Long-term Outcomes of Treat and Extend Regimen of Anti-vascular Endothelial Growth Factor in Neovascular Age-related Macular Degeneration
J Ophthalmic Vis Res. 2020 Aug 6;15(3):331-340.
Andy Lee, Pooja G Garg, Alice T Lyon, Rukhsana Mirza, Manjot K Gill
PMID: 32864064 PMCID: PMC7431723 DOI: 10.18502/jovr.v15i3.7452
Purpose: This study describes the long-term visual and anatomic outcomes of anti-vascular endothelial growth factor (VEGF) treatment using a treat and extend dosing regimen.
Methods: This cross-sectional cohort study consisted of 224 treatment-naïve eyes with neovascular age-related macular degeneration (NV-AMD) from 202 patients that were treated with anti-VEGF agents bevacizumab, ranibizumab, and aflibercept using a treat and extend (TAE) regimen by four physician investigators in a large urban referral center from 2008 to 2015. Subjects were evaluated for visual acuity, injection frequency, and optical coherence tomography (OCT).
Results: Over a seven-year follow-up period (mean 3.4 years), an average 20.2 ± 14.7 injections were administered with 8.4 injections in the first year and 5.5 injections by the seventh year of remaining eyes undergoing treatment. Visual acuity was 0.70 logMAR (20/100 Snellen) at the first visit and 0.67 logMAR (20/93 Snellen) at the final visit, with 74% of eyes maintaining or gaining more than 2 lines of vision. Long-term, 45.1% of eyes achieved 20/50 or better, while 27.1% were 20/200 or worse. Of the treated patients, 61.2% received monotherapy with no difference in visual acuity outcomes or number of injections between the agents used. OCT analysis showed decreased fluid from initial to final follow-up visit: 70.1-15.6% with sub-retinal fluid (SRF) and 47.3-18.8% with intra-retinal fluid (IRF) with no difference between the agents were used.
Conclusion: This study demonstrates that most patients (74%) improve or maintain visual acuity long-term using a TAE model with a significant portion (45.1%) achieving 20/50 or better visual acuity with sustained treatment.
Laser and anti-vascular endothelial growth factor treatment for drusenoid pigment epithelial detachment in age-related macular degeneration
Sci Rep. 2020 Sep 1;10(1):14370.
Min Seok Kim, Na-Kyung Ryoo, Kyu Hyung Park
PMID: 32873842 PMCID: PMC7462975 DOI: 10.1038/s41598-020-71401-3
This study aims to report the 12 months results of efficacy and safety of laser photocoagulation and anti-vascular endothelial growth factor (VEGF) injections for drusenoid pigment epithelial detachment (dPED). In this prospective study, patients with treatment naïve bilateral intermediate age-related macular degeneration, featuring dPED, with visual acuity ≤ 83 letters were enrolled. The study group received PASCAL laser (532 nm) along the periphery of the dPED, and the fellow eye served as a control group. To prevent complications of choroidal neovascularization, intravitreal anti-VEGF injections to laser treated eye were performed on a 3-month interval up to 1 year. Primary outcomes-drusen area, PED height-and secondary outcomes-best-corrected visual acuity (BCVA), contrast sensitivity, degree of metamorphopsia, NEI-VFQ 25, and fundus autofluorescence-were analyzed. Among 21 patients, a total of 20 patients satisfied the 12 months follow-up. Drusen area and PED height decreased significantly in the laser group, while no significant change appeared in the control group (74.1% vs. - 3.5%, P < 0.001; 76.6% vs. 0.1%, P < 0.001). Mean BCVA improved 4.6 letters in the laser group (vs. 1.1 letters in the control group, P = 0.019). As for safety, one study eye developed retinal pigment epithelial tear, and one control eye developed retinal angiomatous proliferation. Low energy laser photocoagulation and anti-VEGF injection in eyes with dPED showed some improvement in visual acuity. dPED regressed without developing center involving GA in the study eye, but a longer term follow-up is necessary to reveal the efficacy and safety of these treatments. The 2-year results of this study will be followed to reveal long term efficacy and safety of the treatment for dPED.
DS-7080a, a Selective Anti-ROBO4 Antibody, Shows Anti-Angiogenic Efficacy with Distinctly Different Profiles from Anti-VEGF Agents
Transl Vis Sci Technol. 2020 Aug 5;9(9):7.
Yoshitaka Isumi, Shinko Hayashi, Tatsuya Inoue, Yasushi Yoshigae Toshiyuki Sato, Jun Hasegawa, Toshinori Agatsuma
PMID: 32879763 PMCID: PMC7442859 DOI: 10.1167/tvst.9.9.7
Purpose: Neovascular age-related macular degeneration (nAMD) results from choroidal neovascularization (CNV) and causes severe vision loss. Intravitreal anti-vascular endothelial growth factor (VEGF) therapies have significantly improved therapeutic outcomes; however, a substantial number of patients experience disease progression. Roundabout 4 (ROBO4) has been reported to be a vascular-specific protein that stabilizes vasculature in ocular pathological angiogenesis. To explore ROBO4 targeting as a novel treatment against neovascularization, we generated a humanized anti-human ROBO4 antibody, DS-7080a, and evaluated its efficacy.
Methods: ROBO4 mRNA in human whole eye cross-sections was examined by in situ hybridization. Human umbilical vein endothelial cell (HUVEC) migration was measured in the presence of VEGF, basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), or conditioned medium of primary human retinal pigment epithelial (HRPE) cells. CNV was induced in cynomolgus monkeys by laser irradiation. Vascular leakage was measured by fluorescein angiography, and pathological changes were determined by histology.
Results: ROBO4 mRNA was detected in choroidal vessels of nAMD patients. DS-7080a suppressed HGF- or bFGF-induced HUVEC migration in addition to that induced by VEGF. Further, HUVEC migration induced by HRPE-conditioned medium was inhibited by either DS-7080a or ranibizumab in a similar manner, and the combination of these showed further inhibition. In a laser-induced CNV monkey model, single intravitreous administration of 1.1 mg/eye of DS-7080a reduced the incidence of grade 4 leakage from 44.45% in control eyes to 1.85% (P < 0.05 by Dunnett's test).
Conclusions: Anti-ROBO4 antibody DS-7080a suppressed HUVEC migration in a distinctly different fashion from anti-VEGF agents and improved laser-induced CNV in non-human primates.
Translational relevance: DS-7080a may be a novel treatment option for nAMD.
DIAGNOSIS & IMAGING
Exploratory Study on Visual Acuity and Patient-Perceived Visual Function in Patients with Subretinal Drusenoid Deposits
J Clin Med. 2020 Sep 1;9(9):E2832.
Manjot K Grewal, Shruti Chandra, Sarega Gurudas, Alan Bird, Glen Jeffery Sobha Sivaprasad
PMID: 32882940 DOI: 10.3390/jcm9092832
To investigate the value of visual acuity and patient-perceived visual function test when subretinal drusenoid deposits (SDD) are incorporated into the classification of age-related macular degeneration (AMD). A total of 50 participants were recruited into the study in these groups: healthy ageing (n = 11), intermediate AMD (iAMD) with no SDD (n = 17), iAMD with SDD (n = 11) and non-foveal atrophic AMD (n = 11) confirmed by two retinal imaging modalities. Best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) were measured and low luminance deficit (LLD) was calculated. Participants were also interviewed with the low luminance questionnaire (LLQ). Linear regression was used to assess function-function relations. Compared with healthy participants, BCVA and LLVA scores were significantly reduced in the atrophic AMD group (p < 0.0001 and p = 0.00016, respectively) and in patients with SDD (p = 0.028 and p = 0.045, respectively). Participants with atrophy also had reduced BCVA (p = 0.001) and LLVA (p = 0.009) compared with the iAMD no SDD group. However, there were no differences in visual function tests between healthy aging and iAMD without SDD and between iAMD with SDD and atrophic AMD groups. The LLD score did not differ between groups. BCVA and LLVA correlated well. The LLQ did not correlate with visual function tests. This study shows that LLD is not a marker of disease severity as assessed clinically. Although LLQ is a good marker for disease severity using the current AMD classification, it does not differentiate between eyes with and without SDD. Eyes with non-macular geographic atrophy and SDD had lower function than eyes with no SDD and healthy controls.
Reading with central vision loss: binocular summation and inhibition
Ophthalmic Physiol Opt. 2020 Sep 4.
Valeria Silvestri, Paola Sasso, Paola Piscopo, Filippo Amore, Stanislao Rizzo, Robert G Devenyi, Luminita Tarita-Nistor
PMID: 32885878 DOI: 10.1111/opo.12726
Purpose: There are conflicting reports as to whether there is a binocular advantage or disadvantage when reading with central vision loss. This study examined binocular reading summation in patients with macular degeneration.
Methods: Seventy-one patients with bilateral central vision loss [mean age: 63 (S.D. = 21) years] participated. Reading performances during binocular and monocular viewing with the better eye (i.e., the eye with the best monocular visual acuity) were evaluated using different versions of the Italian MNREAD reading chart (www.precision-vision.com). Fixation stability and preferred retinal loci (PRLs) were recorded monocularly for each eye. The overall sample was split into inhibition, equality, and summation groups based on the binocular ratio (i.e., binocular/monocular) of the maximum reading speed.
Results: 41% of patients experienced binocular inhibition, 42% summation, and 17% equality. Binocular reading speed of the inhibition group was approximately 30 words per minute slower than those of the equality and summation groups, although the inhibition group had the best visual acuity. These patients generally had monocular PRLs in non-corresponding locations temporal or nasal to the scotoma, had the largest interocular acuity difference and lacked residual stereopsis. The three groups did not differ in fixational control, contrast sensitivity or critical print size.
Conclusions: Equal proportions of patients with central vision loss show binocular reading summation and inhibition. Patients with binocular reading inhibition have poorer reading performance and different clinical characteristics than those with binocular reading summation and equality.
Retinal Imaging using a confocal scanning laser ophthalmoscope-based high magnification module
Ophthalmol Retina. 2020 Aug 27;S2468-6530(20)30346-8.
Eleni K Konstantinou, Luísa S M Mendonça, Phillip Braun, Kyle M Monahan, Nihaal Mehta, Isaac Gendelman, Emily S Levine, Caroline R Baumal, Andre J Witkin, Jay S Duker, Nadia K Waheed
PMID: 32861857 DOI: 10.1016/j.oret.2020.08.014
Purpose: To evaluate the utility of a high magnification module (HMM) lens to visualize retinal photoreceptors, nerve fiber layer (NFL) and superficial retinal vasculature in physiologic and pathologic retinal conditions.
Design: Observational descriptive study.
Participants: Thirty-two subjects with normal and pathologic retina examinations METHODS: Normal and pathologic maculae were imaged in vivo using still and video HMM lens modes, with fixation and contrast adjustments to enhance visualization. HMM images were qualitatively classified based on structures identified as either good (photoreceptors [PR] seen), average (PR mosaic cannot be clearly visualized, retinal vessels and other retinal changes can be seen) or poor (no identifiable structures). Selected eyes were imaged with fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), indocyanine green angiography (ICGA) and fluorescein angiography (FA) for comparison for the pathologic maculae.
Main outcomes measures: Description of HMM module obtained macula images.
Results: From 32 eyes imaged (16 normal and 16 pathologic retinas), 12 of 16 normal and 11 of 16 pathologic retinas demonstrated at least average image quality, in which retinal vasculature and landmarks can be visualized. The mosaic pattern of hexagonal shapes representing photoreceptors could not be resolved in the majority of pathologic retinas. For the retinas in which the photoreceptor mosaics were visualized (12 of 16 normal and 2 of 16 pathologic retinas) parafoveal mosaic patterns appeared denser with better image quality for all subjects compared to foveal photoreceptors. Difficulty in resolving the photoreceptors in the umbo, fovea, and peri-fovea was encountered, similar to what has been reported with adaptive optics (AO) devices. The NFL was seen as arcuate hyperreflective bundles. Flow was observed in the macular microvasculature. Poorly resolved photoreceptors and scattered hyperreflective foci were correlated with changes in the RPE in eyes with age-related macular degeneration or central serous chorioretinopathy. Macular striae were seen in eyes with epiretinal membrane.
Conclusion: In the majority of eyes irrespective of whether retinal pathology was present, it was challenging to obtain average quality (or better) images. In the few cases with good quality imaging, the parafoveal photoreceptor mosaic, vascular flow and various features of pathologic eyes could be visualized.
Association of imaging biomarkers and local activation of complement in aqueous humor of patients with early forms of age-related macular degeneration
Graefes Arch Clin Exp Ophthalmol. 2020 Sep 2.
Vasilena Sitnilska, Philip Enders, Claus Cursiefen, Sascha Fauser, Lebriz Altay
PMID: 32876798 DOI: 10.1007/s00417-020-04910-6
Purpose: To investigate a possible correlation between established imaging biomarkers for age-related macular degeneration and local complement system activation, measured in aqueous humor (AH) of patients with early stages of age-related macular degeneration (AMD) and controls.
Methods: This analysis included prospectively acquired AH samples of 106 eyes (35 with early/intermediate AMD, 71 controls). The levels of complement protein 3 (C3), 4 (C4), 5 (C5); activation products of complement factor 3a (C3a) and Ba, C3b/iC3b; complement factors B, D, H, I (CFB, CFD, CFH, CFI); and total protein concentration were analyzed. Quantitative levels of complement factors were correlated to the presence of reticular pseudodrusen (RPD), the presence of hyperreflective foci (HRF), and total drusen volume (DV) graded on imaging by spectral-domain optical coherence tomography and using Spearman's rank correlation test.
Results: DV correlated with C3b/iC3b (r = 0.285; P = 0.034), C3a (r = 0.200; P = 0.047), Ba (r = 0.262; P = 0.009), and C5 (r = 430; P = 0.005), and showed a tendency towards correlation with C3a (r = 0.198; P = 0.057). HRF correlated significantly with C5 (r = 0.388; P = 0.011) and RPD showed a tendency towards correlation with CFB (r = 0.196; P = 0.050).
Conclusion: In patients with early AMD, HRF and drusen parameters but not RPD show low to fair levels of correlation with local complement activation in patients' AH. Better understanding of complement activation could provide some insights into the pathogenesis of AMD. Imaging biomarkers could be useful to identify suitable patients for future clinical trials with complement-modulating therapies.
Prevalence and predictors of myopic macular degeneration among Asian adults: pooled analysis from the Asian Eye Epidemiology Consortium
Br J Ophthalmol. 2020 Sep 2;bjophthalmol-2020-316648.
Yee Ling Wong, Xiangjia Zhu, Yih Chung Tham, Jason C S Yam, Keke Zhang, Charumathi Sabanayagam, Carla Lanca, Xiujuan Zhang, So Young Han, Wenwen He, Pradeep Susvar, Mihir Trivedi, Nan Yuan, Sarang Lambat, Rajiv Raman, Su Jeong Song, Ya Xing Wang, Mukharram M Bikbov, Vinay Nangia, Li Jia Chen, Tien Yin Wong, Ecosse Luc Lamoureux, Chi-Pui Pang, Ching Yu Cheng, Yi Lu, Jost B Jonas, Seang Mei Saw, Asian Eye Epidemiology Consortium (AEEC)
PMID: 32878826 DOI: 10.1136/bjophthalmol-2020-316648
Aims: To determine the prevalence and predictors of myopic macular degeneration (MMD) in a consortium of Asian studies.
Methods: Individual-level data from 19 885 participants from four population-based studies, and 1379 highly myopic participants (defined as axial length (AL) >26.0 mm) from three clinic-based/school-based studies of the Asian Eye Epidemiology Consortium were pooled. MMD was graded from fundus photographs following the meta-analysis for pathologic myopia classification and defined as the presence of diffuse choroidal atrophy, patchy chorioretinal atrophy, macular atrophy, with or without 'plus' lesion (lacquer crack, choroidal neovascularisation or Fuchs' spot). Area under the curve (AUC) evaluation for predictors was performed for the population-based studies.
Results: The prevalence of MMD was 0.4%, 0.5%, 1.5% and 5.2% among Asians in rural India, Beijing, Russia and Singapore, respectively. In the population-based studies, older age (per year; OR=1.13), female (OR=2.0), spherical equivalent (SE; per negative diopter; OR=1.7), longer AL (per mm; OR=3.1) and lower education (OR=1.9) were associated with MMD after multivariable adjustment (all p<0.001). Similarly, in the clinic-based/school-based studies, older age (OR=1.07; p<0.001), female (OR=2.1; p<0.001), longer AL (OR=2.1; p<0.001) and lower education (OR=1.7; p=0.005) were associated with MMD after multivariable adjustment. SE had the highest AUC of 0.92, followed by AL (AUC=0.87). The combination of SE, age, education and gender had a marginally higher AUC (0.94).
Conclusion: In this pooled analysis of multiple Asian studies, older age, female, lower education, greater myopia severity and longer AL were risk factors of MMD, and myopic SE was the strongest single predictor of MMD.
Association between cardiorespiratory fitness and handgrip strength with age-related macular degeneration: a population-based study
Br J Ophthalmol. 2020 Aug 28;bjophthalmol-2020-316255.
Andreas Katsimpris, Clemens Jürgens, Lisa Lüdtke, Bahls Martin, Till Ittermann, Sven Gläser, Marcus Dörr, Ralf Ewert, Konstantinos Volaklis, Stephan B Felix, Frank Tost, Henry Völzke, Christa Meisinger, Sebastian E Baumeister
PMID: 32859720 DOI: 10.1136/bjophthalmol-2020-316255
Aim: To assess whether cardiorespiratory fitness (CRF) and handgrip strength, two objective markers of physical fitness, are associated with age-related macular degeneration (AMD).
Methods: We analysed cross-sectional data from the population-based Study of Health in Pomerania (2008-2012) including 1173 adult men and women aged 20-79 years. Fundus photography of the central retina was recorded with a non-mydriatic camera, and images were graded according to an established clinical AMD classification scale by an experienced reader. CRF was measured using peak oxygen uptake (peakVO2), oxygen uptake at the anaerobic threshold ([email protected]), and maximum power output (Wmax) from standardised cardiopulmonary exercise testing on a bicycle ergometer according to a modified Jones protocol. Handgrip strength was assessed using a handheld dynamometer. Adjusted prevalence ratios (PR) for the associations of peakVO2, [email protected], Wmax and handgrip strength with AMD were derived from multivariable Poisson regression models.
Results: PeakVO2, [email protected], Wmax and handgrip strength were not associated with AMD. Adjusted PR for AMD associated with a 1-SD increment in peakVO2, [email protected], Wmax and handgrip strength were 1.05 (95% CI 0.82 to 1.34), 0.96 (95% CI 0.78 to 1.18), 1.10 (95% CI 0.86 to 1.41) and 1.01 (95% CI 0.79 to 1.30), respectively. These associations were not modified by age, sex, smoking, body mass index and diabetes. Estimates in sensitivity analysis for confounding, selection bias and missing data were similar.
Conclusion: In our study, CRF and handgrip strength were not associated with AMD. Nevertheless, longitudinal studies with bigger sample sizes are needed to furtherly examine these associations.
Transferrin Non-Viral Gene Therapy for Treatment of Retinal Degeneration
Pharmaceutics. 2020 Sep 1;12(9):E836.
Karine Bigot, Pauline Gondouin, Romain Bénard, Pierrick Montagne, Jenny Youale, Marie Piazza, Emilie Picard, Thierry Bordet, Francine Behar-Cohen
PMID: 32882879 DOI: 10.3390/pharmaceutics12090836
Dysregulation of iron metabolism is observed in animal models of retinitis pigmentosa (RP) and in patients with age-related macular degeneration (AMD), possibly contributing to oxidative damage of the retina. Transferrin (TF), an endogenous iron chelator, was proposed as a therapeutic candidate. Here, the efficacy of TF non-viral gene therapy based on the electrotransfection of pEYS611, a plasmid encoding human TF, into the ciliary muscle was evaluated in several rat models of retinal degeneration. pEYS611 administration allowed for the sustained intraocular production of TF for at least 3 and 6 months in rats and rabbits, respectively. In the photo-oxidative damage model, pEYS611 protected both retinal structure and function more efficiently than carnosic acid, a natural antioxidant, reduced microglial infiltration in the outer retina and preserved the integrity of the outer retinal barrier. pEYS611 also protected photoreceptors from N-methyl-N-nitrosourea-induced apoptosis. Finally, pEYS611 delayed structural and functional degeneration in the RCS rat model of RP while malondialdehyde (MDA) ocular content, a biomarker of oxidative stress, was decreased. The neuroprotective benefits of TF non-viral gene delivery in retinal degenerative disease models further validates iron overload as a therapeutic target and supports the continued development of pEY611 for treatment of RP and dry AMD.
Reproducible production and image-based quality evaluation of retinal pigment epithelium sheets from human induced pluripotent stem cells
Sci Rep. 2020 Sep 1;10(1):14387.
Ke Ye, Yuto Takemoto, Arisa Ito, Masanari Onda, Nao Morimoto, Michiko Mandai, Masayo Takahashi, Ryuji Kato, Fumitaka Osakada
PMID: 32873827 PMCID: PMC7462996 DOI: 10.1038/s41598-020-70979-y
Transplantation of retinal pigment epithelial (RPE) sheets derived from human induced pluripotent cells (hiPSC) is a promising cell therapy for RPE degeneration, such as in age-related macular degeneration. Current RPE replacement therapies, however, face major challenges. They require a tedious manual process of selecting differentiated RPE from hiPSC-derived cells, and despite wide variation in quality of RPE sheets, there exists no efficient process for distinguishing functional RPE sheets from those unsuitable for transplantation. To overcome these issues, we developed methods for the generation of RPE sheets from hiPSC, and image-based evaluation. We found that stepwise treatment with six signaling pathway inhibitors along with nicotinamide increased RPE differentiation efficiency (RPE6iN), enabling the RPE sheet generation at high purity without manual selection. Machine learning models were developed based on cellular morphological features of F-actin-labeled RPE images for predicting transepithelial electrical resistance values, an indicator of RPE sheet function. Our model was effective at identifying low-quality RPE sheets for elimination, even when using label-free images. The RPE6iN-based RPE sheet generation combined with the non-destructive image-based prediction offers a comprehensive new solution for the large-scale production of pure RPE sheets with lot-to-lot variations and should facilitate the further development of RPE replacement therapies.
Visual Function Endpoints to Enable Dry AMD Clinical Trials
Drug Discov Today Ther Strateg. Spring 2013;10(1):e43-e50.
Luis Andres Lesmes, Mary Lou Jackson, Peter Bex
PMID: 32863843 PMCID: PMC7453884 DOI: 10.1016/j.ddstr.2012.11.002
The slow progression of non-exudative age-related macular degeneration (dry AMD) presents challenges for drug discovery. The standard endpoint used for ophthalmic clinical trials, best-corrected visual acuity, is insensitive to the early stages and slow progression of dry AMD. Effective drug discovery for dry AMD treatments will therefore require novel applications of more effective visual function endpoints. This review will present candidates for visual function endpoints for dry AMD clinical trials. The promising visual assessments include contrast sensitivity, reading speed, microperimetry, and dark adaptation. Their adoption as exploratory endpoints in future trials will be critical for determining their accuracy, precision, and applicability, and ultimately determine their value for drug discovery.
The Role of Optical Coherence Tomography Angiography in Ranibizumab-Treated Choroidal Neovascularization in Choroidal Osteoma
Case Rep Ophthalmol. 2020 Jul 17;11(2):370-376.
William J Carroll, Yi Stephanie Zhang, Lee M Jampol, Manjot K Gill
PMID: 32884552 PMCID: PMC7443623 DOI: 10.1159/000508032
In this study, we report the initial evaluation of choroidal neovascularization (CNV) secondary to choroidal osteoma and subsequent response to anti-vascular endothelial growth factor (anti-VEGF) treatment monitored with optical coherence tomography angiography (OCT-A). A 38-year-old female presented with an initial visual acuity of 20/150 in the left eye. Clinical examination revealed a choroidal osteoma. OCT demonstrated both subretinal and intraretinal fluid. OCT-A was performed and showed CNV. A course of ten treatments with ranibizumab showed an improvement of visual acuity to 20/30-3, improvement of subretinal and intraretinal fluid, as well as attenuation of CNV. Our report demonstrates OCT-A as a useful tool for both initial evaluation of CNV and following treatment response to anti-VEGF therapy.