Diabetic retinopathy (DR) is a serious complication of diabetes caused by long-term hyperglycemia that leads to microvascular and neuronal damage in the retina. The molecular mechanisms of DR involve oxidative stress, inflammatory responses, neurodegenerative changes, and vascular dysfunction triggered by hyperglycemia. Oxidative stress activates multiple metabolic pathways, such as the polyol, hexosamine, and protein kinase C (PKC) pathways, resulting in the production of, which in turn promote the formation of advanced glycation end products (AGEs). These pathways exacerbate vascular endothelial damage and the release of inflammatory factors, activating inflammatory signaling pathways such as the NF-κB pathway, leading to retinal cell damage and apoptosis. Additionally, DR involves neurodegenerative changes, including the activation of glial cells, neuronal dysfunction, and cell death. Research on the multiomics molecular markers of DR has revealed complex mechanisms at the genetic, epigenetic, and transcriptional levels. Genome-wide association studies (GWASs) have identified multiple genetic loci associated with DR that are involved in metabolic and inflammatory pathways. Noncoding RNAs, such as miRNAs, circRNAs, and lncRNAs, participate in the development of DR by regulating gene expression. Proteomic, metabolomic and lipidomic analyses have revealed specific proteins, metabolites and lipid changes associated with DR, providing potential biomarkers for the early diagnosis and treatment of this disease. This review provides a comprehensive perspective for understanding the molecular network of DR and facilitates the exploration of innovative therapeutic approaches.

The purpose of this study was to evaluate the angiographic predictors of response to the anti-vascular endothelial growth factor-C/-D agent, sozinibercept.

Prespecified and post hoc subgroup analyses of a phase 2b, randomized, double-masked, sham-controlled trial of 240 participants with treatment-naïve neovascular age-related macular degeneration, comparing monthly intravitreal sozinibercept 0.5 mg or 2 mg, plus ranibizumab 0.5 mg, versus monthly ranibizumab monotherapy.

Visual acuity benefits at week 24 were greatest in participants with occult lesions receiving 2 mg sozinibercept combination therapy (+15.65 [n = 53] letters versus +9.62 [n = 51] with ranibizumab monotherapy; least squares mean difference +6.03; P = 0.0009). A composite analysis of occult and minimally classic lesions excluding retinal angiomatous proliferation (n = 175/240) also favored sozinibercept over control (+16.08 versus +10.34 letters; +5.74; P = 0.0002). Structural outcomes mirrored sozinibercept visual acuity benefits, with less leakage and smaller lesions on multimodal imaging.

Angiographic lesion characteristics were found to predict the response to sozinibercept combination therapy. [Ophthalmic Surg Lasers Imaging Retina 2025;56:287-296.].

Compounding and storage of intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents in syringes is commonly performed in an off-label manner. However, the preservation of compound integrity and microbiological safety must be guaranteed. The aim of this study was to compare the chemical and physical stability, sterility and binding affinity to vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) of faricimab, a novel bispecific anti-VEGF/Ang-2 biologic, after compounding and storage in two different polypropylene syringe types for up to 28 days.

Faricimab was compounded into silicone oil-free and silicone oil-containing polypropylene syringes under controlled aseptic clean room conditions and stored under light protection at 2-8 °C for up to 28 days. Compound integrity was analysed by size exclusion chromatography, nano differential scanning fluorimetry, UV-vis and dynamic light scattering. The analysis of the simultaneous binding of VEGF and Ang-2 was performed by grating-coupled interferometry. Additionally, samples were tested for sterility and presence of bacterial endotoxins. One-way ANOVA test was used to analyse statistical significance (p ≤ 0.05).

No significant differences in VEGF and ANG-2 binding affinity were found in faricimab samples stored in either syringe type after 28 days compared to control. Chemical and physical stability testing revealed no statistically significant variation. Furthermore, sterility and the absence of bacterial endotoxins could be maintained.

Our findings confirm the pharmaceutical safety of compounded faricimab after storage for up to 28 days. This may facilitate a cost-effective off-label use of faricimab in clinical practice while maintaining safety in the treatment of patients.

Diabetic macular edema (DME) is the most common cause of vision loss in people with diabetes. Tight junction disruption of the retinal pigment epithelium (RPE) cells has been reported to induce DME development. SMAD-specific E3 ubiquitin protein ligase (SMURF) 1 was associated with the tight junctions of cells. However, the mechanism of SMURF1 in the DME process remains unclear.

To investigate the role of SMURF1 in RPE cell tight junction during DME.

ARPE-19 cells treated with high glucose (HG) and desferrioxamine mesylate (DFX) for establishment of the DME cell model. DME mice models were constructed by streptozotocin induction. The trans-epithelial electrical resistance and permeability of RPE cells were analyzed. The expressions of tight junction-related and autophagy-related proteins were determined. The interaction between insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) and SMURF1 mRNA was verified by RNA immunoprecipitation (RIP). SMURF1 N6-methyladenosine (m6A) level was detected by methylated RIP.

SMURF1 and vascular endothelial growth factor (VEGF) were upregulated in DME. SMURF1 knockdown reduced HG/DFX-induced autophagy, which protected RPE cell tight junctions and ameliorated retinal damage in DME mice. SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor (WIF) 1 ubiquitination and degradation. IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.

M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation, which activated autophagy to inhibit RPE cell tight junctions, ultimately promoting DME progression.

To describe cardiovascular adverse reactions reported after intravitreal injections of vascular endothelial growth factor inhibitors (I-VEGF) as registered in the French Pharmacovigilance Database (FPVDB).

This retrospective study assessed spontaneous adverse drug reactions reported to the French pharmacovigilance system and registered in the FPVDB from April 2007 to June 2023. Eligible cases of thromboembolic events and arterial hypertension associated with three I-VEGFs (aflibercept, ranibizumab and bevacizumab) were selected.

A total of 127 cases were included (83 for ranibizumab, 37 for aflibercept, and 7 for bevacizumab), including 21 cases of arterial hypertension and 106 cases of thromboembolic events. The median onset time for thromboembolic events ranged from 1 to 119days following injection, and from 0 to 30days for arterial hypertension. The median number of injections ranged from 1 to 24 before the occurrence of an adverse drug reaction. In 23% of cases, no risk factor was found for the occurrence of a cardiovascular or thromboembolic adverse event. In two cases, a positive rechallenge was documented.

The rational use of pharmacological data, some relevant spontaneous reports and some pharmacoepidemiological studies are a prompt to health professionals to take precautions in patients with risk factors requiring I-VEGF. However, European Summaries of Product Characteristics do not give a clear picture to healthcare professionals concerning the precautions to take for patients with risk factors.

We evaluated the safety and bioactivity of carboxyamidotriazole (CAI) using two approaches, a polymeric CAI-PLGA nanoemulsion in the mouse model of choroidal neovascularization (CNV) and CAI-loaded bioresorbable intravitreal implant in a rabbit model of vascular leakage.

Mice underwent laser rupture of Bruch's membrane to induce CNV followed by a single (2 µL volume) intravitreal injection of either vehicle (n = 11); CAI nanoparticles (0.5 µg, 1 µg, 2 µg, 400 nM, 800 nM, and 1.6 µM, respectively); aflibercept 10 µg; or CAI nanoparticles (1 µg) + aflibercept 10 µg. New Zealand white rabbits underwent either sham intravitreal injection, aflibercept 500 µg injection, or CAI-PLGA intravitreal implant. Vascular leakage was induced with injections of VEGF on days 23 and 53. On days 30 and 60, all groups underwent vitreous fluorophotometry and fundus imaging. On day 60, the rabbits were euthanized, and their eyes were enucleated.

Intravitreal injection of the CAI-Nano at the dose of 1 µg significantly decreased choroidal neovascular volume, to 25% of saline on day 7 and 30% on day 14, which was comparable to aflibercept. Vitreous fluorophotometry revealed significantly lower levels of fluorescein in the aflibercept and CAI implant groups compared to the sham group on day 30. On day 60, the CAI implant group showed significantly reduced neovascularization as compared with the aflibercept groups. No toxicity was observed in any group.

CAI in nanoparticle formulation or as a sustained release bioresorbable implant showed potent efficacy and caused no retinal toxicity in murine and rabbit models.

CAI demonstrates strong potential as a sustained release anti-angiogenic therapy with effective long-term durability.

The inherent limitations of traditional treatments for Diabetic Retinopathy (DR) have spurred the development of various nanotechnologies, offering a safer and more efficient approach to managing the disease. Nanomedicine platforms present promising advancements in the diagnosis and treatment of DR by enhancing imaging capabilities, enabling targeted and controlled drug delivery. These innovations ultimately lead to more effective and personalized treatments with fewer side effects. This review highlights the progress, challenges, and opportunities in developing effective diagnostics and therapeutics for DR. Additionally, it explores innovative engineering techniques that leverage our growing understanding of nano-bio interactions to create more potent nanotherapeutics for patients.

Pathological neovascularization is a hallmark of many vision-threatening diseases. However, some patients exhibit poor responses to current anti-VEGF therapies due to resistance and limited efficacy. Recent studies have highlighted the roles of noncoding RNAs in various biological processes, paving the way for RNA-based therapeutics. In this study, we report a marked down-regulation of miR-205 under pathological conditions. miR-205 potently inhibits endothelial cell functions critical for pathological neovascularization, including proliferation, migration, and tube formation. Furthermore, miR-205 strengthens the endothelial barrier, thereby reducing vascular leakage. In mouse models of retinal and choroidal neovascularization, miR-205 administration effectively suppresses abnormal blood vessel formation and leakage. Mechanistically, miR-205 directly targets VEGFA and ANGPT2, which are key drivers of pathological neovascularization. To improve delivery, we successfully loaded miR-205 into exosomes derived from mesenchymal stem cells. This innovative approach avoids cytotoxicity while preserving therapeutic efficacy in both cellular and animal models. Collectively, our findings highlight miR-205 as a promising therapeutic for ocular neovascularization, with exosome delivery offering a novel and efficient strategy for treating vision-threatening vascular diseases.

This study evaluates the efficacy of intravitreal Faricimab in reducing pigment epithelium detachment (PED) and fluid volumes in both treatment-naïve eyes and eyes unresponsive to anti-VEGF mono-therapies, all diagnosed with type 1 macular neovascularization (T1 MNV) over a period of 12-month.

A retrospective, single-center cohort study was conducted at the Jules Gonin Eye Hospital, Lausanne, Switzerland. Clinical records of treatment-naïve and non-responder switch patients presenting T1 MNV secondary to neovascular age-related macular degeneration (nAMD) from September 2022 to March 2023 were reviewed. Patients received a loading dose of three monthly Faricimab injections followed by a treat-and-extend (T&E) regimen. Multimodal imaging, including structural OCT and AI-assisted analysis, was used to quantify PED volumes and related fluid biomarkers at baseline, 3-month, 6-month, and 12-month follow-up. Statistical analyses included linear mixed models to evaluate differences and trends in intraretinal (IRF), subretinal fluid (SRF) and PED volumes.

65 eyes of 65 patients were enrolled (female: 70.7%; mean age = 80.7yrs, SD = 6.9yrs). 80% had received anti-VEGF treatment (Switch group) and 20% were treatment-Naïve at baseline. At 12 months, intravitreal treatments were more frequent in the Switch group (mean number = 8.3 vs. 6.0; p = 0.009). BCVA improved at the 12-month follow-up in Naïve eyes (+ 6.9 ETDRS letters from baseline, p = 0.053) and was maintained in Switch eyes. No cases of intraocular inflammation were observed. Significant reduction in SRF and IRF volumes were noted in both groups. A significant reduction in PED volume was observed over the follow-up period in both groups (mean slope = -206 nL, 95%CL = -273/-138; p-value < 0.001).

Intravitreal Faricimab significantly reduced PED volumes in both treatment-Naïve and non-responder Switch patients over 12 months. The study highlights Faricimab's potential as an effective treatment option for T1 MNV in nAMD, offering significant improvements in PED volume and related fluid biomarkers.

Retinal degeneration (RD) is a group of ocular diseases characterized by progressive photoreceptor apoptosis and visual impairment. Mitochondrial malfunction, excessive oxidative stress, and chronic activation of neuroglia collectively contribute to the development of RD. Currently, there is a lack of efficacious therapeutic interventions for RD. Stanniocalcin-1 (STC-1) is a promising candidate molecule to decelerate photoreceptor cell death. STC-1 is a secreted calcium/phosphorus regulatory protein that exerts diverse protective effects. Accumulating evidence suggests that STC-1 protects retinal cells from ischemic injury, oxidative stress, and excessive apoptosis through enhancing the expression of uncoupling protein-2 (UCP-2). Furthermore, STC-1 exerts its antiinflammatory effects by inhibiting the activation of microglia and macrophages, as well as the synthesis and secretion of proinflammatory cytokines, such as TNF-α, IL-1, and IL-6. By employing these mechanisms, STC-1 effectively shields the retinal photoreceptors and optic nerve, thereby slowing down the progression of RD. We summarize the STC-1-mediated therapeutic effects on the degenerating retina, with a particular focus on its underlying mechanisms. These findings highlight that STC-1 may act as a versatile molecule to treat degenerative retinopathy. Further research on STC-1 is imperative to establish optimal protocols for its clinical use.

Anti-vascular endothelial growth factor (VEGF) therapies have revolutionized the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. However, the necessity for repeated intravitreal injections and the observation of variable treatment responses calls for new treatment modalities where fewer and more effective interventions can result in a clinical effect. Gene therapy might be such an alternative, and therefore the development and clinical application of gene therapy aimed at modifying gene expression has received considerable attention. The article reviews current knowledge of the background, pathophysiological mechanisms, technologies, limitations, and future directions for gene therapy aimed at modifying the synthesis of compounds involved in acquired and senescent retinal disease. The authors have contributed to the field by developing gene therapy to reduce the expression of vascular endothelial growth factor (VEGF), as well as multiple gene therapy for simultaneous downregulation of the synthesis of VEGF and upregulation of pigment epithelium-derived factor (PEDF) using adeno-associated virus (AAV) vectors. It is suggested that such multi-target gene therapy might be included in future treatments of retinal diseases where the underlying mechanisms are complex and cannot be attributed to one specific mediator. Such diseases might include dry AMD (dAMD) with geographic atrophy, but also diabetic macular edema (DME) and retinal vein occlusion (RVO). Gene therapy can be expected to be most beneficial for the patients in need of multiple intra-vitreal injections and in whom the therapeutic response is insufficient. It is concluded, that in parallel with basic research, there is a need for clinical studies aimed at identifying factors that can be used to identify patients who will benefit from gene therapy already at the time of diagnosis of the retinal disease.

Age-related macular degeneration (AMD) is a retinal disorder characterized by central retinal (macular) damage. Approximately 10% to 20% of non-exudative AMD cases progress to the exudative form, which may result in rapid deterioration of central vision. Individuals with exudative AMD (eAMD) need prompt consultation with retinal specialists to minimize the risk and extent of vision loss. Traditional methods of diagnosing ophthalmic disease rely on clinical evaluation and multiple imaging techniques, which can be resource-consuming. Tests leveraging artificial intelligence (AI) hold the promise of automatically identifying and categorizing pathological features, enabling the timely diagnosis and treatment of eAMD.

To determine the diagnostic accuracy of artificial intelligence (AI) as a triaging tool for exudative age-related macular degeneration (eAMD).

We searched CENTRAL, MEDLINE, Embase, three clinical trials registries, and Data Archiving and Networked Services (DANS) for gray literature. We did not restrict searches by language or publication date. The date of the last search was April 2024.

Included studies compared the test performance of algorithms with that of human readers to detect eAMD on retinal images collected from people with AMD who were evaluated at eye clinics in community or academic medical centers, and who were not receiving treatment for eAMD when the images were taken. We included algorithms that were either internally or externally validated or both.

Pairs of review authors independently extracted data and assessed study quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool with revised signaling questions. For studies that reported more than one set of performance results, we extracted only one set of diagnostic accuracy data per study based on the last development stage or the optimal algorithm as indicated by the study authors. For two-class algorithms, we collected data from the 2x2 table whenever feasible. For multi-class algorithms, we first consolidated data from all classes other than eAMD before constructing the corresponding 2x2 tables. Assuming a common positivity threshold applied by the included studies, we chose random-effects, bivariate logistic models to estimate summary sensitivity and specificity as the primary performance metrics.

We identified 36 eligible studies that reported 40 sets of algorithm performance data, encompassing over 16,000 participants and 62,000 images. We included 28 studies (78%) that reported 31 algorithms with performance data in the meta-analysis. The remaining nine studies (25%) reported eight algorithms that lacked usable performance data; we reported them in the qualitative synthesis. Study characteristics and risk of bias Most studies were conducted in Asia, followed by Europe, the USA, and collaborative efforts spanning multiple countries. Most studies identified study participants from the hospital setting, while others used retinal images from public repositories; a few studies did not specify image sources. Based on four of the 36 studies reporting demographic information, the age of the study participants ranged from 62 to 82 years. The included algorithms used various retinal image types as model input, such as optical coherence tomography (OCT) images (N = 15), fundus images (N = 6), and multi-modal imaging (N = 7). The predominant core method used was deep neural networks. All studies that reported externally validated algorithms were at high risk of bias mainly due to potential selection bias from either a two-gate design or the inappropriate exclusion of potentially eligible retinal images (or participants). Findings Only three of the 40 included algorithms were externally validated (7.5%, 3/40). The summary sensitivity and specificity were 0.94 (95% confidence interval (CI) 0.90 to 0.97) and 0.99 (95% CI 0.76 to 1.00), respectively, when compared to human graders (3 studies; 27,872 images; low-certainty evidence). The prevalence of images with eAMD ranged from 0.3% to 49%. Twenty-eight algorithms were reportedly either internally validated (20%, 8/40) or tested on a development set (50%, 20/40); the pooled sensitivity and specificity were 0.93 (95% CI 0.89 to 0.96) and 0.96 (95% CI 0.94 to 0.98), respectively, when compared to human graders (28 studies; 33,409 images; low-certainty evidence). We did not identify significant sources of heterogeneity among these 28 algorithms. Although algorithms using OCT images appeared more homogeneous and had the highest summary specificity (0.97, 95% CI 0.93 to 0.98), they were not superior to algorithms using fundus images alone (0.94, 95% CI 0.89 to 0.97) or multimodal imaging (0.96, 95% CI 0.88 to 0.99; P for meta-regression = 0.239). The median prevalence of images with eAMD was 30% (interquartile range [IQR] 22% to 39%). We did not include eight studies that described nine algorithms (one study reported two sets of algorithm results) to distinguish eAMD from normal images, images of other AMD, or other non-AMD retinal lesions in the meta-analysis. Five of these algorithms were generally based on smaller datasets (range 21 to 218 participants per study) yet with a higher prevalence of eAMD images (range 33% to 66%). Relative to human graders, the reported sensitivity in these studies ranged from 0.95 and 0.97, while the specificity ranged from 0.94 to 0.99. Similarly, using small datasets (range 46 to 106), an additional four algorithms for detecting eAMD from other retinal lesions showed high sensitivity (range 0.96 to 1.00) and specificity (range 0.77 to 1.00).

Low- to very low-certainty evidence suggests that an algorithm-based test may correctly identify most individuals with eAMD without increasing unnecessary referrals (false positives) in either the primary or the specialty care settings. There were significant concerns for applying the review findings due to variations in the eAMD prevalence in the included studies. In addition, among the included algorithm-based tests, diagnostic accuracy estimates were at risk of bias due to study participants not reflecting real-world characteristics, inadequate model validation, and the likelihood of selective results reporting. Limited quality and quantity of externally validated algorithms highlighted the need for high-certainty evidence. This evidence will require a standardized definition for eAMD on different imaging modalities and external validation of the algorithm to assess generalizability.

Aflibercept is a biopharmaceutical targeting vascular endothelial growth factor (VEGF) that has shown promise in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) in adults. Quality control studies of aflibercept employing non-reduced SDS-PAGE (nrSDS-PAGE) have shown that a significant variant band (IM1) is consistently present below the main band. Considering the quality control strategy of biopharmaceuticals, structural elucidation and functional studies are required.

In this study, the variant bands in nrSDS-PAGE were collected through electroelution and identified by peptide mass fingerprinting based on liquid chromatography-tandem MS (LC-MS/MS). This variant was expressed using knob-into-hole (KIH) design transient transfection for the detection of ligand affinity, binding activity and biological activity.

The variant band was formed by C-terminal truncation at position N99 of one chain in the aflibercept homodimer. Then, this variant was successfully expressed using KIH design transient transfection. The ligand affinity of the IM1 truncated variant was reduced by 18-fold, and neither binding activity nor biological activity were detected.

The efficacy of aflibercept is influenced by the loss of biological activity of the variant. Therefore, this study supports the development of a quality control strategy for aflibercept.

Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM) and a significant cause of acquired blindness in the working-age population worldwide. Aging is considered as an important risk factor for DR development. Macrophages in aged mice bear typical M2 marker proteins but simultaneously express a pro-inflammatory factor profile. This may explain why the level of intraocular inflammation does not decrease during proliferative diabetic retinopathy (PDR) despite the occurrence of neovascularization and fibrosis (M2 activation). α-Klotho (KL) was originally discovered as a soluble anti-aging factor, which is mainly expressed in kidney tubular epithelium, choroid plexus in the brain and secreted in the blood. However, the role of KL in DR pathophysiology has not been previously reported.

Type 1 (streptozotocin [STZ]-induced) and type 2 (a high-fat diet along with a low dose of STZ) diabetic mouse models were established and injected with or without KL adenovirus via the tail vein for 12 weeks. Vldlr-/- mice were injected intravitreally with or without soluble KL protein from P8 to P15. The retinal structure and function were analyzed by electroretinogram and optical coherence tomography. The neovascular lesions were analyzed by retinal flat mount and RPE flat mount. The senescence markers, macrophage morphology, and KL expression levels were detected by immunofluorescence staining. A cell model was constructed using RAW264.7 cells stimulated by 4-hydroxynonenal (4HNE) and transfected with or without KL adenovirus. The senescence-associated secretory phenotypes were detected by qRT-PCR. Senescence was detected by SA-β-Gal staining. Serum, aqueous humor, and vitreous humor KL levels of proliferative diabetic retinopathy (PDR) patients were measured by enzyme-linked immunosorbent assay. Quantitative proteomics and bioinformatics were applied to predict the change of proteins and biological function after overexpression of KL in macrophages. The effects of KL on the HECTD1 binding to IRS1 were analyzed by bioinformatics, molecular docking, and Western Blot.

Serum, aqueous humor, and vitreous humor KL levels were lower in patients with PDR than in those with cataracts. KL relieved the retinal structure damage, improved retina function, and inhibited retinal senescence in diabetic mice. KL administration attenuated the neovascular lesions in VLDLR-/- mice by decreasing the secretion of VEGFA and FGF2 from macrophages. KL also protected RAW264.7 cells from 4HNE-induced senescence. Additionally, it inhibited E3 ubiquitin ligase HECTD1 expression in both diabetic mouse peripheral blood mononuclear cells and 4HNE-treated RAW264.7 cells. KL inhibited HECTD1 binding to IRS1 and reduced the ubiquitination of IRS1.

Macrophage aging is involved in DM-induced retinopathy. KL alleviates DM-induced retinal macrophage senescence by downregulating HECTD1 and decreasing IRS1 ubiquitination and degradation. Meanwhile, KL administration attenuated the neovascular lesions by altering the activation state of macrophages and decreasing the expression of VEGFA and FGF2.

Purpose: To report a case of retinal vasculitis after intravitreal faricimab-svoa injection. Methods: A case and its management were reviewed. Results: A 77-year-old woman presented with a painless decrease in visual acuity (VA) to counting fingers after receiving an intravitreal faricimab-svoa injection for neovascular age-related macular degeneration. An examination showed an anterior chamber reaction without hypopyon. Vitritis was present with numerous scattered retinal hemorrhages. Fluorescein angiography showed delayed filling with extensive vascular leakage consistent with nonocclusive vasculitis. The patient was immediately treated with intravenous steroids, resulting in rapid improvement and recovery of her 20/40 baseline VA. The vasculitis resolved without occlusion. Conclusions: Faricimab-svoa can be associated with significant vasculitis. Prompt treatment with intravenous steroids can be beneficial in the recovery of sight.

To assess the anatomical and functional outcomes in eyes with persistent diabetic macular oedema (pDME) on chronic anti-vascular endothelial growth factor therapy switched to intravitreal faricimab.

Patients with pDME on chronic anti-vascular endothelial growth factor therapy that were switched to faricimab and received at least three injections at our institution between April 2022 and May 2023 were included in this study. Patients were excluded if they had complete response to previous treatment but were switched to extend treatment intervals if they had steroid or laser treatment for DME within 6 months prior to switch. Clinical and imaging data were extracted from the electronic medical record. Central foveal thickness (CFT) and Snellen visual acuity (VA) were obtained before and after three intravitreal faricimab injections. Generalised estimating equations were used to analyse the change in CFT and VA.

During the study period, 69 eyes of 53 patients met inclusion criteria. The mean age was 68.6±9.0 years. The mean number of injections prior to switch was 18.1±16.0. Pre-switch mean logarithm of the minimal angle of resolution VA was 0.40±0.30 (Snellen equivalent 20/50) and 0.38±0.27 (Snellen equivalent 20/48) after three faricimab injections (p=0.397). Mean CFT improved from 380±155 microns to 323±147 microns (p<0.001). No ophthalmic or systemic adverse events occurred during the study period.

Intravitreal faricimab can improve anatomic outcomes while maintaining visual acuity in eyes with pDME previously treated with anti-VEGF therapy.

Diabetic retinopathy (DR) is a severe ocular complication of diabetes which can leads to irreversible vision loss in its late-stage. Chronic inflammation results from long-term hyperglycemia contributes to the pathogenesis and progression of DR. In recent years, the interleukin-17 (IL-17) family have attracted the interest of researchers. IL-17A is the most widely explored cytokine in IL-17 family, involved in various acute and chronic inflammatory diseases. Growing body of evidence indicate the role of IL-17A in the pathogenesis of DR. However, the pro-inflammatory and pro-angiogenic effect of IL-17A in DR have not hitherto been reviewed. Gaining an understanding of the pro-inflammatory role of IL-17A, and how IL-17A control/impact angiogenesis pathways in the eye will deepen our understanding of how IL-17A contributes to DR pathogenesis. Herein, we aimed to thoroughly review the pro-inflammatory role of IL-17A in DR, with focus in how IL-17A impact inflammation and angiogenesis crosstalk.

Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss and disability worldwide. Although intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is an effective treatment option that helps to prevent vision loss or to improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems. A biosimilar is a biological product that has been developed to be nearly identical to a previously approved biological product. The use of biosimilars may help reduce costs and so may increase patient access to effective biologic medicines with similar levels of safety to the drugs on which they are based.

To assess the benefits and harms of anti-VEGF biosimilar agents compared with their corresponding anti-VEGF agents (i.e. the reference products) that have obtained regulatory approval for intravitreal injections in people with neovascular AMD.

We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries together with reference checking and contact with study authors to identify studies that are included in the review. The latest search date was 2 June 2023.

We included randomized controlled trials (RCTs) that compared approved anti-VEGF biosimilars with their reference products for treating the eyes of adult participants (≥ 50 years) who had an active primary or recurrent choroidal neovascularization lesion secondary to neovascular AMD.

Our outcomes were: best-corrected visual acuity (BCVA), central subfield thickness (CST), vision-related quality of life, serious ocular and non-ocular adverse events (AE), treatment-emergent adverse events (TEAEs), anti-drug antibodies (ADAs), and serum concentrations of biosimilars and reference drugs.

We assessed the risk of bias (RoB) for seven outcomes reported in a summary of findings table by using the Cochrane RoB 2 tool.

We synthesized results for each outcome using meta-analysis, where possible, by calculating risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. Where this was not possible due to the nature of the data, we summarized the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes.

We included nine parallel-group multi-center RCTs that enrolled a total of 3814 participants (3814 participating eyes), with sample sizes that ranged from 160 to 705 participants per study. The mean age of the participants in these studies ranged from 67 to 76 years, and the proportion of women ranged from 26.5% to 58.7%. Ranibizumab (Lucentis) was the reference product in seven studies, and aflibercept (Eyelea) was the reference product in two others. All the included studies had been supported by industry. The follow-up periods ranged from 12 to 52 weeks (median 48 weeks). Five studies (56%) were conducted in multi-country settings across Europe, North America and Asia, two studies in India, and one each in Japan and the Republic of Korea. We judged all the included studies to have met high methodological standards.

With regard to efficacy, our meta-analyses demonstrated that anti-VEGF biosimilars for neovascular AMD resulted in little to no difference compared with the reference products for BCVA change at 8 to 12 weeks (MD -0.55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% CI -1.17 to 0.07; 8 studies, 3603 participants; high-certainty evidence) and the proportion of participants who lost fewer than 15 letters in BCVA at 24 to 48 weeks (RR 0.99, 95% CI 0.98 to 1.01; 7 studies, 2658 participants; moderate-certainty evidence). Almost all participants (96.6% in the biosimilar group and 97.0% in the reference product group) lost fewer than 15 letters in BCVA. The evidence from two studies suggested that there was no evidence of difference between biosimilars and reference products in vision-related quality of life measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) summary scores at 24 to 48 weeks (MD 0.82, 95% CI -0.70 to 2.35; 2 studies, 894 participants; moderate-certainty evidence). With regard to the safety profile, meta-analyses also revealed little to no difference between anti-VEGF biosimilars and the reference products for the proportion of participants who experienced serious ocular AEs (RR 1.24, 95% CI 0.68 to 2.26; 7 studies, 3292 participants; moderate-certainty evidence), and for TEAEs leading to investigational product discontinuation or death (RR 0.96, 95% CI 0.63 to 1.46; 8 studies, 3497 participants; moderate-certainty evidence). Overall, 1.4% of participants in the biosimilar group and 1.2% in the reference product group experienced serious ocular adverse events. The most frequently documented serious ocular AEs were retinal hemorrhage and endophthalmitis. Although the evidence is of low certainty due to imprecision, meta-analysis suggested that anti-VEGF biosimilars led to no difference compared with the reference products for cumulative incidence of ADAs (RR 0.84, 95% CI 0.58 to 1.22; 8 studies, 3066 participants; low-certainty evidence) or mean maximum serum concentrations (MD 0.42 ng/mL, 95% CI -0.22 to 1.05; subgroup of 3 studies, 100 participants; low-certainty evidence). We judged the overall risk of bias to be low for all studies.

In our review, low to high certainty evidence suggests that there is little to no difference, to date, between the anti-VEGF biosimilars approved for treating neovascular AMD and their reference products in terms of benefits and harms. While anti-VEGF biosimilars may be a viable alternative to reference products, current evidence for their use is based on a limited number of studies - particularly for comparison with aflibercept - with sparse long-term safety data, and infrequent assessment of quality of life outcomes. Our effect estimates and conclusions may be modified once findings have been reported from studies that are currently ongoing, and studies of biosimilar agents that are currently in development.

Cochrane Eyes and Vision US Project is supported by grant UG1EY020522, National Eye Institute, National Institutes of Health. Takeshi Hasegawa and Hisashi Noma were supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239).

Protocol available via doi.org/10.1002/14651858.CD015804.

This study aims to investigate the impact of continuous 4C nursing on patients with diabetes retinopathy (DR) and its influence on self-care ability. A total of 100 DR patients admitted to our hospital from October 2020 to October 2022 were randomly divided into a control group and an observation group, with 50 cases in each group. The control group received routine care, while the observation group received continuous 4C care. The nursing effects of both groups were compared. After nursing, the observation group showed a lower self-rating anxiety scale score and a higher self-care ability scale score compared to the control group (P < .05). The SQQL-VI scores for all social activities were also higher in the observation group (P < .05). Additionally, the observation group had lower levels of fasting blood glucose, 2-hour postprandial blood glucose, and glycated hemoglobin than the control group (P < .05). Moreover, the observation group had higher visual acuity and lower intraocular pressure than the control group (P < .05). The visual impairment rate was lower and the overall compliance rate was higher in the observation group compared to the control group (P < .05). After nursing, both groups showed improvements in symptoms, visual function, physical function, psychological and social activity scores, visual acuity, and patient satisfaction scores. The observation group showed greater improvements compared to the control group (P < .05). The application of continuous 4C nursing in DR patients has shown positive effects, including improved patient compliance and satisfaction, enhanced patient quality of life and visual acuity. These findings suggest that continuous 4C nursing should be widely promoted and applied in clinical practice.

Age-related Macular Degeneration (AMD) is a multifactorial ocular pathology that destroys the photoreceptors of the macula. Two forms are distinguished, dry and wet AMD, with different pathophysiological mechanisms. Although treatments were shown to be effective in wet AMD, they remain a heavy burden for patients and caregivers, resulting in a lack of patient compliance. For dry AMD, no real effective treatment is available in Europe. It is, therefore, essential to look for new approaches. Recently, the use of long-chain and very long-chain polyunsaturated fatty acids was identified as an interesting new therapeutic alternative. Indeed, the levels of these fatty acids, core components of photoreceptors, are significantly decreased in AMD patients. To better understand this pathology and to evaluate the efficacy of various molecules, in vitro and in vivo models reproducing the mechanisms of both types of AMD were developed. This article reviews the anatomy and the physiological aging of the retina and summarizes the clinical aspects, pathophysiological mechanisms of AMD and potential treatment strategies. In vitro and in vivo models of AMD are also presented. Finally, this manuscript focuses on the application of omega-3 fatty acids for the prevention and treatment of both types of AMD.

To assess the anatomic and functional outcomes in eyes with neovascular age-related macular degeneration (nAMD) previously treated with anti-VEGF therapy in response to intravitreal faricimab.

Retrospective, interventional, consecutive case series.

Patients with previously treated nAMD who received ≥ 4 consecutive injections of faricimab were included. The study period was from March through November 2022.

Clinical and imaging data were extracted from the electronic medical record. Central foveal thickness (CFT), maximum fibrovascular pigment epithelial detachment (fvPED) height, and Snellen visual acuity (VA) were obtained. Generalized estimating equations were used to analyze the change in CFT, maximum fvPED height, and logarithm of the minimum angle of resolution VA.

Change in CFT, maximum fvPED height, and Snellen VA before faricimab and after ≥ 4 faricimab intravitreal injections.

During the study period, 218 eyes of 191 patients met inclusion criteria. Mean age was 79.9 (range, 70.6-89.2) years. The mean number of intravitreal anti-VEGF injections received before faricimab was 34.2 (range, 6.4-62). The following results were found after ≥ 4 faricimab injections. Mean logarithm of the minimum angle of resolution VA before switching to faricimab was 0.58 (Snellen VA ∼20/76; range, 20/22-20/264) and was 0.55 (Snellen VA ∼20/71; range, 20/21-20/235; P = 0.20) after switching. Mean maximum fvPED height was 195.0 (range, 50.2-339.8) μm before switching to faricimab and improved to 165.0 (range, 33.6-296.4; P < 0.001) μm after switching. Mean CFT was 354.8 (range, 184.7-524.9) μm before switching to faricimab and improved to 306.6 (range, 144.4-468.8; P < 0.001) after switching. The proportion of eyes with intraretinal fluid was 36.7% (80/218 eyes) before switching, and decreased to 24.8% (54/218 eyes, P < 0.001) after switching. The proportion of eyes with subretinal fluid was 53.2% (116/218 eyes) before switching and decreased to 26.6% (58/218 eyes, P < 0.001) after switching.

Intravitreal faricimab may improve anatomic outcomes in patients with previously treated nAMD, while maintaining VA in the short-term.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

Diabetic retinopathy (DR) is a highly tissue-specific neurovascular complication of type 1 and type 2 diabetes mellitus and is among the leading causes of blindness worldwide. Pathophysiological changes in DR encompass neurodegeneration, inflammation, and oxidative stress. Current treatments for DR, including anti-vascular endothelial growth factor, steroids, laser photocoagulation, and vitrectomy have limitations and adverse reactions, necessitating the exploration of novel treatment strategies. This review aims to summarize the current pathophysiology, therapeutic approaches, and available drug-delivery methods for treating DR, and discuss their respective development potentials. Recent research indicates the efficacy of novel receptor inhibitors and agonists, such as aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, peroxisome proliferator-activated receptor alpha agonists, and novel drugs in delaying DR. Furthermore, with continuous advancements in nanotechnology, a new form of drug delivery has been developed that can address certain limitations of clinical drug therapy, such as low solubility and poor penetration. This review serves as a theoretical foundation for future research on DR treatment. While highlighting promising therapeutic targets, it underscores the need for continuous exploration to enhance our understanding of DR pathogenesis. The limitations of current treatments and the potential for future advancements emphasize the importance of ongoing research in this field.

BI-X, a therapeutic protein under development for the treatment of human ocular disease via intravitreal administration, binds to its therapeutic targets and endogenous albumin in the vitreous humor. A monkey ocular pharmacokinetic (PK) study following BI-X administration was conducted to measure drug and albumin levels in plasma, the vitreous humor, the aqueous humor, and retina tissue at various timepoints post-dose. A comprehensive bioanalytical approach was implemented in support of this study. Five immunocapture-LC-MS/MS assays were developed and qualified for quantitating BI-X in different matrices, while ELISA was used for albumin measurement. Immunocapture at the protein or peptide level was evaluated to achieve adequate assay sensitivity. Drug and albumin assays were applied for the analysis of the monkey study samples.

It has previously been reported that antioxidant vitamins can help reduce the risk of vision loss associated with progression to advanced age-related macular degeneration (AMD), a leading cause of visual impairment among the elderly. Nonetheless, how oxidative stress contributes to the development of choroidal neovascularization (CNV) in some AMD patients and geographic atrophy (GA) in others is poorly understood. Here, we provide evidence demonstrating that oxidative stress cooperates with hypoxia to synergistically stimulate the accumulation of hypoxia-inducible factor (HIF)-1α in the retinal pigment epithelium (RPE), resulting in increased expression of the HIF-1-dependent angiogenic mediators that promote CNV. HIF-1 inhibition blocked the expression of these angiogenic mediators and prevented CNV development in an animal model of ocular oxidative stress, demonstrating the pathological role of HIF-1 in response to oxidative stress stimulation in neovascular AMD. While human-induced pluripotent stem cell (hiPSC)-derived RPE monolayers exposed to chemical oxidants resulted in disorganization and disruption of their normal architecture, RPE cells proved remarkably resistant to oxidative stress. Conversely, equivalent doses of chemical oxidants resulted in apoptosis of hiPSC-derived retinal photoreceptors. Pharmacologic inhibition of HIF-1 in the mouse retina enhanced-while HIF-1 augmentation reduced-photoreceptor apoptosis in two mouse models for oxidative stress, consistent with a protective role for HIF-1 in photoreceptors in patients with advanced dry AMD. Collectively, these results suggest that in patients with AMD, increased expression of HIF-1α in RPE exposed to oxidative stress promotes the development of CNV, but inadequate HIF-1α expression in photoreceptors contributes to the development of GA.

More than 76 million people worldwide are afflicted with the neurodegenerative eye diseases described and grouped together as glaucoma. A common feature amongst the many forms of glaucoma is chronically elevated intraocular pressure (IOP) within the anterior chamber of the eye that physically damages the retina, optic nerve and parts of the brain connected with visual perception. The mediators of the contusing raised IOP responsible for such damage and loss of vision include locally released inflammatory agents, tissue remodeling enzymes and infiltrating immune cells which damage the retinal ganglion cell (RGC) axons and eventually kill a significant number of the RGCs. Additional culprits include genetic defects of the patient that involve aberrations in receptors, enzymes and/or endogenous ligands and possible over- or under-production of the latter. Other genetic abnormalities may include issues with signal transduction machinery within key cells of critical tissues in the front (e.g. trabecular meshwork [TM] and Schlemm's canal [SC]) and back of the eye (e.g. retinal ganglion cells and their axons). Genome-wide associated studies (GWAS) coupled with next generation sequencing have provided powerful linkage of certain gene defects and polymorphic variants to the onset and progression of diseases of the tissues involved in fluid dynamics in the TM and SC, and many retinal elements (lamina cribosa, optic nerve head) at the back of the eye which cause ocular hypertension (OHT) and glaucomatous optic neuropathy (GON), respectively. Despite the availability of some drugs, fluid drainage microshunts and full surgical techniques to lower and control intraocular pressure, the major modifiable biomarker of open-angle and other forms of glaucoma, their side-effect profiles, less than optimum effectiveness and short duration of action present opportunities to clinically manage the glaucomas with next generation of treatments with high therapeutic indices, including gene therapies. Thus, identification, characterization and deployment of genetic data coupled with traditional drug discovery and novel gene replacement, gene editing and genetic engineering technologies may provide some solutions to the aforementioned problems. These aspects will be discussed in this article.

Age related macular degeneration (AMD) is the major cause of visual loss in the aging population in the Western world. In past decade, intra ocular injections of anti-vascular endothelial growth factor (anti-VEGF) pharmaceuticals have revolutionized therapy for exudative (edematous-wet) AMD and become standard practice for the near term. However repeated intra-ocular injections are required for years and long terms results have been limited. The pathogenesis of this condition is multifactorial involving genetic, ischemic, inflammatory factors leading to neovascularization, edema and retinal pigment epithelial scaring resulting in photoreceptor destruction. Based on coincidental observation in reduction in AMD related macular edema on ocular coherence tomography (OCT) in a BoNT A treated patient with facial movement disease, BoNT-A at conventional doses targeting the para orbital area was added to therapeutic regiment in a small number of patients with exudative macular degeneration or related diseases. Measurements of edema and choriocapillaris using Spectral Doman (OCT) and Ocular Coherence Angiography (OCT-A) and Snellen visual acuity were made over the evaluation period. 15 eyes in 14 patients averaged 361 μm central sub foveal edema (CSFT) pre injection and average of 266 μm (CSFT) post injection over an average of 21 months and 5.7 cycles using BoNT A alone at conventional doses (n = 86 post injection measurements, paired t-test p < 0.001 two tailed). Visions at baseline in patients with 20/40 or worse averaged 20/100- pre injection improved to an average of 20/40- in the post injection period (n = 49 measurements p < 0.002 paired t-test). The previous data was added to a group of 12 more severely afflicted patients receiving anti VEGF (aflibercept or bevacizumab) (total 27 patients). With this 27-patient group, patients were followed for an average of 20 months and receiving average of 6 cycles at conventional doses. Improvement in exudative edema and vision were noted with pre injection baseline CSFT average 399.5, post injection average 267, n = 303 post measurement, independent t-test P < 0.0001.). Snellen vision 20/128 baseline average improved to average of 20/60- during post injection period (n = 157 post injection measurements, p < 0.0001 paired t-test to baseline). No substantial adverse effects were noted. Cyclic effects were noted corresponding to duration of action of BoNT-A on a number of patients. The above data is preliminary and is skewed toward early leakage for all conditions. BoNT A may have a role in the treatment of aged related macular degeneration. Controlled studies are needed with careful staging and baseline stratifications for multi-modal management paradigms. The findings are discussed relative to known botulinum toxin type A pharmacology and AMD pathogenesis.

Retinal neovascularization (RNV) is the leading cause of vision loss in diseases like proliferative diabetic retinopathy (PDR). A significant failure rate of current treatments indicates the need for novel treatment targets. Animal models are crucial in this process, but current diabetic retinopathy models do not develop RNV. Although the nondiabetic oxygen-induced retinopathy (OIR) mouse model is used to study RNV development, it is largely unknown how closely it resembles human PDR.

We therefore performed RNA sequencing on murine (C57BL/6J) OIR retinas (n = 14) and human PDR RNV membranes (n = 7) extracted during vitrectomy, each with reference to control tissue (n=13/10). Differentially expressed genes (DEG) and associated biological processes were analyzed and compared between human and murine RNV to assess molecular overlap and identify phylogenetically conserved factors.

In total, 213 murine- and 1223 human-specific factors were upregulated with a small overlap of 94 DEG (7% of human DEG), although similar biological processes such as angiogenesis, regulation of immune response, and extracellular matrix organization were activated in both species. Phylogenetically conserved mediators included ANGPT2, S100A8, MCAM, EDNRA, and CCR7.

Even though few individual genes were upregulated simultaneously in both species, similar biological processes appeared to be activated. These findings demonstrate the potential and limitations of the OIR model to study human PDR and identify phylogenetically conserved potential treatment targets for PDR.

Elevated intraocular pressure (IOP) in glaucoma causes retinal ganglion cell (RGC) loss and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. In this paper, we aimed to develop a novel gene therapy for glaucoma using an AAV2-based thioredoxin 2 (Trx2)-exoenzyme C3 transferase (C3) fusion protein expression vector (scAAV2-Trx2-C3). We evaluated the therapeutic effects of this vector in vitro and in vivo using dexamethasone (DEX)-induced glaucoma models. We found that scAAV2-Trx2-C3-treated HeLa cells had significantly reduced GTP-bound active RhoA and increased phosphor-cofilin Ser3 protein expression levels. scAAV2-Trx2-C3 was also shown to inhibit oxidative stress, fibronectin expression, and alpha-SMA expression in DEX-treated HeLa cells. NeuN immunostaining and TUNEL assay in mouse retinal tissues was performed to evaluate its neuroprotective effect upon RGCs, whereas changes in mouse IOP were monitored via rebound tonometer. The present study showed that scAAV2-Trx2-C3 can protect RGCs from degeneration and reduce IOP in a DEX-induced mouse model of glaucoma, while immunohistochemistry revealed that the expression of fibronectin and alpha-SMA was decreased after the transduction of scAAV2-Trx2-C3 in murine eye tissues. Our results suggest that AAV2-Trx2-C3 modulates the outflow resistance of the trabecular meshwork, protects retinal and other ocular tissues from oxidative damage, and may lead to the development of a gene therapeutic for glaucoma.

Intravitreal injection (IVI) of antibody biologics is a key treatment approach in ophthalmology. Pharmaceutical compounding and storage of prefilled syringes for IVI must take place without impairing the structure and function of the biologics. This study investigated the effect of withdrawing and storing the therapeutic antibody faricimab (Vabysmo, Roche, Basel, Switzerland) in the Zero Residual silicone oil-free, 0.2-mL syringe (SJJ Solutions, The Hague, the Netherlands).

To assess the effect of syringe withdrawal on faricimab, we compared samples from syringes prepared at day 0 with samples taken directly from faricimab vials. To assess the effect of syringe storage on faricimab, we kept prefilled syringes in the dark at 4 oC for 7, 14, or 37 days and compared samples from these syringes with day 0. We measured protein concentration (with spectrophotometry), stability and integrity (with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size-exclusion chromatography (SEC), and melting temperature (Tm)), as well as binding of faricimab to its cognate antigens: vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2) (with enzyme-linked immunosorbent assay (ELISA)).

Faricimab migrated in line with its expected molecular mass under both reducing and non-reducing conditions for all time points when analyzed with SDS-PAGE, without any sign of degradation products or aggregation. The SEC elution profiles were identical for all time points. There were slight variations in Tm for different time points compared to day 0 but without consistent relationship with storage time. ELISA did not detect differences in VEGF-A or Ang-2 binding between time points, and faricimab did not bind the neonatal Fc receptor.

Withdrawal and storage of faricimab in syringes for up to day 37 did not impair the structure and bi-specific binding properties of the therapeutic antibody.

Age-related macular degeneration (AMD) is one of the main causes of visual impairment and severe visual loss, and can progress to two advanced forms-neovascularization and atrophic. The field of anti-AMD drugs has undergone huge developments in recent years, from single-target intravitreal administration to current clinical studies with multi-target and non-invasive agents, offering interesting new pharmacological opportunities for the treatment of this disease. Hence, we summarize some of the approved anti-vascular endothelial growth factor (VEGF) drugs for neovascular AMD, especially their structural characteristics, clinical manifestations, dosing regimens, and safety issues of the anti-VEGF drugs highlighted. In addition, advances in atrophic AMD drug research are also briefly described.

Neovascular age-related macular degeneration AMD (nAMD) is characterized by choroidal neovascularization (CNV) and could lead to irreversible blindness. However, anti-vascular endothelial growth factor (VEGF) therapy has limited efficacy. Therefore, we generated a chimpanzee adenoviral vector (AdC68-PFC) containing three genes, pigment endothelial-derived factor (PEDF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble forms of CD59 (sCD59), to treat nAMD. The results showed that AdC68-PFC mediated a strong onset of PEDF, sFlt-1, and sCD59 expression both in vivo and in vitro. AdC68-PFC showed preventive and therapeutic effects following intravitreal (IVT) injection in the laser-induced CNV model and very low-density lipoprotein receptor-deficient (Vldlr-/-) mouse model. In vitro assessment indicated that AdC68-PFC had a strong inhibitory effect on endothelial cells. Importantly, the safety test showed no evidence of in vivo toxicity of adenovirus in murine eyes. Our findings suggest that AdC68-PFC may be a long-acting and safe gene therapy vector for future nAMD treatments.

Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10-15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery.

The measurement of therapeutic drug concentrations is used to assess drug exposure and the relationship between therapeutic pharmacokinetics (PK) and pharmacodynamics (PD), which help determine the optimal dose for patients. Ligand binding assays (LBAs) are often the method of choice for evaluation of drug concentration and use either the therapeutic target protein or antibodies to the therapeutic as capture and/or detection reagents. Due to the bivalency of antibody therapeutics, heterogeneous states of the drug/target complex can exist in the presence of soluble targets which can complicate measurement of unbound drug. In the case of bispecific antibodies, measurement of drug can be even more complicated and depend upon the levels of both targets to each arm. Measuring the total drug allows for PKPD modeling prediction of human dose projections in addition to overcoming challenges associated with measuring free drug for bispecific antibodies. Here, we present a study in which a sandwich ELISA format was used to measure total anti-KLK5/KLK7 antibody concentrations. This assay utilized a non-blocking anti-idiotype (ID) antibody to one arm of the antibody for capture and an antibody to target bound to the other arm of the antibody for detection. Our qualified assay showed acceptable precision, accuracy, dilutional linearity, and reproducibility and enabled detection of a total bispecific antibody at high levels of two targets. To confirm that our assay was detecting total drug, a subset of samples was evaluated in a generic total LC-MS/MS assay.

Many biotherapeutics such as monoclonal antibodies (mAbs) consist of various glycoforms, which can have different PK properties upon administration to animals and human. As a result, it is necessary to monitor the abundance of glycoforms and limit lot-to-lot variability during the manufacturing process. However, limited information is known about the clearance of mAb glycoforms from ocular space upon intravitreal injection. We present here an assessment of glycoform clearance of a biotherapeutic mAb (IgG1) from rabbit vitreous humor, aqueous humor and retina tissue using LC/MS. The results show that G0, G0F and G1F have similar T1/2, while mannose-5 has a longer T1/2 and is cleared slower in rabbit ocular space, which contradicted with what has been reported in the literature in which Mann5 was cleared faster systematically.

The reconstruction of blood vessels plays a critical role in the tissue regeneration process. However, existing wound dressings in tissue engineering face challenges due to inadequate revascularization induction and a lack of vascular structure. In this study, we report the modification of mesoporous silica nanospheres (MSNs) with liquid crystal (LC) to enhance bioactivity and biocompatibility in vitro. This LC modification facilitated crucial cellular processes such as the proliferation, migration, spreading, and expression of angiogenesis-related genes and proteins in human umbilical vein endothelial cells (HUVECs). Furthermore, we incorporated LC-modified MSN within a hydrogel matrix to create a multifunctional dressing that combines the biological benefits of LC-MSN with the mechanical advantages of a hydrogel. Upon application to full-thickness wounds, these composite hydrogels exhibited accelerated healing, evidenced by enhanced granulation tissue formation, increased collagen deposition, and improved vascular development. Our findings suggest that the LC-MSN hydrogel formulation holds significant promise for the repair and regeneration of soft tissues.

Ocular vascular diseases are common causes of visual impairment and blindness, for which anti-vascular endothelial growth factor (anti-VEGF) is the first-line therapy. Current study describes the profile of patients receiving intravitreal anti-VEGF injections (IVI), and gender variation in Bhutan. The study was designed to inform national health policy.

Retrospective cross-sectional study.

We reviewed the surgical registers of the vitreoretinal (VR) units across Bhutan over three years. Patient demography, clinical findings, diagnostic tests performed, and diagnoses or indications for IVI were logged. A descriptive analysis was performed.

Despite limited availability of anti-VEGF, a total of 381 patients received IVI in operating theatres as mandated by the national guidelines. The majority of patients were males (230, 60.4%, p = 0.004). The mean age was 65.2 ± 13.5 years (range 13 years to 90 years), and a median of 69 years. The majority of the treated eyes (117, 30.7%) had BCVA <3/60 to light perception (PL), and another 51 eyes (13.4%) had < 6/60 to 3/60. The most common indication for IVI was neovascular age-related macular degeneration (nAMD) (168 cases, 42.2%), followed by retinal vein occlusion (RVO) (132 cases, 34.6%), diabetic macular oedema (DMO) and retinopathy (DR) (50 cases, 13.1%), and myopic choroidal neovascular membrane (11 cases, 0.03%).

Limited human resources for managing VR diseases in Bhutan are compounded by economic and geographic challenges. With increasing VR diseases such as nAMD and myopia and complications of systemic diseases such as DR, DMO and RVO, there is a need to improve VR services. Currently, anti-VEGF is procured only for a pooled patients requiring IVI, and patients are lost due to longer waiting periods. Bhutan needs to assess if females are reporting less or are not receiving treatment due to cultural barriers and social stigma.

Angiogenesis is an essential process in normal development and in adult physiology, but can be disrupted in numerous diseases. The concept of targeting angiogenesis for treating diseases was proposed more than 50 years ago, and the first two drugs targeting vascular endothelial growth factor (VEGF), bevacizumab and pegaptanib, were approved in 2004 for the treatment of cancer and neovascular ophthalmic diseases, respectively. Since then, nearly 20 years of clinical experience with anti-angiogenic drugs (AADs) have demonstrated the importance of this therapeutic modality for these disorders. However, there is a need to improve clinical outcomes by enhancing therapeutic efficacy, overcoming drug resistance, defining surrogate markers, combining with other drugs and developing the next generation of therapeutics. In this Review, we examine emerging new targets, the development of new drugs and challenging issues such as the mode of action of AADs and elucidating mechanisms underlying clinical benefits; we also discuss possible future directions of the field.

Nowadays; intravitreal anti-vascular endothelial growth factor (VEGF) drugs are considered the first-line therapeutic strategy for treating macular exudative diseases; including wet age-related macular degeneration (w-AMD) and diabetic macular edema (DME). Despite the important clinical achievements obtained by anti-VEGF drugs in the management of w-AMD and DME; some limits still remain; including high treatment burden; the presence of unsatisfactory results in a certain percentage of patients and long-term visual acuity decline due to complications such as macular atrophy and fibrosis. Targeting the angiopoietin/Tie (Ang/Tie) pathway beyond the VEGF pathway may be a possible therapeutic strategy; which may has the potential to solve some of the previous mentioned challenges. Faricimab is a new; bispecific antibody targeting both VEGF-A and the Ang-Tie/pathway. It was approved by FDA and; more recently; by EMA for treating w-AMD and DME. Results from phase III trials TENAYA and LUCERNE (w-AMD) and RHINE and YOSEMITE (DME) have shown the potential of faricimab to maintain clinical efficacy with more prolonged treatment regimens compared to aflibercept (12 or 16 weeks) with a a good safety profile.