Treatment Of Age-related Macular Degeneration Research Articles

LIGHTSITE II Randomized Multicenter Trial: Evaluation of Multiwavelength Photobiomodulation in Non-exudative Age-Related Macular Degeneration.

Photobiomodulation (PBM) represents a potential treatment for non-exudative age-related macular degeneration (AMD). PBM uses wavelengths of light to target components of the mitochondrial respiratory chain to improve cellular bioenergetic outputs. The aim of this study was to further investigate the effects of PBM on clinical, quality of life (QoL) and anatomical outcomes in subjects with intermediate stage non-exudative AMD. The multicenter LIGHTSITE II study was a randomized clinical trial evaluating safety and efficacy of PBM in intermediate non-exudative AMD. The LumiThera Valeda® Light Delivery System delivered multiwavelength PBM (590, 660 and 850nm) or sham treatment 3 × per week over 3-4weeks (9 treatments per series) with repeated treatments at baseline (BL), 4 and 8months. Subjects were enrolled with 20/32 to 20/100 best-corrected visual acuity (BCVA) and no central geographic atrophy (GA) within the central fovea (500μm). LIGHTSITE II enrolled 44 non-exudative AMD subjects (53 eyes). PBM-treated eyes showed statistically significant improvement in BCVA at 9months (n = 32 eyes, p = 0.02) with a 4-letter gain in the PBM-treated group versus a 0.5-letter gain in the sham-treated group (ns, p < 0.1) for patients that received all 27 PBM treatments (n = 29 eyes). Approximately 35.3% of PBM-treated eyes showed ≥ 5-letter improvement at 9months. Macular drusen volume was not increased over time in the PBM-treated group but did show increases in the sham-treated group. While PBM and sham groups both showed GA lesion growth in the trial period, there was 20% less growth in the PBM group over 10months, suggesting potential disease-modifying effects. No safety concerns or signs of phototoxicity were observed. These results confirm previous clinical testing of multiwavelength PBM and support treatment with Valeda as a novel therapy with a unique mechanism of action as a potential treatment for non-exudative AMD. Clinicaltrial.Gov Registration Identifier: NCT03878420.

Rol polimorfizmiv heniv HTRA serynovoi peptydazy 1, faktora rostu endoteliiu sudyn, faktora nekrozu pukhlyn u likuvanni «volohoi» formy vikovoi makuliarnoi deheneratsii

Introduction. Age-related macular degeneration (AMD) of the retina is still considered the leading cause of vision loss in the elderly. The multifactoriality of the disease impairs the clinical effectiveness of modern AMD treatment methods. however, the study of single-nucleotide polymorphisms, in particular, of the HtrA serine peptidase 1 (HTRA1), vascular endothelial growth factor A (VEGF A) and tumor necrosis factor (TNF) genesis a promising link on the way to improve and develope more effective treatment strategies of the disease. The Aim of the Study. To investigate role of HTRA 1, VEGF A and TNF gene polymorphisms in the treatment of wet age-related macular degeneration. Materials and Methods. 162 people with diagnosed wet AMD took part in the investigation. They received anti-VEGF A therapy in the form of injections of aflibercept monthly for half a year. Structural changes of the eyes were studied using optical coherence tomography (OCT); polymerase chain reaction (PCR) studies were performed using a Bio-Rad CFX 96 apparatus (BioRad, USA) using a reagent package (Lytech, Russia). Statistical analysis of the obtained results was performed using a set of software packages Statistica 10 (StatSoft, Inc., USA) and SPSS 23.0. Results. It was revealed best prognostic significance in patients with the TC rs2010963 genotype of the VEGFA gene was registered during the analysis of OCT 2 (RR=2.7; 95% CI 1.556 – 4.8), OCT 4 (RR=2.9 ; 95% CI 1.7 – 5.03) and OCT 8 (RR=2.6; 95% CI 1.6 – 4.12) sections, while in patients with the CC genotype these indicators in the OCT 2 section were: RR= 6.1; 95% CI 3.66 – 10.27; in OCT zone 4 RR=4.9; 95% CI 2.9 – 8.29, and in the OCT section 8: RR=4.23; 95% CI 2.7 – 6.556, which indicates a more pronounced influence of the CC genotype. When analyzing rs1800629 of the TNF gene, the best prognostic significance of the GA genotype was established in the OCT 4 (RR=1.77; 95% CI 1.218 – 2.56) and OCT 8 (RR=1.9; 95% CI 1.17 – 3.175) areas (p-value less than 0.05), with the AA genotype in OCT 4 (RR=3.77; 95% CI 2.17 – 6.58), OCT 8 (RR=3.1; 95% CI 1 .7 – 5.59) zones and when evaluating changes in visual acuity of patients with wet AMD (RR=4.2; 95% CI 2 – 8.98). No statistically significant results were found in the evaluation of the HTRA1 gene rs11200638 (p-value more than 0.05). Conclusions. The data obtained in our study indicate a direct influence of the vascular endothelial growth factor A (rs2010963) and tumor necrosis factor (rs1800629) polymorphisms on the emergence of resistance to aflibercept. However, the study of this influence in the presence of the HtrA serine peptidase 1 gene rs11200638 requires further research.

Experience with Brolucizumab Treatment of Neovascular Age-Related Macular Degeneration

Purpose: To assess efficacy and safety profile of intravitreal brolucizumab in patients with neovascular age-related macular degeneration (nAMD) in real clinical practice.Patients and Methods. This study enrolled 21 patients with nAMD (treatment-naïve), including 12 women, 9 men, mean age was 73.5 ± 9.8 years. One patient was excluded from the study after 3 intravitreal injection (IVI) due to the development of the intraocular inflammation (IOI). All patients received 5 IVI of brolucizumab (in total, 100 injections). All patients were determined best-corrected visual acuity (BCVA). Intraretinal fluid (IRF), subretinal fluid (SRF), central macular thickness (CMT), and pigment epithelial detachment (PED) were evaluated by optical coherence tomography. Intraocular pressure (IOP) was measured before IVI, after 1 minute, 30 minutes. Patients were examined before treatment, after 3 and 5 IVI.Results. The average follow-up period for patients was 31 ± 2.5 weeks, the average interval after 3 loading doses was 8.4 ± 1.2 weeks, the average interval between 4 IVI and 5 IVI was 10.7 ± 1.9 weeks. The BCVA improved significantly after 3 IVI and after 5 IVI of brolucizumab (p &lt; 0.001). There was a statistically significant decrease in CMT and PED height (p &lt; 0.001), as well as a resolution of all types of fluid (p &lt; 0.001). All patients showed a significant increase in IOP immediately after injection (1 min) with normalization of IOP after 30 min. One case of IOI was registered 16 weeks after the start of treatment, cured by IVI of dexamethasone implant Ozurdex.Conclusion. Patients with nAMD (treatment-naïve) who received 5 IVI of brolucizumab demonstrated a significant improvement of morphological and functional parameters. Brolucizumab has shown efficacy in the treatment of nAMD despite a small risk of IOI.

Каротиноиды в терапии возрастной макулярной дегенерации: система доставки имеет значение

Age-related macular degeneration (AMD) is one of the leading causes of low vision and blindness worldwide for people over age 60. By 2040, the number of people living with macular degeneration is expected to reach 288 million due to the exponential acceleration of population aging. A decline in visual functions caused by AMD has a significant economic impact in all countries. Besides aging, there are other multiple heterogenic risk factors associated with AMD: gender, environmental condition, lifestyle, genetic characteristics, chronic inflammatory processes in the human body, level of education, etc. It is important for the ophthalmologist to be aware of modifiable risk factors and thus to collect a comprehensive medical history, interact with patients using motivational interviewing and to involve promptly other healthcare specialists into the patient management strategy. Etiopathogenesis of AMD is still not entirely understood. However, it is known that the major pathways include age-related alterations of retinal pigment epithelium (RPE) cells, oxidative stress, dysregulated lipid metabolism, inflammation, hemodynamic changes, and neovascularization. Carotenoids lutein and zeaxanthin are natural compounds with a proven efficacy in reducing AMD progression, which have been demonstrated to act as medications for patients with early AMD stages. The micro- encapsulated formula offers such an advantage as gradual and controlled release of active substances. Keywords: age-related macular degeneration, risk factors, etiopathogenesis, carotenoids, lutein, zeaxanthin, microcapsules. For citation: Maksimov M.L., Oganezova J.G., Kanner I.D., Voznesenskaya A.A. Carotenoids in the treatment of age-related macular degeneration: a drug delivery system does matter. Russian Journal of Clinical Ophthalmology. 2023;23(1):60–65 (in Russ.). DOI: 10.32364/2311-7729-2023-23-1-60-65.

Repurposing Drugs for Treatment of Age-Related Macular Degeneration.

The need for new drugs to treat dry forms of age-related macular degeneration remains high. A promising approach is repurposing of FDA-approved medications to treat AMD. Databases containing medical and drug records allow for retroactive identification of drugs whose use correlates with reduced AMD diagnosis. This short review summarizes progress in several classes of drugs considered for repurposing: GPR-143 agonists (L-DOPA), anti-diabetic drugs (metformin, acarbose, empagliflozin, fenofibrate), mitochondrial activators (PU-91), and serotonin pathway drugs (fluoxetine, flibanserin, xaliproden, buspirone). The promises and caveats of repurposing are discussed herein.

Modern trends in anti-VEGF therapy for age-related macular degeneration

Age-related macular degeneration (AMD) develops in people aged 50 years and older, its pathogenesis involves progressive destruction of the retinal pigment epithelium and Bruch's membrane. There are eight currently known anti-VEGF drugs for treating the neovascular form of AMD, four of them have already been registered and are used in clinical practice. The first registered drug was pegaptanib, which selectively blocks VEGF165. Subsequently, a molecule with a similar mechanism of action was developed and named ranibizumab, which is a humanized monoclonal Fab fragment; it was specifically designed for ophthalmology. Its advantage over pegaptanib was neutralization of all active VEGF-A isoforms. Aflibercept and conbercept are recombinant fusion proteins that act as soluble decoy receptors for VEGF family proteins. Phase III data from the VIEW 1 and 2 studies showed that intraocular injections (IVI) of aflibercept every 1 or 2 months for a year resulted in comparable functional outcomes to monthly IVI of ranibizumab for one year. The next molecule for anti-VEGF therapy that showed effectiveness was brolucizumab - a single-chain fragment of a humanized antibody that binds with high affinity to various VEGF-A isoforms. Simultaneously with studying brolucizumab, another study was conducted involving Abicipar pegol, but that drug showed a high rate of complications. The latest drug registered for the treatment of neovascular AMD is faricimab. The molecule of this drug is a humanized immunoglobulin G antibody that acts on two key points of angiogenesis: VEGF-A and angiopoietin-2 (Ang-2). Thus, the strategy for advancing anti-VEGF therapy lies in the development of molecules with greater efficiency (better effect on newly formed vessels leading to resorption of exudate in the retina, under the neuroepithelium and under the retinal pigment epithelium), which allows not just to preserve vision, but to also significantly improve it when there is no macular atrophy.

Variable response of sub-retinal hyper-reflective membranes to anti-vascular endothelial growth factor treatment in bilateral neo-vascular age-related macular degeneration: A case report

Variable response of sub-retinal hyper-reflective membranes to anti-vascular endothelial growth factor treatment in bilateral neo-vascular age-related macular degeneration: A case report

Research Advances of the Method of Replenishing Deficiency and Removing Dirty Stasis in the Treatment of Wet Age-Related Macular Degeneration

Research Advances of the Method of Replenishing Deficiency and Removing Dirty Stasis in the Treatment of Wet Age-Related Macular Degeneration

Cooling Anesthesia for Intravitreal Injections - A Review.

Intravitreal (IVT) injections are the most common procedure performed in retinal clinics today. It has revolutionized the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular edema, macular edema due to veinous occlusive disease and other forms of exudative maculopathy. Though IVT injections prevent vision loss, the discomfort at the time of the injection has been troublesome to patients. This has led to patients missing their regular and routine dosage of treatment. Various modes of pre-injection anesthetic methods have been tried but in vain. Lidocaine-based topical anesthesia, in the form of pledgets, topical gel or subconjunctival lidocaine injection, has been the standard of care (SOC) for IVT injections worldwide. This article highlights the role of cooling anesthesia in reducing pain, anxiety and discomfort associated with needle penetration at the time of injection. PubMed and MedLine search were related to anesthesia for intravitreal injections, cooling anesthesia, mechanism of cooling anesthesia, COOL-1 trial, COOL-2 trial, results of COOL-1 trial and ultrarapid cooling anesthesia.

Self-Healing Alginate Hydrogel Formed by Dynamic Benzoxaborolate Chemistry Protects Retinal Pigment Epithelium Cells against Oxidative Damage

Oxidative stress is considered as a major factor causing retinal pigment epithelium (RPE) dysfunction and finally leading to retinal diseases such as age-related macular degeneration (AMD). Developing hydrogels for RPE cell delivery, especially those with antioxidant feature, is emerging as a promising approach for AMD treatment. Herein, a readily prepared antioxidant alginate-based hydrogel was developed to serve as a cytoprotective agent for RPE cells against oxidative damage. Alg-BOB was synthesized via conjugation of benzoxaborole (BOB) to the polysaccharide backbone. Hydrogels were formed through self-crosslinking of Alg-BOB based on benzoxaborole-diol complexation. The resulting hydrogel showed porous micro-structure, pH dependent mechanical strength and excellent self-healing, remolding, and injectable properties. Moreover, the hydrogel exhibited excellent cytocompatibility and could efficiently scavenge reactive oxygen species (ROS) to achieve an enhanced viability of ARPE-19 cells under oxidative condition. Altogether, our study reveals that the antioxidant Alg-BOB hydrogel represents an eligible candidate for RPE delivery and AMD treatment.

A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negative CFI variants in age-related macular degeneration.

Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H (CFH; FH) and factor I (CFI; FI) are associated with AMD. FH acts as a soluble cofactor to facilitate FI's cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin-CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD.

Safeguarding genome integrity during gene-editing therapy in a mouse model of age-related macular degeneration

Ensuring genome safety during gene editing is crucial for clinical translation of the high-efficient CRISPR-Cas9 toolbox. Therefore, the undesired events including chromosomal translocations, vector integrations, and large deletions arising during therapeutic gene editing remain to be adequately addressed or tackled in vivo. Here, we apply CRISPR-Cas9TX in comparison to CRISPR-Cas9 to target Vegfa for the treatment of age-related macular degeneration (AMD) disease in a mouse model. AAV delivery of both CRISPR-Cas9 and CRISPR-Cas9TX can efficiently inhibit laser-induced neovascularization. Importantly, Cas9TX almost eliminates chromosomal translocations that occur at a frequency of approximately 1% in Cas9-edited mouse retinal cells. Strikingly, the widely observed AAV integration at the target Vegfa site is also greatly reduced from nearly 50% of edited events to the background level during Cas9TX editing. Our findings reveal that chromosomal structural variations routinely occur during in vivo genome editing and highlight Cas9TX as a superior form of Cas9 for in vivo gene disruption.

Choice of an experimental model and modeling method in the study of the pathogenesis and methods of treatment of age-related macular degeneration (review)

Background. Experimental modeling of various pathological processes in the organ of vision is an integral part of both fundamental and applied research. For a deeper understanding of the pathogenesis of age-related macular degeneration (AMD) and testing of new methods of its treatment, various experimental models of AMD in animals have been developed. However, at the stage of setting up the experiment, each researcher faces the difficult task of choosing an adequate animal model that has the closest homology with human anatomy and pathology, as well as a method for modeling it.Purpose. To analyze the literature data concerning the choice of AMD experimental model and methods for its modeling, to assess the advantages and limitations of their use in the study of the pathogenesis and effectiveness of modern methods for treating this ophthalmopathology.Materials and methods. The analysis of publications on PubMed, eLibrary, Cyberleninka resources for the period from 2000 year to the present has been carried out.Results. The review considers the criteria for selecting experimental models and groups of animals most often used as an object of study (mice, rats, rabbits, pigs and primates). Among the methods for AMD modeling, chemically induced methods (using sodium iodate, N-methyl-N-nitrosourea and cobalt chloride), as well as physically induced methods (mechanical and light damage to reti na) were analyzed.Conclusion. The use of rabbits as an object of study, even though the macular area is absent, is a well-established model of AMD, in view of the fact that the structure of their reti na corresponds to the general structure of the mammalian retina in areas of greatest visual acuity. Light-induced retinal damage occupies a leading position among AMD modeling methods, which is characterized by a number of advantages – control of the time and intensity of exposure to obtain the required degree of degeneration. The information presented in this review will allow researchers to choose the most adequate model among experimental animals and a method for modeling AMD.

Emerging Pharmacological Targets for Treatment of Dry Age-related Macular Degeneration and Geographical Atrophy

Age-related macular degeneration (AMD) is difficult to treat and causes visual impairment worldwide, especially for dry AMD. The aging phenomenon can affect macular function, manifesting as blurred central vision. There are two types of AMD: dry and wet. By 2040, some variants of AMD are estimated to affect 288 million people globally. Although wet (exudative) AMD accounts for 10% of all AMD cases, it also contributes to 90% of the cases of patients with vision loss. Therapeutic options for wet age-related macular degeneration have expanded during the last few years. The therapeutic strategies mainly rely on anti-vascular endothelial growth factor (anti-VEGF) drugs and photodynamic therapy (PDT), though the treatment approaches for dry AMD are limited to dietary supplementation to delay progression. Moreover, clinical trials with potential candidate molecules for wet AMD exceed those for dry AMD. Although the disease is not rare, there are few therapeutic targets in the pipeline for dry AMD, and these targets may serve as promising pharmacotherapeutic options in the future. The current review sheds light on successes and failures of the existing novel drug molecules and potential targets for treating dry AMD in clinical trials registered at the Clinical Trials.gov registry run by the United States Food and Drug Administration (U.S. FDA) and published in relevant journals.

Immunogenicity With Ranibizumab Biosimilar SB11 (Byooviz) and Reference Product Lucentis and Association With Efficacy, Safety, and Pharmacokinetics

SB11 and reference ranibizumab (RBZ) are monoclonal anti-vascular endothelial growth factor (VEGF)-A antibodies approved for the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. The association of ranibizumab immunogenicity and treatment outcomes in patients with nAMD is unclear but relevant regarding concerns about immunogenicity of anti-VEGF biological products. To examine the association of immunogenicity to ranibizumab products (SB11 and RBZ) with efficacy, safety, and pharmacokinetics. This was a post hoc analysis of a randomized, double-masked, parallel-group phase 3 equivalence study with participants from 75 centers in 9 countries conducted from March 14, 2018, to December 9, 2019. Included were participants 50 years or older with nAMD and active subfoveal choroidal neovascularization lesions. Intravitreal injection of SB11 or RBZ, 0.5 mg, every 4 weeks through week 48. Serum antidrug antibodies (ADAs) were analyzed during the study period until week 52 to measure immunogenicity. Analyses were performed on immunogenicity (overall ADA positivity) with best-corrected visual acuity (BCVA) and central subfield thickness (CST). Adverse events associated with intraocular inflammation (IOI) and serum ranibizumab levels were compared between overall ADA-positive and ADA-negative participants. A total of 705 participants (mean [SD] age, 74.1 [8.5] years; 403 female individuals [57.2%]) were included in the study. The overall incidence of ADA-positivity was 32 of 657 (4.9%) at week 52. The least-squares mean (SE) differences between overall ADA-positive and ADA-negative participants up to week 52 for BCVA and CST, respectively, were 1.6 (2.2) letters (95% CI, -2.7 to 5.8; P = .46) and 3 (13) μm (95% CI, -23 to 29; P = .83). IOI-related events occurred in 1 of 32 overall ADA-positive participants (3.1%) and 4 of 620 overall ADA-negative participants (0.6%). Mean (SD) serum ranibizumab concentrations over time were slightly lower in overall ADA-positive participants compared with those of ADA-negative participants, with a maximum value of 1389.3 (875.4) pg/mL at week 16 vs 1665.4 (1124.0) pg/mL at week 36, respectively. Results of this post hoc analysis of an equivalence trial suggest that immunogenicity was not associated with efficacy and safety of SB11 and RBZ in participants with nAMD. With a low overall ADA incidence, no clear association was identified between overall ADA positivity and pharmacokinetics. These findings support the biosimilarity of SB11 and RBZ, with no safety concern identified for SB11 vs RBZ associated with immunogenicity. ClinicalTrials.gov Identifier: NCT03150589.

Acute Retinal Pigment Epithelium Tear Four Days Post Intravitreal Aflibercept Injection: A Case Report

Retinal Pigment Epithelium (RPE) tear is an uncommon but recognized complication of anti-Vascular Endothelial Growth Factor (anti-VEGF) treatment for neovascular age-related macular degeneration. This has predominantly been reported in association with bevacizumab (Avastin), ranibizumab (Lucentis), and pegaptanib (Macugen). Herein, we report a unique case of early RPE tear four days following an intravitreal aflibercept (Eylea) injection. To the best of our knowledge, this describes the earliest RPE tear following intravitreal aflibercept injection.

Injectable Anti-Inflammatory Supramolecular Nanofiber Hydrogel to Promote Anti-VEGF Therapy in Age-Related Macular Degeneration Treatment.

Age-related macular degeneration (AMD) is a major cause of visual impairment and severe vision loss worldwide, while the currently available treatments are often unsatisfactory. Previous studies have demonstrated both inflammation and oxidative-stress-induced damage to the retinal pigment epithelium are involved in the pathogenesis of aberrant development of blood vessels in wet AMD (wet-AMD). Although antivascular endothelial growth factor (VEGF) therapy (e.g., Ranibizumab) can impair the growth of new blood vessels, side effects are still found with repeated monthly intravitreal injections. Here, an injectable antibody-loaded supramolecular nanofiber hydrogel is fabricated by simply mixing betamethasone phosphate (BetP), a clinic anti-inflammatory drug, anti-VEGF, the gold-standard anti-VEGF drug for AMD treatment, with CaCl2 . Upon intravitreal injection, such BetP-based hydrogel (BetP-Gel),while enabling long-term sustained release of anti-VEGF to inhibit vascular proliferation in the retina and attenuate choroidal neovascularization, can also scavenge reactive oxygen species to reduce local inflammation. Remarkably, such BetP-Gel can dramatically prolong the effective treatment time of conventional anti-VEGF therapy. Notably, anti-VEGF-loaded supramolecular hydrogel based on all clinically approved agents may be readily translated into clinical use for AMD treatment, with the potential to replace the current anti-VEGF therapy.

Association Between Oral Metformin Use and the Development of Age-Related Macular Degeneration in Diabetic Patients: A Systematic Review and Meta-Analysis.

Metformin is a biguanide derivative that is commonly used for the treatment of diabetes mellitus (DM). It demonstrates antioxidative, anti-inflammatory, and antiangiogenic activity within the ocular tissue and thus may be implicated in the treatment of age-related macular degeneration (AMD). However, epidemiological studies have shown conflicting results. The Ovid MEDLINE/Embase, Cochrane Library, and Web of Science databases were systematically searched from inception through August 3, 2022. Studies reporting the association between metformin use and odds of AMD were enrolled. Adjusted odds ratios (ORs) of AMD were extracted and pooled with random-effects model meta-analysis. Subgroup analyses based on AMD subtypes, ethnicity, study design, sex, and confirmation of AMD diagnosis were conducted. A total of 9 observational studies with 1,446,284 participants were included in the analysis. The meta-analysis showed that metformin use was associated with a significant reduction in the odds of AMD (pooled ORs = 0.81, 95% confidence interval [CI] = 0.70-0.93). Subgroup analyses revealed that metformin use was not significantly associated with dry or wet AMD. Black (pooled ORs = 0.61, 95% CI = 0.58-0.64) and Hispanic populations (pooled ORs = 0.85, 95% CI = 0.81-0.89) demonstrated significantly lower odds of AMD. This systematic review and meta-analysis found that patients with DM with metformin usage were at lower odds of developing AMD. Future prospective clinical trials are needed to confirm this association.

Trends in the Cumulative Post-Marketing Reporting Rates of Retinal Vasculitis and/or Retinal Vascular Occlusion and Associated Vision Loss with Brolucizumab.

Brolucizumab, a low-molecular weight anti-vascular endothelial growth factor, was approved in the USA in October 2019 for the treatment of neovascular age-related macular degeneration. Following post-marketing reports of vasculitis, including retinal occlusive vasculitis, a safety signal of retinal vasculitis (RV) and/or retinal vascular occlusion (RO) that may result in severe vision loss was confirmed. This brief communication reviews the trends in the cumulative reporting rates of RV and/or RO and associated vision loss from May 2020 to September 2022. This is a descriptive analysis of the cumulative post-marketing reporting rates of RV and/or RO cases, and associated vision loss included in the Novartis safety database between May 2020 and September 2022, utilizing an enhanced pharmacovigilance program. The RV-alone rates demonstrated an upward trend, rising to 5.1 events per 10,000 injections by October 2020 and subsequently remained stable until July 2021. Thereafter, the rate for RV-alone events increased modestly until October 2021 and then remained stable until September 2022. The RO-alone rates increased to 3.4 events per 10,000 injections by January 2021 and subsequently remained stable until September 2022. The combined reports of RV and RO showed an upward trend until December 2020 (7.5 events per 10,000 injections), followed by a plateau until September 2021 and then a downward trend until September 2022. Vision loss associated with RV and/or RO progressively increased until December 2020 (5.9 events per 10,000 injections) followed by a declining trend until September 2022 to the most recent reporting rate of 4.1 events per 10,000 injections. The cumulative post-marketing reporting rates of vision loss associated with RV and/or RO, following brolucizumab treatment, have shown a declining trend after an initial rise in the reporting rates immediately after identification of the safety signal.

Neuroprotection for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Early to intermediate AMD is characterized by the accumulation of lipid- and protein-rich drusen. Late stages of the disease are characterized by the development of choroidal neovascularization, termed "exudative" or "neovascular AMD," or retinal pigment epithelium (RPE) cell and photoreceptor death, termed "geographic atrophy" (GA) in advanced nonexudative AMD. Although we have effective treatments for exudative AMD in the form of anti-VEGF agents, they have no role for patients with GA. Neuroprotection strategies have emerged as a possible way to slow photoreceptor degeneration and vision loss in patients with GA. These approaches include reduction of oxidative stress, modulation of the visual cycle, reduction of toxic molecules, inhibition of pathologic protein activity, prevention of cellular apoptosis or programmed necrosis (necroptosis), inhibition of inflammation, direct activation of neurotrophic factors, delivery of umbilical tissue-derived cells, and RPE replacement. Despite active investigation in this area and significant promise based on preclinical studies, many clinical studies have not yielded successful results. We discuss selected past and current neuroprotection trials for AMD, highlight the lessons learned from these past studies, and discuss our perspective regarding remaining questions that must be answered before neuroprotection can be successfully applied in the field of AMD research.