapeutics.Dec 2019.523-524.http://doi.org/10.1089/jop.2019.29060.gdnPublished in Volume: 35 Issue 10: December 6, 2019Online Ahead of Print:October 23, 2019PDF download

'You've got dry macular degeneration, end of story': a qualitative study into the experience of living with non-neovascular age-related macular degeneration.

To investigate the impact of non-neovascular (dry) age-related macular degeneration (AMD) on the person with respect to diagnosis, vision loss and coping strategies. Volunteers with dry AMD with a range of disease severity were given an eye examination and asked to describe aspects of their experience with dry AMD in a semi-structured interview. Interviews were audio-recorded, transcribed, and subjected to Framework analysis. Overarching themes were pre-defined, whilst subthemes were derived from the data. Twenty-seven participants (81% female), with early (n = 3), intermediate (n = 16) and advanced dry AMD (GA; n = 8) were interviewed. Median (interquartile range) age (years), logMAR binocular visual acuity and Pelli-Robson contrast sensitivity were 76 (71, 80), 0.2 (0.18, 0.40) and 1.65 (1.35, 1.93), respectively. Overarching themes (and subthemes) were: diagnosis (relationship with healthcare professional, psychological impact of diagnosis, and knowledge of AMD, both pre- and post-diagnosis), impact of visual loss (functional and psychological) and coping strategies (help from others and personal strategies). Many participants reported feelings of distress at the time of diagnosis and, particularly noteworthy, several reported a constant fear of their condition worsening. Dry AMD, for which there is currently no treatment, can have a significant impact on individuals, even in its early stages, before significant functional vision loss is manifest, as well as in its intermediate and advanced stages. Results from this study offer important insight into the experience of living with dry AMD not previously explored. Moreover, the results have the potential to serve as an educational resource for eyecare professionals.

QUANTITATIVE ANALYSIS OF THE INNER RETINAL LAYER THICKNESSES IN AGE-RELATED MACULAR DEGENERATION USING CORRECTED OPTICAL COHERENCE TOMOGRAPHY SEGMENTATION.

To characterize inner retinal damage in patients with dry age-related macular degeneration (AMD) using high-resolution spectral domain optical coherence tomography images. Sixty eyes of 60 patients with AMD were categorized using the Age-Related Eye Disease Study (AREDS) severity scale. Spectral domain optical coherence tomography images of these patients were quantified by manually correcting the segmentation of each retinal layer, including the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer to ensure accurate delineation of layers. The mean ganglion cell complex thickness values (ganglion cell layer + inner plexiform layer + retinal nerve fiber layer) were compared with 30 eyes of 30 healthy subjects. Ninety percent of eyes (81 eyes) required manual correction of segmentation. Compared with healthy subjects, mean ganglion cell complex thicknesses significantly decreased in more advanced dry AMD eyes, and this decrease was predominantly related to a change in inner plexiform layer thickness. There was no significant difference in thickness-related measurements between milder dry AMD (AREDS-2) eyes and healthy eyes (P > 0.05). In patients with dry AMD, automatic optical coherence tomography segmentation algorithms may be erroneous. As the severity of dry AMD increases, the inner plexiform layer layer becomes thinned, suggesting that transsynaptic degeneration may be occurring, as the photoreceptor layer is affected by AMD.

Viscoelastic properties of the posterior eye of normal subjects, patients with age-related macular degeneration, and pigs.

The purpose of this study is to measure, characterize, and compare the viscoelastic properties of the posterior eye of advanced dry age-related macular degeneration (AMD) patients, age-matched normal subjects, and pigs (3 groups). Ten horizontal and ten vertical strips of the macula retina and the underneath choroid and sclera were obtained for each group, respectively. They were examined by incremental stress-relaxation cycles in body-temperature saline. Mechanical response was characterized by the quasi-linear viscoelastic model. All the tissues were shown to be nonlinear viscoelastic. Stiffening and isotropization, increased relaxation, and softening and isotropization were found in AMD retina, choroid, and sclera, respectively, which are the mechanical features of the atherosclerotic process. The patients' medical records were in accordance with epidemiological studies indicating a relationship between the advanced AMD and atherosclerotic vascular disease (ASVD). Moreover, many differences were found between the viscoelastic properties of porcine and normal human retina, choroid, and sclera. The results suggest that AMD is associated with ASVD through a mechanism involving abnormal retinal, choroidal, and scleral mechanics similar to those seen in the atherosclerotic process. Moreover, researchers should be aware of mechanical differences when using porcine posterior eyes as a substitute for human posterior eyes. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2151-2157, 2018.

Evaluating role of bone marrow-derived stem cells in dry age-related macular degeneration using multifocal electroretinogram and fundus autofluorescence imaging.

To evaluate the role of bone marrow-derived stem cells in the treatment of advanced dry age-related macular degeneration (AMD) using multifocal electroretinogram (mf-ERG) and fundus autofluorescence imaging. Thirty patients (60 eyes) with bilateral central geographic atrophy (GA) were recruited. Worse eye of each patient received autologous bone marrow-derived hematopoietic stem cells (BM-HSCs) (group 1) and the fellow eye with better visual acuity served as control (group 2). The effect of stem cell therapy was determined in terms of visual acuity, amplitude and implicit time in mf-ERG and size of GA on fundus autofluorescence imaging. These tests were performed at presentation and first, third and sixth month follow up. Adverse events (if any) were also monitored. At 6mo follow-up there was no statistically significant improvement in median logMAR best corrected visual acuity (BCVA) in either group. Mf-ERG revealed significant improvement in amplitude and implicit time in the intervention group. A significant decrease was also noted in greatest linear dimension (GLD) of GA in the eyes receiving stem cells [6.78±2.60 mm at baseline to 6.56±2.59 mm at 6mo (P=0.021)]. However, no such improvement was noted in the control group. Electrophysiological and anatomical improvement in the intervention group sheds light on the therapeutic role of BM-HSCs. Further studies are required to determine the stage of disease at which the maximal benefit can be achieved and to standardize the dose and frequency of stem cell injection.

PSS31 - Health-Related Quality of Life in Patients with Moderate to Advanced Dry Age-Related Macular Degeneration: Results from a Phase 1/2a Clinical Trial of Cnto 2476

PSS31 - Health-Related Quality of Life in Patients with Moderate to Advanced Dry Age-Related Macular Degeneration: Results from a Phase 1/2a Clinical Trial of Cnto 2476

Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects.

Geographic atrophy (GA) of the retinal pigment epithelium (RPE) is a devastating complication of age-related macular degeneration (AMD). GA may be classified as drusen-related (drusen-associated GA) or neovascularization-related (neovascular-associated GA). Drusen-related GA remains a large public health concern due to the burden of blindness it produces, but pathophysiology of the condition is obscure and there are no proven treatment options. Genotyping, cell biology, and clinical imaging point to upregulation of parainflammatory pathways, oxidative stress, and choroidal sclerosis as contributors, among other factors. Onset and monitoring of progression is accomplished through clinical imaging instrumentation such as optical coherence tomography, photography, and autofluorescence, which are the tools most helpful in determining end points for clinical trials at present. A number of treatment approaches with diverse targets are in development at this time, some of which are in human clinical trials. Neovascular-associated GA is a consequence of RPE loss after development of neovascular AMD. The neovascular process leads to a plethora of cellular stresses such as ischemia, inflammation, and dramatic changes in cell environment that further taxes RPE cells already dysfunctional from drusen-associated changes. GA may therefore develop secondary to the neovascular process de novo or preexisting drusen-associated GA may continue to worsen with the development of neovascular AMD. Neovascular-associated GA is a prominent cause of continued vision loss in patients with otherwise successfully treated neovascular AMD. Clearly, treatment with vascular endothelial growth factor (VEGF) inhibitors early in the course of the neovascular disease is of great clinical benefit. However, there is a rationale and some suggestive evidence that anti-VEGF agents themselves could be toxic to RPE and enhance neovascular-associated GA. The increasing prevalence of legal blindness from this condition due to the aging of the general population lends urgency to the search for a therapy to ameliorate GA.

Injectable intraocular telescope: Pilot study

To assess the feasibility of a new injectable telescopic intraocular lens (IOL). London Eye Hospital, London, United Kingdom. Prospective interventional pilot study. Eyes with bilateral, intermediate, or advanced dry age-related macular degeneration (AMD); preoperative decimal corrected distance visual acuity (CDVA) of 0.25 or less; and improvement with extraocular simulation of the intervention had implantation of 2 IOLs designed for use together in a Galilean telescope configuration (iolAMD). Patients were followed for 4 months. Safety was assessed by monitoring visual acuity, intraocular pressure, specular microscopy, and anterior segment and macular optical coherence tomographies. Fixation stability and macular sensitivity were determined using microperimetry in some eyes. There were no significant intraoperative or postoperative complications. In 1 eye, an anterior sulcus IOL was replaced; there were no sequelae. The mean endothelial cell density was reduced by 18%. The mean decimal CDVA improved from 0.12 preoperatively to 0.20 at 4 months, a 67% gain. The mean change in spherical equivalent after implantation was -1.5 diopters (D) with 0.5 D of induced astigmatism. Microperimetric testing indicated a magnification effect and a deviation of the retinal image by up to 5 degrees, with improved fixation stability. This injectable intraocular miniature telescope appears safe in the short to medium term and capable of improving visual function. No significant issues were encountered regarding candidate eye selection or patient retention and cooperation. Further work is needed to evaluate the safety and efficacy of the device, particularly with respect to daily-living activities and the range of indications. Dr. Qureshi has a financial interest in London Eye Hospital Pharma. No other author has a financial or proprietary interest in any material or method mentioned.

Much awaited AREDS 2 results show lutein and zeaxanthin supplementation slow AMD progression only in subjects with low dietary intakes

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly and the primary cause in industrialized countries. With an increase in life expectancy, age-related eye diseases such as AMD and cataract are more prevalent and adequate treatment options are required to maintain quality of life. AMD affects the macula, a region 5-6 mm in diameter in the posterior pole of the retina that is responsible for sharp central vision. Dry AMD accounts for 90% of the cases and can advance slowly to advanced dry AMD or wet AMD (also known as choroidal neovascularization or exudative AMD). There are treatment options for wet AMD which delay AMD progression but none for dry AMD. Nutritional interventions are part of the efforts for preventing progression of dry AMD.

Inhibiting Alternative Pathway Complement Activation by Targeting the Factor D Exosite

By virtue of its amplifying property, the alternative complement pathway has been implicated in a number of inflammatory diseases and constitutes an attractive therapeutic target. An anti-factor D Fab fragment (AFD) was generated to inhibit the alternative complement pathway in advanced dry age-related macular degeneration. AFD potently prevented factor D (FD)-mediated proteolytic activation of its macromolecular substrate C3bB, but not proteolysis of a small synthetic substrate, indicating that AFD did not block access of the substrate to the catalytic site. The crystal structures of AFD in complex with human and cynomolgus FD (at 2.4 and 2.3 Å, respectively) revealed the molecular details of the inhibitory mechanism. The structures show that the AFD-binding site includes surface loops of FD that form part of the FD exosite. Thus, AFD inhibits FD proteolytic function by interfering with macromolecular substrate access rather than by inhibiting FD catalysis, providing the molecular basis of AFD-mediated inhibition of a rate-limiting step in the alternative complement pathway.