Search Results (631)

Subretinal and intravitreal injection of retinal gene therapy is associated with serious adverse events and poor efficacy. We sought to improve retinal gene therapy delivery by developing fibrin hydrogel encapsulated adeno-associated virus (FE-AAV). Here we investigate conditions for storage and stability for FE-AAV. FE-AAV containing 1.9 × 10⁹ genome copies of AAV2/2-CMV-GFP was manufactured using fibrinogen reconstituted in 0.01 M sodium citrate, pH 7 (NaC) or phosphate-buffered saline containing 0.001% (v/v) Pluronic F68 (F68). Samples were stored at either −80 °C or 4 °C for up to 16 weeks. Changes in transduction efficiency, and mechanical and physical properties were evaluated. In vitro transduction was significantly (p < 0.05) reduced for FE-AAV manufactured with NaC. In contrast, we observed no change in transduction through 16 weeks for FE-AAV made with F68. Physical changes occurred in FE-AAV stored at −80 °C. In contrast to FE-AAV formulated with NaC, FE-AAV formulated with F68 and stored at 4 °C for 16 weeks was essentially equivalent to freshly made FE-AAV and retained the ability to transduce retinal pigment epithelial (RPE) cells in the pig eye. We conclude that FE-AAV formulated with F68 and stored at 4 °C is stable and shows potential for retinal gene therapy for at least 4 months following manufacture. Full article

Background: Brolucizumab has demonstrated efficacy for diabetic macular edema (DME) in pivotal clinical trials; however, comparative real-world data directly contrasting treatment-naive and anti-VEGF-switched eyes over a prolonged follow-up period remain limited. This case series evaluated 48-week functional, anatomical, and safety outcomes of intravitreal brolucizumab (IVBr) in treatment-naive and switched DME eyes in routine clinical practice. Methods: This retrospective, two-center case series included 21 eyes with center-involving DME treated with IVBr between May 2022 and April 2024. Eyes were classified into a treatment-naive group (n = 10), which included only eyes with no prior anti-VEGF treatment for DME, and a switched group (n = 11), which included eyes previously treated with other anti-VEGF agents but not achieving dry macula. Dry macula was defined as the absence of fovea-involving fluid on OCT. BCVA (logMAR), central retinal thickness (CRT), dry macula rate, the proportion of eyes gaining ≥2 lines of BCVA, number of injections, mean injection interval, and intraocular inflammation (IOI) were assessed at baseline and at 6, 12, 24, and 48 weeks. Results: At baseline, BCVA was 0.44 ± 0.27 in the treatment-naive group and 0.46 ± 0.28 in the switched group (p = 0.943), and CRT was 435.8 ± 150.1 μm and 461.8 ± 139.8 μm, respectively (p = 0.751). In the treatment-naive group, BCVA improved from 0.44 ± 0.27 to 0.24 ± 0.19 at week 48 (p = 0.023), and 5 eyes (50.0%) gained ≥2 lines. In the switched group, BCVA did not improve significantly (0.46 ± 0.28 to 0.41 ± 0.40; p = 0.461); 3 eyes (27.3%) gained ≥2 lines, and 1 eye (9.1%) lost ≥2 lines. CRT decreased significantly in treatment-naive eyes (435.8 ± 150.1 to 312.6 ± 106.2 μm, p = 0.020) and showed a non-significant reduction in switched eyes (461.8 ± 139.8 to 363.6 ± 127.4 μm, p = 0.067). Dry macula rates at week 48 were 40.0% and 27.3%, respectively (p = 0.659). Six switched eyes had prior intravitreal corticosteroid treatment for DME. One treatment-naive eye developed IOI, which resolved without permanent visual impairment. Conclusions: In this retrospective case series, IVBr was associated with anatomical improvement over 48 weeks, with clearer functional and anatomical responses in treatment-naive eyes than in switched eyes. However, the switched group was older and had a more heterogeneous treatment history, including prior intravitreal corticosteroid treatment. The findings should therefore be interpreted as exploratory. Full article

Background: Faricimab is one of the most potent anti-vascular endothelial growth factors used in the management of diabetic macular edema (DME). However, real-world benefits regarding its timing and efficacy are still being explored. Methods: This retrospective non-randomized pilot study aimed to evaluate the efficacy of intravitreal faricimab in the treatment of DME. Eyes initially treatment-naïve for DME with a follow-up of 1 year were grouped as: group 1, where faricimab was introduced within the first six months after the start of treatment; group 2, where it was initiated six or more months after treatment with other drugs. Study parameters included changes in best corrected visual acuity (BCVA) and optical coherence tomography based structural parameters within the 6 × 6 mm optical coherence tomography (OCT) scan regions. Results: Forty-two eyes from 26 patients were analyzed. No statistically significant differences were observed between the groups in cluster-weighted proportions of intra- or sub-retinal fluid, retinal thickness or volume parameters, although group 1 showed modest numerical benefits. SRF showed a trend towards qualitative reduction in group 1, although IRF showed persistence in both groups. Adjusted linear mixed-effects modeling demonstrated no significant impact of early faricimab initiation on functional and anatomical outcomes, which appeared to be influenced by the baseline BCVA, glycemic control, and the number of injections, nullifying the benefits. Conclusions: Faricimab demonstrated modest anatomical improvements with earlier treatment in eyes initially treatment-naïve for DME. Further prospective studies are indicated to assess the treatment strategy and the timing of introduction with faricimab in such eyes. Full article

Objectives: To characterize the one-year functional, anatomical, and molecular responses to intravitreal Ranibizumab in treatment-naïve patients with neovascular age-related macular degeneration (nAMD), and to identify systemic immune and miRNA signatures associated with treatment response. Methods: This prospective longitudinal observational study included 44 treatment-naïve patients with nAMD. Patients received up to four monthly intravitreal Ranibizumab injections, followed by a treat-and-extend regimen. Best-corrected visual acuity using ETDRS letters, central retinal thickness by optical coherence tomography, fluorescein angiography, and OCT angiography were assessed at baseline and 12 months. Peripheral blood samples were collected at both time points to quantify seven circulating cytokines using an IMMULITE chemiluminescent immunoassay and to profile 37 candidate miRNAs by TaqMan OpenArray RT-qPCR from leukocyte-derived RNA. Treatment response was classified using composite anatomical and functional criteria, including intraretinal/subretinal fluid resolution, ≥25% central retinal thickness reduction, and a ≥5 ETDRS letter gain. Results: At one year, patients showed significant central retinal thickness reduction and overall visual stabilization, although good and poor responders differed according to composite response criteria. Statin use was numerically more frequent among poor responders, although this difference was not statistically significant. Soluble IL-2R increased significantly over time in the overall cohort, mainly driven by good responders who showed higher median levels at both visits. IL-8 also increased globally, without significant between-group differences. Among differentially expressed miRNAs, miR-3121 was the only candidate reaching statistical significance and was downregulated in good responders. ROC analysis showed moderate discriminative performance for miR-3121, with an AUC of 0.76. Conclusions: One-year response to Ranibizumab in nAMD may involve systemic immune activation and miRNA regulation. miR-3121 emerges as a candidate biomarker of treatment response, supporting further validation in larger independent cohorts. Full article

The vitreous body is not only a transparent filling material of the posterior segment; it is a soft, hydrated, and biologically active matrix that supports structural, optical, and biochemical homeostasis. Vitrectomy therefore leaves a functional deficit that current substitutes only partly address. Intraocular gases, silicone oils, and perfluorocarbon liquids remain essential surgical tools, but they mainly provide mechanical tamponade and do not reproduce native viscoelasticity, diffusion control, or protection against oxidative and inflammatory stress. This review considers vitreous replacement as a functional biomaterials challenge. We discuss native vitreous physiology, the limitations of present tamponade agents, and emerging bioengineered substitutes designed to create a more physiological intravitreal environment. Particular attention is given to hydrogel and polymer-based systems, especially hyaluronic acid-based and in situ crosslinked platforms, which are being developed to combine optical clarity, injectability, soft mechanical support, controlled degradation, and favorable tissue interaction. We also emphasize the need for standardized preclinical testing of swelling, enzymatic stability, drug diffusion, rheology, and long-term biocompatibility. Although next-generation materials may move the field beyond passive space filling, manufacturing reproducibility, regulatory validation, chronic safety, and cautious early-phase trials remain major translational barriers. Full article

(1) Background: Ultra-early optical coherence tomography (OCT) changes following intravitreal injection may reflect transient mechanical compression rather than pharmacologic effects; however, this temporal profile has not been rigorously characterised with appropriate statistical methodology. (2) Methods: In this prospective observational study, 40 eyes of 40 consecutive patients (one per patient) with macular edema secondary to neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), or chronic central serous retinopathy (CSR) underwent intravitreal bevacizumab (n = 35) or triamcinolone acetonide (n = 5). Goldmann applanation tonometry and spectral-domain OCT were performed at baseline, 2–5 min, 15 ± 5 min, 24 h, and 48 h post-injection. Repeated-measures ANOVA with Greenhouse–Geisser correction, linear regression, and Spearman rank correlation were applied. (3) Results: Central subfield thickness (CST) decreased markedly at 15 ± 5 min (mean −24.8 ± 11.5%; 95% CI: −28.5% to −21.1%; p < 0.001; partial η² = 0.70), with near-complete rebound by 48 h (−1.0%; p = 0.400). Peak intraocular pressure (IOP) elevation correlated with CST reduction (Spearman r_s = 0.61; 95% CI: 0.39–0.77; p < 0.001), and baseline CST predicted thinning magnitude (R² = 0.52; p < 0.001). (4) Conclusions: Ultra-early OCT thinning after intravitreal injection is consistent with transient mechanical compression. Retinal thickness measurements within 48 h post-injection should be interpreted with caution when assessing treatment response, as early anatomic reduction may not reflect pharmacologic efficacy. Full article

Background: Intravitreal injections (IVI) are widely used for the management of retinal diseases, yet younger adults are underrepresented in clinical trials and real-world reports. Data on the etiologic distribution and treatment patterns of IVI in patients aged ≤50 years remain limited. This study aimed to characterize the indications, treatment strategies, and visual outcomes of IVI in this age group. Material and Methods: Retrospective, single-center observational study including adults aged 18–50 years who received IVI between January 2020 and December 2023 at a tertiary referral hospital in Spain. Demographic data, diagnosis, treatment modality, regimen, number of injections and best-corrected visual acuity (BCVA) were collected. One eye per patient was included for analysis. Visual outcomes were assessed as change in logMAR BCVA between baseline and final follow-up. Results: A total of 122 patients were included. The most frequent indications were diabetic macular edema (29.5%), macular neovascularization of various etiologies (21.3%), retinal vein occlusion (13.9%) and uveitis (9.8%). Anti-vascular endothelial growth factor (anti-VEGF) agents were used in 80.3% of eyes, corticosteroids in 6.6% and combination therapy in 13.1%. The mean number of injections per patient was 6.0 ± 5.3 over a mean follow-up of 3.0 ± 2.5 years. Overall BCVA improved significantly from 0.50 ± 0.59 to 0.38 ± 0.50 logMAR (p = 0.012). Conclusions: IVI in adults ≤ 50 years is uncommon but encompasses a broad etiologic spectrum. Diabetic macular edema and macular neovascularization of diverse etiologies were the leading indications. Anti-VEGF therapy represented the main treatment modality in this cohort. Full article

Progranulin (PGRN) is a secreted protein composed of 7.5 granulin domains. The protein is implicated in various functions, including cell survival, inflammation, lysosomal homeostasis, tumorigenesis, and aging. Haploinsufficiency and complete loss of PGRN function cause the neurodegenerative disorders frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis type 11, respectively. In the nervous system, administration of exogenous PGRN has been shown to promote the survival of various nerve cell types under different pathological conditions and to stimulate neurite outgrowth in vitro and axonal regeneration in vivo. In the retina, PGRN dysfunction results in photoreceptor and retinal ganglion cell (RGC) loss, whereas PGRN administration promotes photoreceptor cell survival. In the present study, we analyzed whether a sustained intravitreal administration of PGRN promotes the survival of axotomized RGCs and the regrowth of the lesioned axons. To this end, we generated a PGRN-overexpressing clonal neural stem cell line and injected the cells into the vitreous cavity of a mouse optic nerve crush model. The progression of the lesion-induced degeneration of RGCs was studied at different time points after the nerve crush. The regeneration of the injured RGC axons into the distal optic nerve stump was analyzed one month after nerve lesioning. We found that the intravitreally administered PGRN slowed the degeneration of the injured RGCs for up to four months, the latest post-lesion interval analyzed. Furthermore, PGRN stimulated the regeneration of some RGC axons over long distances into the distal optic nerve stumps. Taken together, our results identify PGRN as a novel neurotrophic factor for retinal ganglion cells. Full article

Current treatments for choroidal neovascularization (CNV) and its associated subretinal fibrosis (SRF), major causes of vision loss, are limited by the need for frequent intravitreal injections and the emergence of drug resistance. This study evaluated the safety and efficacy of the intravitreal administration of engineered humanized anti-vascular endothelial growth factor Nanobodies, including a wild-type Nanobody (WHNb) and two mutated variants (MHNb136 and MHNb256), in a rat model of laser-induced CNV and associated SRF. Safety was assessed through in vivo electrophysiological and histopathological analyses following intravitreal injection of Nanobodies at doses of 12.5, 25, 50, and 100 µg. Efficacy was evaluated in rat models of laser-induced CNV and SRF using double immunohistochemistry for isolectin B4 and anti-collagen type I on sclerochoroidal flat mounts. Mean CNV and SRF areas in Nanobody-treated groups were compared with those in bevacizumab-treated and sham control groups. None of the Nanobodies showed retinal toxicity in safety assessments. Compared with bevacizumab, MHNb136 and MHNb256 reduced the CNV area by 1.72-fold and 1.8-fold, respectively (both p < 0.0001), whereas WHNb showed an effect nearly identical to that of bevacizumab. In addition, 12.5 µg MHNb136 and 100 µg MHNb256 reduced the SRF area by 1.3-fold (p = 0.047) and 1.6-fold (p = 0.0007), respectively, relative to bevacizumab. For CNV reduction, 12.5 µg MHNb136 was comparable to 25 µg MHNb256; both outperformed bevacizumab. For SRF reduction, 12.5 µg MHNb136 was more effective than bevacizumab and comparable to 100 µg MHNb256. These findings suggest that 12.5 µg MHNb136 may represent a cost-effective bioengineered Nanobody candidate for future clinical studies. Full article

Background: This study investigated the clinical timeline, patient monitoring behaviors, and cumulative bilateral treatment burden in patients with bilateral neovascular age-related macular degeneration. Methods: We retrospectively analyzed follow-up patterns and treatment intensity from first-eye (FE) diagnosis to second-eye (SE) conversion. Results: SE conversion occurred within a mean of 2.0 years in the FE-active group (62.5%) while the FE remained exudative, contrasting with 6.2 years in the FE-inactive group (37.5%). Upon SE conversion, the total annual intravitreal injection burden escalated 3.4-fold (p = 0.002). Notably, the FE-inactive group exhibited numerically lower annual outpatient visit counts (4.40 ± 2.71 vs. 10.29 ± 5.02; p = 0.116), which potentially widened the monitoring window. Additionally, baseline SE retinal pigment epithelium (RPE) abnormalities independently predicted progression (aOR: 19.04; p = 0.032). Conclusions: While previous literature focuses on individual eyes, our findings highlight a vigilance gap in SE detection based on FE status. Clinicians must maintain proactive surveillance for patients with baseline SE RPE abnormalities, particularly when FE stability or next-generation long-acting therapies extend clinic intervals. Due to the limited sample size, these preliminary findings warrant validation in larger prospective cohorts. Full article

Context/Objective: Fungi of the genus Tolypocladium are known for their diverse metabolic capabilities and medicinal potential. Indole diterpenoids (IDTs) represent a structurally unique class of fungal metabolites. Beyond their established roles as mycotoxins, these compounds have recently shown promise for neuroprotective effects. The objective of this study was to isolate and characterize novel IDTs from Tolypocladium album DWS131 and evaluate their neuroprotective activities and underlying mechanisms. Methods: IDTs were isolated through comprehensive chromatographic techniques. Their structures were elucidated using HRESIMS data, 1D/2D NMR spectra, and quantum chemical calculations. Neuroprotective effects were evaluated using glutamate (Glu)-induced R28 cells in vitro and N-methyl-D-aspartic acid-induced mouse models in vivo. A total of 48 mice were utilized for in vivo evaluations, divided into two separate experimental cohorts. In each cohort, mice were randomly assigned to four groups (n = 6 per group). Post-intravitreal injection, retinal survival and visual function were assessed via Brn3a-stained flat-mounts, H&E staining, f-VEP, f-ERG, and OptoDrum. Mechanisms involving the SLC7A11/GPX4/ACSL4 axis were investigated by Western blotting and immunofluorescence. Results: Seven previously undescribed paxilline-type IDTs, tolypindoles A–G (1–7), and two known analogues (8–9) were identified. Compounds 8 and 9 exhibited significant neuroprotection closely associated with the attenuation of oxidative stress and the modulation of ferroptosis-related pathways in Glu-induced R28 cells. In vivo, they preserved retinal ganglion cells, maintained retinal structure, and protected visual function, with compound 8 demonstrating superior efficacy. Mechanistic investigations revealed that both compounds modulate the SLC7A11/GPX4/ACSL4 signaling axis. Conclusions: This study expands the chemical diversity of T. album DWS131. Compounds 8 and 9, characterized by isopentenyl moieties, highlight a promising therapeutic potential for retinal neurodegenerative diseases such as glaucoma. Full article

Background/Objectives: This retrospective cohort study compared hospitalization and follow-up rates in patients with newly diagnosed proliferative diabetic retinopathy (PDR) versus those without prior diabetic retinopathy (DR) screening. Methods: Using TriNetX, a global electronic health record database, 57,964 patients aged ≥ 40 years with type 2 diabetes and newly diagnosed PDR without diabetic macular edema (DME) requiring panretinal photocoagulation or intravitreal injection were included. Patients were stratified based on the presence or absence of prior DR screening in the last 5 years and balanced using propensity score matching (PSM). Primary outcomes included 30-, 60-, and 90-day hospitalization rates and repeat ophthalmic follow-up as estimated using repeat PDR diagnosis codes and repeat retinal imaging codes, including OCT, fundus photography, and fluorescein angiography. Results: Of 57,964 patients, 25,003 had no prior DR screening and 32,961 had prior DR screening. After matching, 19,316 patients were included per cohort. Patients without known DR screening had significantly higher hospitalization rates at 30 days (RR = 1.78, 95% CI 1.67–1.89), 60 days (RR = 1.59, 95% CI 1.51–1.67), and 90 days (RR = 1.51, 95% CI 1.44–1.58), and lower repeat ophthalmic visits by PDR codes at 30 days (RR = 0.458, 95% CI 0.440–0.476), 60 days (RR = 0.450, 95% CI 0.437–0.463) and 90 days (RR = 0.420, 95% CI 0.408–0.432) or by repeat retinal imaging codes at 30 days (RR = 0.450, 95% CI 0.423–0.478), 60 days (RR = 0.394, 95% CI 0.377–0.411), and 90 days (RR = 0.381, 95% CI 0.366–0.396) (all p < 0.0001). Conclusions: Absence of known prior DR screening in PDR patients is associated with higher hospitalization risk and reduced ophthalmic follow-up, suggesting that a lack of screening indicates broader gaps in healthcare engagement and disease control. Tailored strategies are needed to prevent vision loss as well as systemic complications. Full article

Background: Diabetic macular edema (DME) is a leading cause of vision loss. Although real-world data on faricimab, a bispecific antibody targeting vascular endothelial growth factor-A and Angiopoietin-2, are expanding, its long-term durability in routine clinical practice has not yet been fully established. We evaluated effectiveness, anatomic response and treatment durability of first-line faricimab in treatment-naïve DME. Methods: We conducted a single-center, retrospective cohort study of treatment-naïve DME eyes initiated on intravitreal faricimab (August 2023–October 2024) in a real-world setting. After a loading phase, eyes were managed with a treat-and-extend or pro re nata regimen. The primary endpoint was retreatment interval at 48 weeks. Secondary endpoints were retreatment interval at weeks 12, 24 and 36; change in visual acuity (VA); central subfield thickness (CST); and optical coherence tomography (OCT) fluid. Results: Fifty-two eyes from 40 consecutive patients were included (baseline VA 65.96 ± 13.55 letters; CST 426.56 ± 106.72 µm). Mean injections were 4.02 ± 1.11 between months 1–6 and 1.90 ± 0.98 between months 7–12. VA improved by +8.46, +7.57, +7.65 and +7.72 letters at 12, 24, 36, and 48 weeks (all p < 0.0001), respectively. Relative CST decreased by −28.05%, −27.01%, −29.46% and −25.22% at the same time points (all p < 0.0001). At week 48, 15.4% of eyes were on a treatment interval of less than 12 weeks, 23.1% were between 12 and 16 weeks, and 46.1% were on 16 or more weeks; 15.4% were managed PRN. Conclusions: First-line faricimab in treatment-naïve DME in a real-world setting yielded clinically meaningful and durable extensions in treatment intervals, alongside sustained functional and anatomical improvements. Full article

Background: Posterior segment eye diseases, including age-related macular degeneration and diabetic retinopathy, are preeminent causes of vision loss worldwide. Effective drug delivery to the retina poses an ongoing therapeutic difficulty due to the presence of the anatomical and physiological barriers. Nanotechnology-based drug delivery systems represent a promising strategy to overcome those limitations. Methods: A narrative literature review was conducted using the PubMed, Scopus, and Google Scholar databases, covering publications published between 2019 and 2026. Publications evaluating nanoparticles for the treatment of the vitreoretinal disorders, including pre-clinical in vitro and in vivo studies, were analyzed. Results: Nanocarriers, including liposomes, polymeric nanoparticles, and lipid-based systems, established improved drug bioavailability, stability, and targeted delivery. The analyzed systems facilitate sustained drug release and potentially reduce the prevalence of invasive intravitreal injections. The nanocarriers’ effectiveness is primarily influenced by their physicochemical properties, such as particle size, surface charge, and encapsulation efficiency. Nonetheless, the production costs and safety aspects, including cytotoxicity, oxidative stress, and inflammatory responses, remain as significant limitations. Conclusions: Nanotechnology-based drug delivery systems serve as an auspicious therapeutic approach for posterior segment eye diseases. However, further standardized preclinical and clinical research is required to assure long-term safety and enable successful clinical transition. Full article

Background: Branch retinal vein occlusion (BRVO) represents a segmental retinal ischemic disorder characterized by localized oxidative–inflammatory activation. While redox-driven cytokine responses have been described in central retinal vein occlusion, their role in BRVO-specific macular edema and treatment responsiveness remains unclear. This study investigated whether novel redox-related inflammatory mediators in the aqueous humor are associated with disease severity and structural response to anti-vascular endothelial growth factor (VEGF) therapy in BRVO. Methods: Aqueous humor samples were collected from 30 treatment-naïve patients with BRVO and 19 control patients. Levels of VEGF and the novel redox-related inflammatory factors FMS-related tyrosine kinase 3 ligand (Flt-3L), fractalkine, CXCL-16, and endocan-1 were measured by suspension array, and the severity of macular edema was evaluated by measuring central macular thickness and neurosensory retinal thickness (TNeuro) by spectral-domain optical coherence tomography. Therapeutic response was assessed one month after intravitreal ranibizumab injection (IRI). Results: Aqueous levels of VEGF, Flt-3L, and endocan-1 were significantly higher in the BRVO group, and levels of Flt-3L, CXCL-16, and endocan-1—markers associated with oxidative endothelial damage and leukocyte recruitment—correlated significantly with each other and with aqueous flare values. Notably, baseline Flt-3L levels significantly correlated with the reduction in TNeuro, suggesting that this redox-sensitive signaling molecule is a potential biomarker for treatment sensitivity. Conclusions: These findings suggest that novel inflammatory factors, potentially driven by oxidative-nitrosative stress, play a pivotal role in the pathophysiology of BRVO. Baseline Flt-3L may serve as a predictive biomarker for structural responsiveness to anti-VEGF therapy in BRVO, suggesting that oxidative–inflammatory signaling contributes not only to disease severity but also to therapeutic heterogeneity. Full article