Therapy For Age-related Macular Degeneration Research Articles

Tissue Plasminogen Activator or Perfluoropropane for Submacular Hemorrhage in Age-Related Macular Degeneration

Evidence is limited to support therapies to treat submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD) as an adjunct to anti-vascular endothelial growth factor therapy (anti-VEGF). To determine if intravitreal tissue plasminogen activator (TPA) or gas improves visual acuity or promotes resolution of SMH secondary to neovascular AMD in eyes treated with ranibizumab. This was a double-masked, sham-controlled, factorial randomized clinical trial and feasibility study that recruited participants from June 2014 to March 2019, with 12 months' follow-up. Included in the trial were patients from 4 UK vitreoretinal units who had fovea-involving SMH of at least 1 disc area secondary to neovascular AMD and were evaluated within 14 days of onset. Study eyes received baseline ranibizumab and were then randomized 2:1:1:1 to 1 of 4 intravitreal treatments: sham injection, perfluoropropane (C3F8), TPA, or combined C3F8 and TPA (C3F8 + TPA). All eyes received monthly pro re nata ranibizumab therapy over 12 months. Outcome assessors were masked to intervention assignment. Best-corrected visual acuity (BCVA) at month 3. Fifty-three of 56 participants (95%; mean [SD] age, 81.5 [8.1] years; 33 female [59%]) reached the primary end point. Study eyes were randomized to the following intravitreal treatments: sham injection (n = 23), C3F8 (n = 11), TPA (n = 11), or C3F8 + TPA (n = 11). On factorial analysis, the combined TPA groups had significantly better month 3 mean logMAR BCVA than those not receiving TPA: 0.66 vs 0.98 (μd = -0.32; 95% CI, -0.58 to -0.07; P = .02). There was no statistically significant difference comparing groups that did vs did not receive C3F8: 0.80 vs 0.90 (μd = -0.11; 95% CI, -0.37 to 0.16; P = .43). The combined TPA groups were less likely to have SMH present at month 1 (10 of 18 [55.6%] vs 21 of 24 [87.5%]; P = .03), a benefit not evident in the combined gas groups. The mean logMAR BCVA at 3 months was not significantly different between the groups: monotherapy control, 0.99; C3F8, 0.97 (vs control μd = -0.02; 95% CI, -0.48 to 0.44); TPA, 0.70 (vs control μd = -0.29; 95% CI, -0.79 to 0.21); combined C3F8 and TPA, 0.71 (vs control μd = -0.36; 95% CI, -0.82 to 0.11); P = .11. No safety differences were identified across the treatment groups. Results of this randomized clinical trial suggest that TPA may increase the chance of visual acuity gain when added to ranibizumab therapy for neovascular AMD in eyes with SMH, warranting consideration of additional clinical trials. ClinicalTrials.gov Identifier: NCT01835067.

Cell Therapy for Retinal Degenerative Diseases: Progress and Prospects.

Background/Objectives: Age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are leading causes of vision loss, with AMD affecting older populations and RP being a rarer, genetically inherited condition. Both diseases result in progressive retinal degeneration, for which current treatments remain inadequate in advanced stages. This review aims to provide an overview of the retina's anatomy and physiology, elucidate the pathophysiology of AMD and RP, and evaluate emerging cell-based therapies for these conditions. Methods: A comprehensive review of the literature was conducted, focusing on cell therapy approaches, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and retinal progenitor cells. Preclinical and clinical studies were analyzed to assess therapeutic potential, with attention to mechanisms such as cell replacement, neuroprotection, and paracrine effects. Relevant challenges, including ethical concerns and clinical translation, were also explored. Results: Cell-based therapies demonstrate potential for restoring retinal function and slowing disease progression through mechanisms like neuroprotection and cell replacement. Preclinical trials show promising outcomes, but clinical studies face significant hurdles, including challenges in cell delivery and long-term efficacy. Combination therapies integrating gene editing and biomaterials offer potential future advancements. Conclusions: While cell-based therapies for AMD and RP have made significant progress, substantial barriers to clinical application remain. Further research is essential to overcome these obstacles, improve delivery methods, and ensure the safe and effective translation of these therapies into clinical practice.

Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels. Therapeutically, RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in AMD/MD iPSC-RPE. Ultimately, this study defines a causal role of the MMP2-DAMP-RAGE-sPLA2-IIA axis in AMD/MDs.

Review of Guideline Recommendations for Optimal Anti-VEGF Therapy in Age-Related Macular Degeneration.

Neovascular age-related macular degeneration is a progressive, blinding macular disease that has become a burden both in healthcare systems and the global economy. The vascular endothelial growth factor (VEGF) is the main agent involved in the pathogenic process of the disease. The main goal of the age-related macular degeneration treatment is to maintain and improve visual acuity by injecting intravitreal anti-VEGF agents in either a reactive or proactive manner. Subretinal and intraretinal fluids are the main biomarkers that should be considered when managing the frequency of the therapy. This review discusses both functional and morphological treatment criteria according to current recommendations as opposed to real-life situations encountered during day-to-day clinical practice and highlights situations in which the benefits of continuing therapy are arguable in terms of improving patients' quality of life. Optimizing the treatment regimen represents an important aim of current clinical ophthalmological practice, as age-related macular degeneration patients usually have a long follow-up period.

Macular thickness and visual acuity are characterized by a quadratic nonlinear relation in previously treated neovascular AMD eyes.

To assess the associations between visual acuity (VA) and retinal thickness in age-related macular degeneration (AMD) eyes treated with anti-vascular endothelial growth factor (VEGF) therapy. Sixty-eight patients with neovascular AMD (68 eyes) undergoing anti-VEGF therapy with two years of follow-up imaging data after the initiation of treatment were retrospectively included. Linear and nonlinear regression analyses with curve fitting estimation were performed to explore the relationship between visual acuity and OCT-based parameters at the 3-month and 24-month follow-up visits. Regression analyses were also performed between visual acuity and the retinal thickness deviation which was calculated as the absolute value of the difference between measured and normative retinal thickness values. The VA was not associated with either foveal (R2 = 0.011 and p = .401 at 3 months; R2 = 0.032 and p = .142 at 24 months) or parafoveal (R2 = 0.045 and p = .081 at 3 months; R2 = 0.050 and p = .055 at 24 months) retinal thicknesses. Compared with the linear models, a quadratic function yielded a relative increase in the R2 coefficients. Conversely, the VA was linearly associated with foveal retinal thickness deviation (R2 = 0.041 and p = .037 at 24 months) and parafoveal retinal thickness deviation (R2 = 0.062 and p = .040 at 3 months; R2 = 0.088 and p = .014 at 24 months) values. Although there was no linear relationship between retinal thickness and VA, a weak but statistically significant linear relationship could be observed when a retinal thickness deviation was considered. This suggests that deviation-based parameters may be beneficial for structure-function correlations in the context of anti-VEGF therapy for neovascular AMD.

Autophagy in drusen biogenesis secondary to age-related macular degeneration.

Age-related macular degeneration (AMD) is an emerging cause of blindness in aged people worldwide. One of the key signs of AMD is the degeneration of the retinal pigment epithelium (RPE), which is indispensable for the maintenance of the adjacent photoreceptors. Because of impaired energy metabolism resulting from constant light exposure, hypoxia, and oxidative stress, accumulation of drusen in AMD-affected eyes is observed. Drusen contain damaged cellular proteins, lipoprotein particles, lipids and carbohydrates and they are related to impaired protein clearance, inflammation, and extracellular matrix modification. When autophagy, a major cellular proteostasis pathway, is impaired, the accumulations of intracellular lipofuscin and extracellular drusen are detected. As these aggregates grow over time, they finally cause the disorganisation and destruction of the RPE and photoreceptors leading to visual loss. In this review, the role of autophagy in drusen biogenesis is discussed since impairment in removing cellular waste in RPE cells plays a key role in AMD progression. In the future, means which improve intracellular clearance might be of use in AMD therapy to slow the progression of drusen formation.

Challenges and opportunities of developing small-molecule therapies for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of vision loss in senior adults. The disease can be categorized into two types: wet AMD and dry AMD. Wet AMD, also known as exudative or neovascular AMD, is less common but more severe than dry AMD and is responsible for 90% of the visual impairment caused by AMD and affects 20 million people worldwide. Current treatment options mainly involve biologics that inhibit the vascular endothelial growth factor or complement pathways. However, these treatments have limitations such as high cost, injection-related risks, and limited efficacy. Therefore, new therapeutic targets and strategies have been explored to improve the outcomes of patients with AMD. A promising approach is the use of small-molecule drugs that modulate different factors involved in AMD pathogenesis, such as tyrosine kinases and integrins. Small-molecule drugs offer advantages, such as oral administration, low cost, good penetration, and increased specificity for the treatment of wet and dry AMD. This review summarizes the current status and prospects of small-molecule drugs for the treatment of wet AMD. These advances are expected to support the development of effective and targeted treatments for patients with AMD.

Novel fabrication of anti-VEGF drug ranibizumab loaded PLGA/PLA co-polymeric nanomicelles for long-acting intraocular delivery in the treatment of age-related macular degeneration therapy

Age associated macular degeneration is the 3rd primary cause of blind fundus diseases globally. A reliable and long-lasting method of intraocular drug delivery is still needed. Herein, this study was aim to develop the novel fabrication of ranibizumab loaded co-polymeric nanomicelles (Rabz-CP-NMs) for AMD. The CMC of co-polymeric nanomicelles was determined to be low, at 6.2μg/ml. The ring copolymerization method was employed to fabricate the NMs and characterize via FTIR, XRD, TEM, DLS and Zeta potential. Rabz-CP-NMs was spherical shape with 10-50nm in size. Stable and prolonged drug release was achieved with the Rabz from CP-NMs at 48h. D407 and ARPE19 ocular cell lines showed dose-dependent cell viability with Rabz-CP-NMs. The Rabz-CP-NMs also had less toxicity, higher uptake, lower cell death and prolonged VEGF-A inhibition, as shown by cytoviability assay. Thus, Rabz-CP-NMs were safe for ocular use, suggesting that could be used to improve intraocular AMD treatment.

Association of the Complement Factor H Y402H Polymorphism and Response to Anti-Vascular Endothelial Growth Factor Treatment in Age-Related Macular Degeneration: An Updated Meta-Analysis.

Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to several causes, including genetic factors. We evaluated the effects of Complement Factor H (CFH) rs1061170/Y402H polymorphism on the response to anti-VEGF therapy among AMD patients. PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were used for a literature search. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated to assess the effects of CFH Y402H polymorphism on the response to anti-VEGF therapy in AMD. I2 was used to present the amount of heterogeneity. We used STATA version 14.0 software. Twenty-five papers reporting data for 4,681 patients were included in this study. Better response to anti-VEGF therapy was seen in T over C (OR = 1.25, 95% CI = 1.04-1.50), TT over CC (OR = 1.60, 95% CI = 1.06-2.4), and TT + TC over CC (OR = 1.68, 95% CI = 1.23-2.28) genotypes. There was no significant difference in the three other genetic models (TT vs. TC, TT vs. TC + CC, TC vs. TT + CC). In Asians, no significant difference was observed in all six genetic models. Ranibizumab and bevacizumab had similar efficacy; however, conbercept was more effective in homozygous genotypes. The literature indicated that TT and TC genotypes and T allele were associated with a better functional response, while the CC genotype and C alleles had a better anatomical response. The combination of risk alleles in ARMS2 A69S (rs10490924), VEGF-A (rs699947), and VEGF-A (rs833069) with Y420H is a predictor of non-respondents. In patients with AMD, the CFH Y402H is a predictor of the response to anti-VEGF agents and should be considered in the treatment plan.

Fructosyl Amino Oxidase as a Therapeutic Enzyme in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is an age-related disorder that is a global public health problem. The non-enzymatic Maillard reaction results in the formation of advanced glycation end products (AGEs). Accumulation of AGEs in drusen plays a key role in AMD. AGE-reducing drugs may contribute to the prevention and treatment of AGE-related disease. Fructosamine oxidase (FAOD) acts on fructosyl lysine and fructosyl valine. Based upon the published results of fructosamine 3-kinase (FN3K) and FAOD obtained in cataract and presbyopia, we studied ex vivo FAOD treatment as a non-invasive AMD therapy. On glycolaldehyde-treated porcine retinas, FAOD significantly reduced AGE autofluorescence (p = 0.001). FAOD treatment results in a breakdown of AGEs, as evidenced using UV fluorescence, near-infrared microspectroscopy on stained tissue sections of human retina, and gel permeation chromatography. Drusen are accumulations of AGEs that build up between Bruch's membrane and the retinal pigment epithelium. On microscopy slides of human retina affected by AMD, a significant reduction in drusen surface to 45 ± 21% was observed following FAOD treatment. Enzymatic digestion followed by mass spectrometry of fructose- and glucose-based AGEs (produced in vitro) revealed a broader spectrum of substrates for FAOD, as compared to FN3K, including the following: fructosyllysine, carboxymethyllysine, carboxyethyllysine, and imidazolone. In contrast to FN3K digestion, agmatine (4-aminobutyl-guanidine) was formed following FAOD treatment in vitro. The present study highlights the therapeutic potential of FAOD in AMD by repairing glycation-induced damage.

Investigation of novel combination therapy for age-related macular degeneration on ARPE-19 cells

Investigation of novel combination therapy for age-related macular degeneration on ARPE-19 cells

Rediscovering Age-Related Macular Degeneration with Swept-Source OCT Imaging: The 2022 Charles L. Schepens, MD, Lecture

Swept-source OCT angiography (SS-OCTA) scans of eyes with age-related macular degeneration (AMD) were used to replace color, autofluorescence, infrared reflectance, and dye-based fundus angiographic imaging for the diagnosis and staging of AMD. Through the use of different algorithms with the SS-OCTA scans, both structural and angiographic information can be viewed and assessed using both cross sectional and en face imaging strategies. Presented at the 2022 Charles L. Schepens, MD, Lecture at the American Academy of Ophthalmology Retina Subspecialty Day, Chicago, Illinois, on September 30,2022. Patients with AMD. Review of published literature and ongoing clinical research using SS-OCTA imaging in AMD. Swept-source OCT angiography imaging of AMD at different stages of disease progression. Volumetric SS-OCTA dense raster scans were used to diagnose and stage both exudative and nonexudative AMD. In eyes with nonexudative AMD, a single SS-OCTA scan was used to detect and measure structural features in the macula such as the area and volume of both typical soft drusen and calcified drusen, the presence and location of hyperreflective foci, the presence of reticular pseudodrusen, also known as subretinal drusenoid deposits, the thickness of the outer retinal layer, the presence and thickness of basal laminar deposits, the presence and area of persistent choroidal hypertransmission defects, and the presence of treatment-naïve nonexudative macular neovascularization. In eyes with exudative AMD, the same SS-OCTA scan pattern was used to detect and measure the presence of macular fluid, the presence and type of macular neovascularization, and the response of exudation to treatment with vascular endothelial growth factor inhibitors. In addition, the same scan pattern was used to quantitate choriocapillaris (CC) perfusion, CC thickness, choroidal thickness, and the vascularity of the choroid. Compared with using several different instruments to perform multimodal imaging, a single SS-OCTA scan provides a convenient, comfortable, and comprehensive approach for obtaining qualitative and quantitative anatomic and angiographic information to monitor the onset, progression, and response to therapies in both nonexudative and exudative AMD. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Two Cases of Massive Subretinal Fluid Accumulation after Photodynamic Therapy for Age-related Macular Degeneration

Purpose: To report two cases of massive subretinal fluid accumulation at laser irradiated sites after photodynamic therapy in patients with age-related macular degeneration (ARMD).Case summary: (Case 1) A patient with bilateral polypoidal choroidal vasculopathy, who was treated with half-dose verteporfin photodynamic therapy (PDT), developed decreased visual acuity. On fundus examination, massive subretinal fluid accumulation was observed in the laser irradiated sites of both eyes. The subretinal fluid was reabsorbed without further treatment, and the patient's visual acuity has recovered. (Case 2) A patient with ARMD, accompanied by a choroidal neovascular membrane and accumulation of subretinal fluid in the right eye, developed decreased visual acuity on the treated eye a day after receiving half-dose PDT treatment. On fundus examination, the subretinal fluid in the right eye had increased more than 5-fold compared to pre-treatment levels. After one week, the amount of subretinal fluid decreased and the patient's visual acuity improved. However, since retinal exudate still remained, intravitreal bevacizumab treatment was administered. Thereafter, the patient’s fundus findings were unremarkable.Conclusions: In the case of photodynamic therapy for ARMD, a large amount of subretinal fluid may occur as a rare complication. The subretinal fluid was naturally absorbed, but close observation is needed with the possibility of developing subretinal fluid in the event of decreased vision after photodynamic therapy.

Hydrogel-Based Therapy for Age-Related Macular Degeneration: Current Innovations, Impediments, and Future Perspectives.

Age-related macular degeneration (AMD) is an ocular disease that leads to progressive photoreceptor death and visual impairment. Currently, the most common therapeutic strategy is to deliver anti-vascular endothelial growth factor (anti-VEGF) agents into the eyes of patients with wet AMD. However, this treatment method requires repeated injections, which potentially results in surgical complications and unwanted side effects for patients. An effective therapeutic approach for dry AMD also remains elusive. Therefore, there is a surge of enthusiasm for the developing the biodegradable drug delivery systems with sustained release capability and develop a promising therapeutic strategy. Notably, the strides made in hydrogels which possess intricate three-dimensional polymer networks have profoundly facilitated the treatments of AMD. Researchers have established diverse hydrogel-based delivery systems with marvelous biocompatibility and efficacy. Advantageously, these hydrogel-based transplantation therapies provide promising opportunities for vision restoration. Herein, we provide an overview of the properties and potential of hydrogels for ocular delivery. We introduce recent advances in the utilization of hydrogels for the delivery of anti-VEGF and in cell implantation. Further refinements of these findings would lay the basis for developing more rational and curative therapies for AMD.

A New Generation of Gene Therapies as the Future of Wet AMD Treatment.

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms, dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the concept of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the progress to the clinic of "one and done" therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

Management of Wet Age-Related Macular Degeneration: A Case Report

Introduction: Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of the photoreceptors and retinal pigment epithelium (RPE). It is a leading cause of blindness and visual impairment in the elderly population, despite recent advances in treatment. We reported a case of wet AMD and its management.
 Case Presentation: A 69 years old woman complained of blurred vision, especially in the left eye, which she had experienced since 3 years ago, progressively worsen since the last 3 months. Fundoscopy and OCT examination was done. Fundoscopy found no foveal reflex with a drusen and perifoveal haemorrhage found on left eye. She was diagnosed with wet age-related macular degeneration type II of left eye. She had done intravitreal anti-VEGF injection with local anaesthesia.
 Conclusion: AMD management relies heavily on observation, lifestyle changes, frequent follow-up evaluations, early recognition of visual impairment and detection of CNV. Meanwhile, the current modality for wet AMD therapy is intravitreal anti-VEGF injection to preserve patient’s visual acuity and improve quality of life.

An examination of the mechanisms driving the therapeutic effects of an AAV expressing a soluble variant of VEGF receptor-1.

In previous animal model studies, we demonstrated the potential of rAAV2-sVEGFRv-1, which encodes a truncated variant of the alternatively spliced soluble version of VEGF receptor-1 (VEGFR1), as a human gene therapy for age-related macular degeneration (AMD) and diabetic retinopathy (DR). Here, we elucidate in vitro some of the mechanisms by which rAAV2-sVEGFRv-1 exerts its therapeutic effects. Human umbilical vein endothelial cells (HUVECs) were infected with rAAV2-sVEGFRv-1 or a control virus vector in the presence of members of the VEGF family to identify potential binding partners via ELISA, which showed that VEGF-A, VEGF-B, and placental growth factor (PlGF) are all ligands of its transgene product. In order to determine the effects of rAAV2-sVEGFRv-1 on cell proliferation and permeability, processes that are important to the progression AMD and DR, HUVECs were infected with the therapeutic virus vector under the stimulation of VEGF-A, the major driver of the neovascularization that characterizes the forms of these conditions most associated with vision loss. rAAV2-sVEGFRv-1 treatment, as a result, markedly reduced the extent to which these processes occurred, with the latter determined by measuring zonula occludens 1 expression. Finally, the human microglial HMC3 cell line was used to show the effects of the therapeutic virus vector upon inflammatory processes, another major contributor to angiogenic eye disease pathophysiology, with rAAV2-sVEGFRv-1 reducing therein the secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-6. Combined with our previously published in vivo data, the in vitro activity of the expressed transgene here further demonstrates the great promise of rAAV2-sVEGFRv-1 as a potential human gene therapeutic for addressing angiogenic ocular conditions.

Advanced nanomedicines for the treatment of age-related macular degeneration.

The critical and unmet medical need for novel therapeutic advancements in the treatment of age-related macular degeneration (AMD) cannot be overstated, particularly given the aging global population and the increasing prevalence of this condition. Current AMD therapy involves intravitreal treatments that require monthly or bimonthly injections to maintain optimal efficacy. This underscores the necessity for improved approaches, prompting recent research into developing advanced drug delivery systems to prolong the intervals between treatments. Nanoparticle-based therapeutic approaches have enabled the controlled release of drugs, targeted delivery of therapeutic materials, and development of smart solutions for the harsh microenvironment of diseased tissues, offering a new perspective on ocular disease treatment. This review emphasizes the latest pre-clinical treatment options in ocular drug delivery to the retina and explores the advantages of nanoparticle-based therapeutic approaches, with a focus on AMD, the leading cause of irreversible blindness in the elderly.

Comparative efficacy and safety of Faricimab and other anti-VEGF therapy for age-related macular degeneration and diabetic macular edema: A systematic review and meta-analysis of randomized clinical trials.

A systematic review and meta-analysis were conducted to evaluate the efficacy and the overall safety of Faricimab compared with other anti-vascular endothelial growth factors (VEGF) therapy for neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). A systematic literature search of a comprehensive electronic database was performed to identify randomized clinical trials published from January 2013 to January 2023 for Faricimab in AMD and DME. Weighted mean differences and risk ratios were used to integrate the different studies. A total of 4 randomized controlled trials (RCTs) with 1678 AMD patients and 3 RCTs with 20 DME patients were included in the meta-analysis.In patients with AMD, a significant difference was found in the number of injections between Faricimab and other anti-VEGF therapy (MD = -2.42, 95% CI [-3.93 to -0.90], P = .002).No significant difference was found for the change in best corrected visual acuity (BVCA), central subfoveal thickness (CST), and gaining 15 or more letters. Similarly, no significant difference was found for adverse events.In patients with DME, a significant difference was observed for CST (MD = -22.41, 95% CI [-29.95 to -14.86], P < .00001) and the number of injections(MD = -0.93, 95% CI [-1.33 to -0.54], P < .00001). No significant difference was found for BVCA and gaining 15 or more letters, and no significant difference was found for adverse events. Comprehensive evidence confirms that Faricimab achieves non-inferior or even better CST improvement than other anti-VEGF therapies with extended dosing intervals, but more long-term follow-up studies are needed to support our conclusions.

Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60-94 years) using a standardized published protocol. Significant findings were then validated in an independent set of well-characterized donor eyes (n = 85). There was limited overlap between DEGs and DSGs, suggesting distinct mechanisms at play in AMD pathophysiology. A greater number of previously reported AMD loci overlapped with DSGs compared to DEGs between disease states, and no DEG overlap with previously reported loci was found in the macular retina between disease states. Additionally, we explored allele-specific expression (ASE) in coding regions of previously reported AMD risk loci, uncovering a significant imbalance in C3 rs2230199 and CFH rs1061170 in the macular RPE/choroid for normal eyes and intermediate AMD (iAMD), and for CFH rs1061147 in the macular RPE/choroid for normal eyes and iAMD, and separately neovascular AMD (NEO). Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. STAT1, validated between the iAMD vs. normal comparison, and AGTPBP1, BBS5, CERKL, FGFBP2, KIFC3, RORα, and ZNF292, validated between the NEO vs. normal comparison, revealed an intricate regulatory network with transcription factors and miRNAs identifying potential upstream and downstream regulators. Findings regarding the complement genes C3 and CFH suggest that coding variants at these loci may influence AMD development via an imbalance of gene expression in a tissue-specific manner. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes, potential splice variation, and allelic imbalance), which may open new avenues for AMD diagnostics and therapies specific to iAMD and NEO.