Macular Degeneration Research Articles

Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity.

To review the evidence and describe the biological plausibility for the benefits of inhibiting cholesteryl ester transfer protein (CETP) on multiple organ systems through modification of lipoprotein metabolism. Results from observational studies, Mendelian randomization analyses, and randomized clinical trials support the potential of CETP inhibition to reduce atherosclerotic cardiovascular disease (ASCVD) risk through a reduction of apolipoprotein B-containing lipoproteins. In contrast, raising high-density lipoprotein (HDL) particles, as previously hypothesized, did not contribute to ASCVD risk reduction. There is also an expanding body of evidence supporting the benefits of CETP inhibition for safeguarding against other conditions associated with aging, particularly new-onset type 2 diabetes mellitus and dementia, as well as age-related macular degeneration, septicemia, and possibly chronic kidney disease. The latter are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities. At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.

The aryl hydrocarbon receptor: A crucial mediator in ocular disease pathogenesis and therapeutic target.

The aryl hydrocarbon receptor (AHR) is a pivotal nuclear receptor involved in mediating cellular responses to a wide range of environmental pollutants and endogenous ligands. AHR plays a central role in regulating essential physiological processes, including xenobiotic metabolism, immune response modulation, cell cycle control, tumorigenesis, and developmental events. Recent studies have identified AHR as a critical mediator and a potential therapeutic target in the pathogenesis of ocular diseases. This review provides a thorough analysis of the various functions of AHR signalling in the ocular environment, with a specific emphasis on its effects on the retina, retinal pigment epithelium (RPE), choroid, and cornea. We provide a detailed discussion on the molecular mechanisms through which AHR integrates environmental and endogenous signals, influencing the development and progression of age-related macular degeneration (AMD), retinitis pigmentosa, uveitis, and other major ocular disorders. Furthermore, we evaluate the therapeutic potential of modulating AHR activity through novel ligands and agonists as a strategy for treating eye diseases. Understanding the molecular mechanisms of AHR in ocular tissues may facilitate the development of AHR-targeted therapies, which is crucial for addressing the pressing clinical demand for novel treatment strategies in ocular diseases.

Regualtion of LAMTOR1 by Oxidative Stress in Retinal Pigment Epithelium: Implications for Age-Related Macular Degeneration Pathogenesis

Oxidative stress is a critical pathogenic factor for age-related macular degeneration (AMD). Autophagy serves as a mechanism to counteract oxidative stress. LAMTOR1 regulates mTORC1 activity by recruiting or disassembling it on the lysosome under the addition or deprivation of amino acids. This regulation inhibits or enhances autophagy. Our study investigates whether oxidative stress impacts LAMTOR1, thereby adapting to oxidative conditions. We employed oxidative stressors, menadione (VK3) and 4-hydroxynonenal (4-HNE), and observed a reduction of LAMTOR1 in both human and mouse retinal pigment epithelium (RPE) following short-term (1h) and prolonged exposures (24h). Nrf2 overexpression increased both lamtor1 mRNA and LAMTOR1 protein in the RPE. To determine if Nrf2 regulates lamtor1 transcription, we cloned the deletion mutants of the lamtor1 promoter into a luciferase reporter. Although the promoter contained antioxidant response elements, transcriptional activity depended on the interaction between Nrf2 and the constructs containing the transcriptional start site. Moreover, Nrf2-driven transcription was significantly reduced by an inhibitor of histone acetyltransferase, p300. Correspondingly, Nrf2 overexpression increased levels of acetylated histone3 and p300. The reduction in LAMTOR1 by 4-HNE was reversed by pepstatin A and NH4Cl which block lysosomal degradation. 4-HNE increased TFEB nuclear translocation which was reversed by LAMTOR1 overexpression. In vivo, LAMTOR1 levels decreased in the photoreceptor and RPE layers of NaIO3-injected mice, compared to PBS-injected controls. In conclusion, oxidative injury reduces LAMTOR1, predominantly through lysosomal degradation although Nrf2-mediated histone acetylation enhances lamtor1 transcription. This study reveals a previously unrecognized regulatory mechanism of lamtor1 by oxidative stress, suggesting a novel role for LAMTOR1 in the pathogenesis of AMD.

Preclinical evaluation of NG101, a potential AAV gene therapy for wet age-related macular degeneration

Preclinical evaluation of NG101, a potential AAV gene therapy for wet age-related macular degeneration

Thrombospondin 1 Mediates Autophagy Upon Inhibition of the Rho-Associated Protein Kinase Inhibitor

Age-related macular degeneration (AMD) is a degenerative eye disease leading to central vision loss and is characterized by dysregulated autophagy of the retinal pigment epithelium (RPE) layer. Recent studies have suggested that rho-associated protein kinase (ROCK) inhibitors may enhance autophagy in neurodegenerative diseases and promote the survival of RPE cells. This study investigated the effect of ROCK inhibitors on autophagy gene expression and autophagic vacuole formation in a human RPE (ARPE-19) cell line. The highly selective and potent ROCK inhibitor Y-39983 enhanced the expression of autophagy genes in ARPE-19 cells and increased autophagic vacuole formation. A proteomic analysis using mass spectrometry was performed to further characterize the effects of ROCK inhibition at the protein level. Y-39983 downregulated thrombospondin-1 (THBS1), and suppression of THBS1 in ARPE-19 cells resulted in an increase in autophagic vacuole formation. Our data showed that ROCK inhibitor-induced autophagy was mediated by THBS1 downregulation. We identified ROCK and THBS1 as potential novel therapeutic targets in AMD.

Comparative study between swept-source and spectral-domain OCTA for imaging of choroidal neovascularization in age-related macular degeneration

AIM: To compare the differences of choroidal neovascularization (CNV) measurements between swept-source and spectral-domain optical coherence tomography angiography (SS-OCTA and SD-OCTA) in neovascular age-related macular degeneration (nAMD) and the imaging reliability of the two devices. METHODS: Prospective comparative study. SS-OCTA and SD-OCTA were used to scan the same eye with the modes of 3×3 and 6×6 mm2 centered on the neovascularization. Only qualified images were chosen and the border of CNV was manually delineated by two graders independently. The area of CNV (ACNV), vascular perfusion density (PD), and vessel length density (VLD) within the delineation were calculated using Image J. The differences of CNV measurements between the two OCTA devices were compared using Bland-Altman analysis. The agreement between the two graders on the measurements of each device was compared using the intraclass correlation coefficient (ICC). RESULTS: A total of 18 patients (22 eyes) with nAMD were included. The measurements of ACNV, PD, and VLD were 7.247±4.586 and 4.901±3.741 mm2, 43.202±9.636 and 34.904±10.489, 6.339±1.228 and 5.908±1.741 mm-1 for SS-OCTA and SD-OCTA, respectively. The differences between the two devices were 2.346±3.030 mm2 (Z= -3.782, P<0.0001), 8.298±14.160 (Z=-2.419, P=0.016), and 0.431±2.114 mm-1 (Z=-0.828, P=0.408) for ACNV, PD and VLD, respectively. The ICC between two graders were 0.893 (P<0.001), 0.902 (P<0.001), 0.885 (P<0.001) for ACNV, PD, VLD in SS-OCTA, and 0.971 (P<0.001), 0.976 (P<0.001), 0.973 (P<0.001) in SD-OCTA, respectively. CONCLUSION: Both OCTA devices have high imaging reliability. Compared with SD-OCTA, SS-OCTA has a larger ACNV measurements, but doesn't show better resolution of internal vessels of CNV and well signal strength.

Artificial intelligence in assessing progression of age-related macular degeneration

AbstractThe human population is steadily growing with increased life expectancy, impacting the prevalence of age-dependent diseases, including age-related macular degeneration (AMD). Health care systems are confronted with an increasing burden with rising patient numbers accompanied by ongoing developments of therapeutic approaches. Concurrent advances in imaging modalities provide eye care professionals with a large amount of data for each patient. Furthermore, with continuous progress in therapeutics, there is an unmet need for reliable structural and functional biomarkers in clinical trials and practice to optimize personalized patient care and evaluate individual responses to treatment. A fast and objective solution is Artificial intelligence (AI), which has revolutionized assessment of AMD in all disease stages. Reliable and validated AI-algorithms can aid to overcome the growing number of patients, visits and necessary treatments as well as maximize the benefits of multimodal imaging in clinical trials. Therefore, there are ongoing efforts to develop and validate automated algorithms to unlock more information from datasets allowing automated assessment of disease activity and disease progression. This review aims to present selected AI algorithms, their development, applications and challenges regarding assessment and prediction of AMD progression.

Short-term fluctuation of intraocular pressure and influencing factors following intravitreal injection in patients with retinal vascular diseases

AIM: To investigate the patterns of short-term intraocular pressure (IOP) fluctuations and identify the contributing factors following intravitreal injection in patients with retinal vascular diseases. METHODS: Totally 81 patients were enrolled in this case control study. Eyes were categorized into 7 groups, including age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), idiopathic choroidal neovascularization (CNV), proliferative diabetic retinopathy (PDR), diabetic macular edema (DME), macular edema secondary to branch (BVOME) and central (CVOME) retinal vein occlusion. IOP was measured in all patients using rebound tonometer at 7 preset time points perioperatively. Additionally, based on the administered medication, the eyes were classified into three treatment groups, including dexamethasone intravitreal implant (IVO), intravitreal conbercept (IVC), and intravitreal ranibizumab (IVR). To compare IOP values at various time points across groups, we employed one-way ANOVA, independent sample t-test or χ2 test and multivariate logistic regression analysis. RESULTS: Peak IOP values across all groups were observed at 40s, and 5min after intravitreal injection. Statistical differences in IOP were detected at the 5min among the 7 indication groups (F=2.50, P=0.029). When examing the impact of medications, the IVO group exhibited lower average IOP values at both 40s and 5min compared to the IVC and IVR groups (P<0.001; P=0.007). The IOP values at 40s and 5min were significantly higher in BVOME and CVOME group compared to non-retinal vein occlusion-secondary macular edema (RVOME) group (P<0.001). Multivariate logistic regression analysis further confirmed that IOP measurement at 40s was significantly higher in CVOME group than in non-RVOME group (OR=1.64, 95%CI: 1.09-2.47; P=0.018). CONCLUSION: Needle size plays a crucial role in the transient changes of IOP following intravitreal injection. Before administering intravitreal injection to patients with central retinal vein occlusion, it is essential to exclude any underlysing causes of increased IOP.

Anti-VEGF treatment outcome prediction based on optical coherence tomography images in neovascular age-related macular degeneration using a deep neural network.

Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the number of affected patients is increasing worldwide. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard therapy for neovascular AMD (nAMD), and optical coherence tomography (OCT) is a crucial tool for evaluating the anatomical condition of the macula. However, OCT has limitations in accurately predicting the degree of functional and morphological improvement following intravitreal injections. Artificial intelligence (AI) has been proposed as a tool for predicting the treatment response of nAMD based on OCT biomarkers. Our study focuses on the development and assessment of an AI model utilizing the DenseNet201 algorithm. The model aims to predict anatomical improvement based on OCT images before, and during anti-VEGF therapy. The training process involves two scenarios: (1) using only preinjection OCT images and (2) utilizing both OCT images before and during anti-VEGF therapy for model training. The outcomes of our investigation, involving 2068 images from a cohort of 517 Korean patients diagnosed with nAMD, indicate that the AI model we introduced surpassed the predictive performance of ophthalmologists. The model exhibited a sensitivity of 0.915, specificity of 0.426, and accuracy of 0.820. Notably, its predictive capabilities were further enhanced with the inclusion of additional OCT images taken after the first and second injections during the loading phase. The treatment prediction performance of the model was the highest when using all input modalities (before injection, and after the first and second injections) and concatenation-based fusion layers. This study highlights the potential of AI in assisting individualized and tailored nAMD treatment.

Efficacy of intravitreal faricimab therapy for polypoidal choroidal vasculopathy: A systematic review and meta-analysis.

Polypoidal choroidal vasculopathy (PCV) is an aneurismal type of macular neovascularization that show similarities with age-related macular degeneration and diseases that are part of the pachychoroid disease spectrum. Exudative changes in PCV can be treated with intravitreal anti-vascular endothelial growth factor monotherapy; however, a combination therapy with photodynamic therapy may be required. In this systematic review and meta-analysis, we evaluated the efficacy of faricimab for PCV. We searched 12 literature databases for eligible studies. All study evaluation and data extraction were made by two authors in duplicate. Studies eligible for analysis were included for a qualitative and quantitative review. We identified seven studies with data from 150 eyes with PCV, five studies were of treatment-naïve eyes who were commenced in faricimab monotherapy, and two studies were of switch-over to faricimab from other anti-VEGF drugs. After faricimab loading dose in treatment-naïve eyes, the best-corrected visual acuity (BCVA) remained stable at -0.09 (95% CI: -0.20-0.03) logMAR, central retinal thickness (CRT) decreased -169 (95% CI: -311--27) μm, and 48.7 (95% CI: 32.5-65.0) % of eyes obtained polyp closure. In switch-over eyes, 57%-67% experienced fluid reduction and 21% were able to extend their treatment interval. In conclusion, faricimab monotherapy for PCV leads to acceptable clinical outcomes in terms of stable BCVA, reduction of CRT, and high incidence of polyp closure. Some cases may benefit from a switch to faricimab. However, long-term efficacy studies and controlled comparative studies are warranted.

The renal-retinal connection - The eye in chronic kidney disease

Chronic kidney disease (CKD) is linked with several systemic complications, including ocular manifestations that can adversely affect quality of life. The prevalence and types of ocular changes in CKD patients, particularly their correlation with disease stages, are not well-documented. This study aims to evaluate the ocular manifestations in CKD and their association with different stages of the disease.A cross-sectional study on 70 CKD patients revealed a high prevalence of ocular abnormalities, including diabetic retinopathy, hypertensive retinopathy, and age-related macular degeneration. These conditions often worsened as CKD progressed, emphasizing the need for regular eye exams in CKD patients to prevent vision loss and address complications promptly. To investigate the prevalence and types of ocular manifestations in patients with chronic kidney disease (CKD) and to analyse their correlation with the stages of CKD. This cross-sectional, descriptive, non-interventional, hospital-based study was conducted over four months from May 2024 to August 2024 in the Department of Nephrology. Seventy patients with diagnosed CKD, aged 18 years and older, were included. Exclusion criteria were patients with reversible causes of renal failure, those who had undergone renal transplantation, and those who did not consent. A comprehensive ocular examination was performed on 140 eyes from the enrolled patients, assessing anterior and posterior segment findings, including visual acuity, eyelid conditions, conjunctival status, lens status, and fundus examination. The study included 38 males (54.3%) and 32 females (45.7%) with a mean age of 57 years. Hypertension and diabetes mellitus were the most common comorbidities, present in 71.4% and 64.3% of patients, respectively. Visual acuity deteriorated with advancing stages of CKD, with significant impairment and blindness observed predominantly in CKD stages 4 and 5. Anterior segment examination revealed that 62% of eyes had immature cataracts, and 38% were pseudophakic. Fundoscopic examination showed that 51.4% of patients had abnormal findings, including non-proliferative and proliferative diabetic retinopathy, hypertensive retinopathy, age-related macular degeneration, and glaucomatous disc changes. The severity of fundus abnormalities increased with the progression of CKD, highlighting a strong correlation between the degree of renal dysfunction and ocular health. Ocular manifestations are common in CKD patients and correlate with the severity of kidney disease. The prevalence of both anterior and posterior segment abnormalities underscores the need for regular ophthalmic evaluations in CKD patients to prevent vision loss and manage ocular complications early.

Multiwavelength photobiomodulation in atrophic age-related macular degeneration.

To evaluate photobiomodulation (PBM) safety and efficacy in patient with atrophic AMD and to explore tissue effects using Spectrally Resolved Autofluorescence (SrAF) to identify a potential biomarker indicative of mitochondrial activity, the primary PBM target. This retrospective, non-comparative case series involved six eyes of five patients with atrophic AMD, conducted at the Medical Retina and Imaging Unit, IRCCS San Raffaele Hospital in Milan, Italy. At baseline and follow-ups (after one and three months) a complete ophthalmological assessment and multimodal imaging, including spectrally resolved autofluorescence (SrAF), were performed. PBM treatment (Valeda Light Delivery System - LumiThera) was administered in nine sessions over three weeks. The SrAF images were analyzed to evaluate the effect of the treatment. Six eyes of five patients with atrophic AMD received PBM at baseline. Best corrected visual acuity (BCVA), mean central macular thickness (CMT), mean retinal sensitivity on microperimetry and the atrophic area have remained stable. No eyes developed foveal atrophy after the treatment. The image analysis in SrAF showed an increase in the highlighted area of 4.89% after one month and 17.11% after three months. No adverse systemic or local side effects were reported. PBM is a safe treatment for the human retina. The evaluation of the retinal area within the green light spectrum (575 nm) in SrAF is a potential indirect biomarker of mitochondrial activity and could be used to assess treatment efficacy in clinical studies.

Topographic and quantitative correlation of structure and function using deep learning in subclinical biomarkers of intermediate age-related macular degeneration.

To examine the morphological impact of deep learning (DL)-quantified biomarkers on point-wise sensitivity (PWS) using microperimetry (MP) and optical coherence tomography (OCT) in intermediate AMD (iAMD). Patients with iAMD were examined by OCT (Spectralis). DL-based algorithms quantified ellipsoid zone (EZ)-thickness, hyperreflective foci (HRF) and drusen volume. Outer nuclear layer (ONL)-thickness and subretinal drusenoid deposits (SDD) were quantified by human experts. All patients completed four MP examinations using an identical custom 45 stimuli grid on MP-3 (NIDEK) and MAIA (CenterVue). MP stimuli were co-registered with corresponding OCT using image registration algorithms. Multivariable mixed-effect models were calculated. 3.600 PWS from 20 eyes of 20 patients were analyzed. Decreased EZthickness, decreased ONLthickness, increased HRF and increased drusen volume had a significant negative effect on PWS (all p < 0.001) with significant interaction with eccentricity (p < 0.001). Mean PWS was 26.25 ± 3.43dB on MP3 and 22.63 ± 3.69dB on MAIA. Univariate analyses revealed a negative association of PWS and SDD (p < 0.001). Subclinical changes in EZintegrity, HRF and drusen volume are quantifiable structural biomarkers associated with reduced retinal function. Topographic co-registration between structure on OCT volumes and sensitivity in MP broadens the understanding of pathognomonic biomarkers with potential for evaluation of quantifiable functional endpoints.

Progression to complete retinal pigment epithelium and outer retinal atrophy (cRORA): post hoc analysis of the GATHER1 trial.

Determine rates of progression of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) to complete retinal pigment epithelium and outer retinal atrophy (cRORA) and rates of progression of drusen to iRORA/cRORA in eyes with geographic atrophy (GA) treated with avacincaptad pegol (ACP). Post hoc analysis of the GATHER1 prospective, randomized, double-masked Phase II/III study that evaluated ACP 2mg vs. sham. Optical coherence tomography (OCT) data from GATHER1 were transferred to the Doheny Image Reading and Research Lab for masked analysis by readers experienced with Classification of Atrophy Meeting (CAM) grading features. Regions of OCT volume scans more than 500µm from the border of GA lesions were evaluated at baseline and at months 6, 12, and 18. Participants with iRORA and/or drusen (≥ 40µm height on OCT) at baseline were included in the analysis. The proportion of eyes progressing from iRORA to cRORA in the ACP 2mg group was 5.0%, 15.0%, and 20.0% at months 6, 12, and 18 respectively, as compared with 11.8%, 30.2%, and 41.8% of eyes in the sham group. The proportion of ACP 2mg-treated eyes progressing from drusen to iRORA or cRORA was 3.8%, 7.6%, and 7.6% at months 6, 12, and 18 compared with 15.9%, 18.1%, and 27.2% of sham-treated eyes. Rates of progression from iRORA to cRORA and drusen to iRORA/cRORA were reduced in eyes treated with ACP 2mg vs. sham, with increasing separation between groups over time, suggesting early intervention may slow disease progression. ClinicalTrials.gov identifier: NCT02686658. Date of registration: February 16, 2016. What is known Geographic atrophy is an advanced form of age-related maculardegeneration (AMD) that leads to irreversible vision loss, presenting a significant public health unmet need. The Classification of Atrophy Meeting (CAM) group recommended a new nomenclature for advanced AMD lesions, based on the affected anatomical layers on optical coherence tomography. Accordingly, the terms incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA) were introduced (Guymer et al., Ophthalmology 127:394-409, 2020; Sadda et al., Ophthalmology 125:537-548, 2018). What is new GATHER1 post hoc analysis shows that treatment with avacincaptad pegol (ACP) 2mg decreases the proportion of eyes that progress from iRORA to cRORA, and from drusen to iRORA or cRORA, compared with sham, over 6, 12, and 18months. These findings suggest a potential role for ACP in delaying the progression of existing pre-atrophic AMD lesions.

Outlier ophthalmologists in the treatment of neovascular age-related macular degeneration with intravitreal therapy

BackgroundTo compare individual ophthalmologists grouped as outliers or non-outliers based on the mean 12-month visual acuity (VA) outcomes for their patients with neovascular age-related macular degeneration (nAMD).MethodsThis prospectively designed database...

Correlation of retinal fluid and photoreceptor and RPE loss in neovascular AMD by automated quantification, a real-world FRB! analysis.

To quantify ellipsoid zone (EZ) loss during anti-VEGF therapy for neovascular age-related macular degeneration (nAMD) and correlate these findings with nAMD disease activity using artificial intelligence-based algorithms. Spectral domain optical coherence tomography (Spectralis, Heidelberg Engineering) images from nAMD treatment-naïve patients from the Fight Retinal Blindness! (FRB!) Registry from Zürich, Switzerland were processed at baseline and over 3 years of follow-up. An approved deep learning algorithm (Fluid Monitor, RetInSight) was used to automatically quantify intraretinal fluid (IRF), subretinal fluid (SRF) and pigment epithelial detachment (PED). An ensemble U-net deep learning algorithm was used to automated quantify EZ integrity based on EZ layer thickness. The impact of fluid volumes on EZ thickness and late-stages outcomes were calculated using Wilcoxon rank-sum tests, a linear mixed model and a longitudinal panel regression model. Two hundred and eleven eyes from 158 patients were included. The mean ± SD EZ loss area in the central 6 mm was 1.81 ± 2.68 mm2 at baseline and reached 6.21 ± 6.15 mm2 at month 36. Higher fluid volumes (top 25%) of IRF and PED in the central 1 and 6 mm of the macula were significantly associated with more advanced EZ thinning and loss compared to the low fluid volume subgroup. The high SRF subgroup in the linear regression model showed no statistically significant association with EZ integrity in the central macula; however, the longitudinal analysis revealed an increased EZ thickness with no additional loss. Intraretinal fluid and PED volumes and their resolution pattern have an impact on alteration of the underlying EZ layer. AI-supported quantifications are helpful in quantifying early signs of macular atrophy and providing individual risk profiles as a basis for tailored therapies for optimized visual outcomes.

Targeting glutamine synthetase with AS1411-modified exosome-liposome hybrid nanoparticles for inhibition of choroidal neovascularization.

Choroidal neovascularization (CNV) is a leading cause of visual impairment in wet age-related macular degeneration (wAMD). Recent investigations have validated the potential of reducing glutamine synthetase (GS) to inhibit neovascularization formation, offering prospects for treating various neovascularization-related diseases. In this study, we devised a CRISPR/Cas9 delivery system employing the nucleic acid aptamer AS1411 as a targeting moiety and exosome-liposome hybrid nanoparticles as carriers (CAELN). Exploiting the binding affinity between AS1411 and nucleolin on endothelial cell surfaces, the delivery system was engineered to specifically target the glutamine synthetase gene (GLUL), thereby attenuating GS levels and continuously suppressing CNV. CAELN exhibited spherical and uniform dispersion. In vitro cellular investigations demonstrated gene editing efficiencies of CAELN ranging from 42.05 to 55.02% and its capacity to inhibit neovascularization in HUVEC cells. Moreover, in vivo pharmacodynamic studies conducted in CNV rabbits revealed efficacy of CAELN in restoring the thickness of intra- and extranuclear tissues. The findings suggest that GS is a novel target for the inhibition of pathological CNV, while the development of AS1411-modified exosome-liposome hybrid nanoparticles represents a novel delivery method for the treatment of neovascular-related diseases.

Alcohol Consumption and Risk of Age-Related Macular Degeneration and Geographic Atrophy Progression: AREDS2 Report 34.

To examine potential relationships between alcohol consumption and age-related macular degeneration (AMD) progression, including progression to late AMD and geographic atrophy (GA) enlargement rate. Post hoc analysis of cohorts within the Age-Related Eye Diseases Study 2 (AREDS2). 6670 eyes (of 3673 participants) with no late AMD at baseline; 1143 eyes (of 841 participants) with GA at ≥2 consecutive visits. Color fundus photographs were collected at annual study visits and graded centrally for late AMD, GA area, and GA proximity. Alcohol consumption was calculated by food frequency questionnaire. Regression analyses of disease progression were performed according to alcohol consumption. Progression to late AMD and its subtypes; GA area-based progression; GA proximity-based progression. Over mean follow-up of 3.8 years, 40.2% of eyes progressed to late AMD. In men, with alcohol tertile 1 (no regular consumption) as reference, hazard ratios for progression to late AMD were 0.69 (95% CI 0.55-0.87, p=0.0015) for tertile 2 and 0.85 (0.71-1.02, p=0.079) for tertile 3. In women, hazard ratios were 1.12 (0.95-1.31, p=0.17) and 0.85 (0.72-1.00, p=0.046), respectively. Over mean follow-up of 3.1 years, GA area-based progression was significantly faster in women than men, at 0.295 (95% CI 0.278-0.311) and 0.260 mm/year (0.241-0.279), respectively (p=0.007). In men, area-based progression differed significantly by alcohol tertile (p=0.0001), at 0.275 (0.248-0.303), 0.183 (0.143-0.223), and 0.280 mm/year (0.254-0.306) in tertiles 1-3, respectively. In women, the area-based rate did not differ significantly by alcohol tertile (p=0.11). In men only, CDC-defined heavy drinking was associated with faster progression (p=0.024), at 0.306 (0.262-0.349) vs 0.252 mm/year (0.233-0.270). In 808 eyes with non-central GA, GA proximity-based progression did not differ significantly by alcohol tertile (p=0.55). Moderate alcohol consumption is associated with decreased risk of progression to late AMD in men. GA progression is faster in women, but its relationship with alcohol consumption is much stronger in men. In men, moderate consumption is associated with slower GA progression and higher consumption with faster progression. Although some of these associations may also relate to confounding, they might suggest that individuals with GA should avoid high alcohol consumption.

FEATURES OF ANTIVASOPROLIFERATIVE THERAPY AFTER SUBMACULAR SURGERY WITH VITREOUS PRESERVATION

Rationale: Age-related macular degeneration in the modern world is one of the leading problems leading to blindness. It is a rapidly progressive disease characterized by damage to the central area of the retina.Objective: The aim of the study was to evaluate the morphological and functional parameters of the retina after surgical treatment of submacular hemorrhages against the background of anti-vasoproliferative therapy in patients with a wet form of age-related macular degeneration.Methods: The study was conducted on the basis of the Ophthalmology Center NMHC named by Pirogov (Moscow). It included 90 participants with an active form of age-related macular degeneration. The average age of the patients was 71.3 ± 8.5 years, including 50 women aged 61 to 82 years and 40 men aged 74 to 78 years. The rationale for the use of the “treat and extend” strategy in this work is the possibility of using fewer intravitreal injections compared to a fixed scheme that gives similar results of visual functions.Conclusion: It can be concluded that the preservation of the vitreous body during minimally invasive vitreoretinal intervention allows you to adhere to the “treat and extend” mode without reducing the inter-injection interval.

Ocular Pharmacokinetics of Faricimab Following Intravitreal Administration in Patients With Retinal Disease.

To characterize faricimab ocular and systemic pharmacokinetics (PK) in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) and to assess the effect of faricimab ocular exposure on clinical endpoints. A population PK (popPK) model was developed using pooled data from phase 1 to 3 studies in patients with nAMD/DME. The dataset included 1095 faricimab aqueous humor (AH) concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients. Following intravitreal administration, faricimab PK was accurately described by a linear three-compartment model with sequential vitreous humor (VH), AH, and plasma compartments. Faricimab VH elimination to AH is the slowest process, with an estimated half-life (t1/2) of 7.5 days. Due to flip-flop kinetics, plasma, AH, and VH concentrations declined in parallel. Disease had no effect on faricimab PK. Plasma exposure was ∼6000-fold lower than VH exposure. Age, anti-drug antibodies, body weight, and sex statistically significantly influenced PK parameters but had no clinically meaningful effect on ocular and systemic exposure. VH t1/2 alone could not explain faricimab dosing frequency. Exposure-response analyses showed similar gains in best-corrected visual acuity across faricimab exposure ranges and dosing regimens. Faricimab ocular and systemic pharmacokinetics were quantified and accurately described by the popPK model, developed using a large dataset from patients with nAMD/DME. Exposure-response analyses suggest that faricimab phase 3 dosing algorithms are appropriate to select the most suitable dosing regimen. The popPK analysis suggested that faricimab dosing frequency was influenced by several factors and not by VH t1/2 alone.