RARE DISEASE
Central retinal vein occlusion
Central retinal vein occlusion
Central retinal vein occlusion
Synonyms: CRVO
Synonyms: CRVO
Synonyms: CRVO
Drug discovery
1
drug
With orphan designation
Overview
Central retinal vein occlusion (CRVO) is a vision-threatening retinal vascular disorder characterized by thrombosis of the central retinal vein, leading to venous stasis, retinal hemorrhage, and macular edema [1][4][9]. Predominantly affecting individuals >50 years, key risk factors include hypertension, diabetes, glaucoma, and atherosclerosis [1][14]. Vision loss stems from ischemic retinal damage or macular edema [4][9]. First-line therapy involves intravitreal anti-VEGF agents (aflibercept, ranibizumab) and corticosteroids, supplemented by laser therapy for neovascular complications [3][7][9].
Population
Primarily occurs in adults >50 years (90% of cases), with hypertension present in 73% of patients [14][10]
Younger patients (<40 years) account for 8-15% of cases, often linked to ocular hypertension, inflammation, or coagulopathies [2][6]
Incidence increases with age, slightly male-predominant (53.8%), and 6-17% risk of bilateral involvement [2][14]
Burden
Affects 4.67 million globally (0.13% prevalence), with 30-50% developing permanent vision impairment [6][10]
Annual healthcare costs exceed $1.5 billion (US) due to frequent monitoring/injections [4][6]
Macular edema occurs in 75% of cases; 50% develop neovascular glaucoma without intervention [9][14]
Therapies
Anti-VEGF therapy: First-line for macular edema (≥3 lines VA improvement in 46-58% with monthly injections) [3][7][9]
Steroids: Dexamethasone implants or triamcinolone for anti-VEGF-resistant cases, despite cataract/glaucoma risks [3][7][12]
Laser photocoagulation: Prevents neovascular glaucoma in ischemic CRVO (50% rubeosis risk without treatment) [9][14]
Categories: rare ophthalmic disorders
Research Papers
2,110 drug discovery papers about Central retinal vein occlusion, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,110 drug discovery papers about Central retinal vein occlusion, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Effect of Topical Bromfenac 0.09% on Pain Following Intravitreal Antivascular Endothelial Growth Factor Injections.
To evaluate the effect of topical bromfenac 0.09% on pain following intravitreal (IVT) injection of antivascular endothelial growth factor (anti-VEGF) medications in patients diagnosed as having choroidal neovascularization secondary to age-related macular degeneration or other etiologies, diabetic macular edema, diabetic retinopathy, or macular edema associated with retinal vein occlusion. A total of 78 adult patients scheduled to receive bilateral anti-VEGF IVT injections were randomized to receive topical bromfenac 0.09% in 1 eye and artificial tears in the fellow eye (control) immediately before the anti-VEGF treatment at 2 academic institutions from March 2021 to June 2022. Pain was evaluated using the Wong-Baker FACES Pain Rating Scale (score range, 0-10) and the Short-Form McGill Pain Questionnaire (score range, 0-5) at baseline (preinjection) and 5 minutes, 6 hours, and 24 hours following injection. Wilcoxon signed-rank sum test was used for statistical comparisons. In total, 156 eyes were analyzed. Mean baseline pain scores were similar between the bromfenac 0.09% and control groups. Five minutes after injection, eyes randomized to receive bromfenac 0.09% had significantly less pain compared with control eyes receiving artificial tears, on both the Wong-Baker FACES scale (mean raw score, 2.29 vs 2.79; P = .0275) and the McGill Pain Questionnaire (mean raw score, 1.13 vs 2.36; P = .0135). No significant difference in pain scores was noted at 6 hours or 24 hours post-IVT injection. Bromfenac 0.09% solution administered to the study eye before IVT anti-VEGF injection reduced pain 5 minutes after injection in comparison with artificial tears. There was no difference in pain between the 2 groups at 6 hours or 24 hours post-IVT injection.
2026-09-25 | Potential protective associations of antidiabetic and lipid-lowering therapies with retinal vein occlusion risk: a systematic review and meta-analysis.
Retinal vein occlusion (RVO) shares key pathophysiological pathways with metabolic and atherothrombotic disorders. Emerging evidence suggests that statins and antidiabetic drugs may be associated with lower RVO incidence, yet their potential to modify RVO risk remains uncertain. A systematic search of MEDLINE, Embase, Scopus, and Web of Science was performed from inception through June 11, 2025, for studies evaluating the association between systemically administered antidiabetic or lipid-lowering agents and RVO. Risk of bias was assessed using the Newcastle-Ottawa Scale. Association between antidiabetic or lipid-lowering therapy and RVO risk was the primary outcome, and drug-class-specific associations, differences by RVO subtype, and related retinal outcomes were the secondary outcomes. Certainty of evidence was appraised. Protocol registered in PROSPERO (CRD420251077729). Ten good-quality studies (six cohorts and four case-control) involving over 2 million adults met eligibility criteria. Meta-analysis results suggest that statin use consistently reduced RVO risk; pooled effect odds ratio (OR) = 0.65 (95% CI = 0.53-0.79; I² = 29%) with moderate certainty. Studies suggest metformin monotherapy halved risk [hazard ratio (HR) = 0.46, 0.30-0.73], and glucagon-like peptide-1(GLP-1) receptor agonists were associated with reduced risk compared to dipeptidyl-peptidase-4 (DPP-4) inhibitors (HR = 0.73, 0.54-0.98). Findings for sodium-glucose cotransporter-2 (SGLT-2) inhibitors were inconsistent, showing harm versus other oral glucose-lowering drugs in 1 Korean study (HR = 1.26, 1.06-1.51) but benefit versus DPP-4 inhibitors in a Taiwanese study (HR = 0.76, 0.59-0.98). Other conventional agents (repaglinide, thiazolidinediones, sulfonylureas, α-glucosidase inhibitors, insulin) yielded imprecise or null estimates. Only statins met criteria for meta-analysis; findings for other drug classes were narratively synthesised from single studies. Statins show moderate evidence of an association with reduced RVO risk. Signals of benefit for metformin and GLP-1 receptor agonists arise from single large cohorts and require independent replication. Additionally, the role of SGLT-2 inhibitors remains uncertain. These indicators warrant confirmation in prospective studies and may inform tailored retinal vascular risk reduction strategies in patients with diabetes and dyslipidaemia.
2026-09-19 | Microglia in retinal vascular diseases: inflammatory mechanism and therapeutic target.
Retinal vascular diseases (RVDs) are leading causes of vision impairment and blindness, often associated with systemic diseases such as diabetes and hypertension. Despite treatment advancements, managing RVDs, particularly retinal vein occlusion (RVO), remains challenging due to the lack of a definitive cure and reliance on controlling complications. Microglia, the retina's resident immune cells, play a crucial role in maintaining retinal health, regulating inflammation, and modulating angiogenesis. In pathological conditions, microglia adopt heterogeneous and context-dependent activation states, contributing to both inflammatory injury and vascular repair. Studies suggest that modulating microglial activation and their secreted cytokines may provide novel therapeutic strategies for RVDs. This review examines the role of microglia in RVDs and their potential as therapeutic targets, exploring strategies such as inhibiting microglial activation, regulating pro-angiogenic factor secretion, and targeting specific signaling pathways. Future research should focus on understanding the specific roles of microglial subtypes, their contributions to disease progression, and developing targeted therapies for early diagnosis and treatment of RVDs.
2026-08-27 | Baicalin Protects ARPE-19 Cells Against BRVO-Related Hypoxic Injury by Preserving Mitochondrial Function and Inhibiting Ferroptosis.
Branch retinal vein occlusion (BRVO) is a retinal vascular disorder characterized by ischemia and hypoxia. These pathological conditions contribute to retinal pigment epithelial (RPE) cell injury through oxidative stress and ferroptosis. However, whether baicalin (BC) protects against hypoxia-induced RPE injury remains unclear. CoCl2-induced hypoxic ARPE-19 cells were used to evaluate the protective effects and potential mechanisms of BC. BC improved cell viability and reduced LDH release under hypoxic conditions. BC markedly suppressed hypoxia-induced inflammatory responses, as evidenced by reduced p65 and ICAM-1 expression and decreased release of pro-inflammatory cytokines. Moreover, BC alleviated oxidative stress by reducing ROS and MDA accumulation and restoring SOD and GSH activity. BC attenuated mitochondrial dysfunction, accompanied by restoration of mitochondrial membrane potential, oxygen consumption rate (OCR), and ATP production. Transmission electron microscopy (TEM) results further confirmed the protective effect of BC on mitochondrial integrity. Mechanistically, BC suppressed ferroptosis by reducing intracellular Fe2+ accumulation and lipid peroxidation, accompanied by downregulation of TFR1, ACSL4, and p53, as well as upregulation of SLC7A11 and GPX4. These findings suggest that BC protects ARPE-19 cells against hypoxia-induced injury through preservation of mitochondrial function and inhibition of ferroptosis.
2026-08-13 | Wnt Pathway Agonism as a Therapeutic Strategy for Retinal Vascular Diseases: A Narrative Review of Evidence to Date.
Breakdown of the blood-retinal barrier (BRB) is implicated in many blinding retinal diseases, including diabetic macular edema, neovascular age-related macular degeneration, and retinal vein occlusion. Anti-vascular endothelial growth factor (anti-VEGF) therapies or laser photocoagulation are currently the standard of care for retinal diseases that are characterized by breakdown of the vascular barrier function and vascular hyperpermeability. However, inadequate response to anti-VEGF therapy is seen in a substantial proportion of patients and laser photocoagulation does not restore vision loss and can lead to collateral damage of the retina. Thus, new therapeutic targets are needed. The β-catenin-dependent wingless-related integration site (Wnt) signaling pathway plays a critical role in inner BRB development and maintenance. There are several potential therapeutics for retinal vascular diseases targeting the Wnt/β-catenin pathway under investigation, including several in preclinical development and one (MK-3000; also known as Restoret and formerly EYE103) with early clinical trial results advancing to late-stage clinical development. In this narrative review we examine the role of Wnt/β-catenin signaling in inner BRB maintenance and in retinal vascular diseases, as well as the potential for Wnt pathway agonism as a therapeutic approach.
antibodies
2026-09-27 | Comparative Analysis of Systemic Complications of Antivascular Endothelial Growth Factor Therapies in Retinal Diseases.
Purpose: To compare the systemic safety profiles of antivascular endothelial growth factor (anti-VEGF) agents using a large real-world dataset. Methods: The TriNetX Research Network database was used to identify adults with macular edema secondary to diabetes, retinal vein occlusion, or age-related macular degeneration who received bevacizumab, ranibizumab, or aflibercept (2012-2022) or faricimab (2022-2024). The bevacizumab cohort was matched with the other cohorts using propensity score matching to account for demographic characteristics and comorbidities. Outcomes included stroke, venous thromboembolism, myocardial infarction, hypertension, brain hemorrhage, and renal function. Results: In the propensity score-matched cohorts comparing outcomes between bevacizumab and aflibercept (each n = 9538), bevacizumab was associated with higher mean blood urea nitrogen level (28.07 mg/dL vs 26.89 mg/dL; P = .017), higher mean serum creatinine level (1.86 mg/dL vs 1.72 mg/dL; P = .004), and lower mean estimated glomerular filtration rate (55.64 mL/min vs 58.01 mL/min; P = .003) at 1 to 6 months' follow-up. Compared with the faricimab cohort, the bevacizumab cohort (each n = 3500) showed increased risk of stroke (risk ratio [RR], 1.71, 95% CI, 1.19-2.48), venous thromboembolism (RR, 1.80, 95% CI, 1.11-2.93), myocardial infarction (RR, 1.72, 95% CI, 1.19-2.49), and hypertension (RR, 1.47, 95% CI, 1.19-1.83) within 2 years of follow-up. No significant differences were found between the bevacizumab and ranibizumab cohorts (each n = 2211). Conclusions: Bevacizumab may confer an increased risk of cardiovascular events and differences in renal function parameters compared with aflibercept and faricimab, but not ranibizumab. This underscores the importance of tailoring anti-VEGF therapy to patient-specific profiles, particularly in patients with underlying cardiovascular and renal comorbidities. Further studies in lower-comorbidity populations are needed to clarify these associations.
2026-09-20 | Real-World Analysis of Switching Between Ranibizumab Biosimilars: Safety and Results - a Multicenter Retrospective Observational Study.
To describe disease-specific visual, anatomical, treatment-exposure, and documented safety outcomes over 24 weeks among eyes undergoing availability-driven switching between ranibizumab biosimilars in routine retinal practice in India. This multicenter retrospective observational cohort study reviewed records from January to December 2024. Baseline was the index-switch visit, before administration of the substituted ranibizumab biosimilar. Only one eye per patient was included; when both eyes were eligible, the right eye was selected by convention. Eligible eyes had at least one documented availability-driven biosimilar-to-biosimilar switch and complete 24-week follow-up. Outcomes were summarized descriptively because there was no non-switch comparator group. Of 742 screened eyes, 595 eyes from 595 patients met the inclusion criteria and received 1625 intravitreal ranibizumab biosimilar injections over 24 weeks (mean, 2.73 injections per eye). One switch was recorded in 466 eyes (78.3%) and two switches in 129 eyes (21.7%). Mean BCVA improved from 0.57 logMAR at baseline to 0.26 at 12 weeks and 0.32 at 24 weeks; the early visual improvement therefore attenuated modestly by week 24 but remained better than baseline. Mean central macular thickness decreased from 490.4 micrometers at baseline to 273.6 micrometers at 24 weeks. At final follow-up, 369 eyes (62.0%) gained at least two lines and 488 eyes (82.0%) maintained or improved vision. No endophthalmitis, retinal detachment, or treatment-related systemic adverse event was documented in the available clinical records. Eyes exposed to availability-driven switching between ranibizumab biosimilars showed favorable short-term visual and anatomical outcomes over 24 weeks. Because this retrospective study lacked a non-switch comparator and protocol-mandated safety or immunogenicity surveillance, it cannot establish an effect attributable to switching, comparative safety, equivalence, or formal interchangeability.
2026-09-17 | Early Macular Leakage Resolution Is Associated with Extended Faricimab Dosing in Retinal Vein Occlusion: A BALATON/COMINO Post Hoc Analysis.
Macular leakage (ML) is a biomarker of disease activity and, in retinal vein occlusion (RVO), is associated with poor vision outcomes. Faricimab, a dual angiopoietin-2 (Ang-2)/vascular endothelial growth factor (VEGF)-A inhibitor, has demonstrated efficacy and durability in RVO. This post hoc analysis of BALATON/COMINO examined the association between week 24 ML resolution and extended faricimab dosing intervals and vision outcomes achieved at week 68 in patients with RVO. BALATON and COMINO (NCT04740905/NCT04740931) were identically designed, phase 3, randomized trials that evaluated the efficacy and safety of faricimab in patients with branch or central/hemiretinal RVO, respectively. Patients initially received faricimab 6 mg every 4 weeks (Q4W) or aflibercept 2 mg Q4W; then from weeks 24-72, all patients received faricimab 6 mg up to Q16W according to a modified treat-and-extend regimen. This analysis included patients who remained in the study at week 68 and had a fluorescein angiography ML reading at week 24. Among 989 patients, 502 had ML resolution (≤ 1 mm2) and 143 had high ML (≥ 10 mm2) at week 24. The proportion of patients who achieved ≥ Q12W faricimab dosing at week 68 was higher among those with ML resolution at week 24 versus those with high ML at week 24 (56.1% vs 38.0%, p = 0.0001). The odds of patients receiving ≥ Q12W faricimab dosing at week 68 were higher among those with ML resolution than among those with high ML at week 24 (odds ratio 2.46, p < 0.001). Patients with ML resolution experienced greater vision gains at week 68 versus patients with high ML at week 24 (18.8 vs 15.0 letters, p = 0.0036). ML resolution at week 24 was associated with extended faricimab dosing intervals and improved vision at week 68 in patients with RVO in the BALATON/COMINO clinical trials. NCT04740905, NCT04740931.
2026-09-15 | Molecular Determinants of Intravitreal Anti-VEGF Durability: Drug Architecture, Intraocular Pharmacokinetics, Target Biology and Treatment Resistance.
Intravitreal inhibition of vascular endothelial growth factor (VEGF) has transformed the management of neovascular age-related macular degeneration, diabetic macular oedema and macular oedema secondary to retinal vein occlusion, but frequent monitoring and retreatment remain major burdens. Ocular half-life is often used as shorthand for durability, although the clinical interval is produced by a wider molecular and biological system. This narrative review examines how dose, molecular format, hydrodynamic size, binding affinity, valency, ligand spectrum, target turnover, tissue distribution and delivery architecture determine the time for which an eye remains controlled. Human ocular pharmacokinetic and pharmacodynamic evidence is interpreted according to compartment, assay and model provenance, with particular attention to the distinction between drug elimination, free-ligand suppression, anatomical control and protocol-assigned treatment interval. Trial evidence for ranibizumab, aflibercept, conbercept, brolucizumab and faricimab shows that extended dosing can arise from greater starting exposure, altered binding architecture or pathway expansion without a proportionate change in intrinsic ocular half-life. Patient phenotype and retreatment rules further modify the observed interval. Refillable reservoirs, biodegradable depots and ocular gene therapy change the governing kinetics from bolus elimination to controlled release or sustained local production, thereby increasing the importance of reversibility and cumulative safety. We propose that durability be defined as a time-to-threshold phenotype integrating active target-site exposure, biological demand, anatomical recurrence, all treatment-related procedures and safety. Standardised estimands, longitudinal human ocular sampling, spatial exposure methods and externally validated mechanism-informed models are needed to make molecular durability comparable and clinically actionable.
2026-09-07 | Faricimab in the Treatment of Retinal Disease: A Narrative Review.
Retinal and choroidal diseases, including diabetic macular edema, neovascular age-related macular degeneration, retinal vein occlusion, and polypoidal choroidal vasculopathy, remain a significant cause of visual impairment around the world, especially among elderly . Although anti-vascular endothelial growth factor (anti-VEGF) therapy remains the standard of care, it is limited by its side effect profile, resistance, and high injection burden. This underscores the need for a more optimal and possible replacement. Faricimab is an emerging bispecific antibody targeting VEGF-A and angiopoietin-2, addressing both angiogenesis and vascular permeability by modulating the tyrosine kinase with immunoglobulin-like domains-2 pathway. This literature review synthesizes information from preclinical studies and randomized controlled trials. It focuses on the molecular reasoning behind the use of faricimab and the safety profile compared with anti-VEGF monotherapy.
proteins
2026-08-15 | Short-term Anatomical and Functional Outcomes of Intravitreal Ziv-aflibercept for Macular Edema Secondary to Central Retinal Vein Occlusion: A Prospective Pilot Interventional Case Series
Background: Central retinal vein occlusion (CRVO) may cause substantial central visual impairment, particularly when macular edema develops. This study evaluated the 24-week visual, anatomical, and safety outcomes of intravitreal ziv-aflibercept in eyes with CRVO-related macular edema. Methods: Nine eyes of nine patients were prospectively evaluated in this pilot interventional case series between September 2024 and March 2025. Patients received three monthly intravitreal injections of ziv-aflibercept 2 mg/0.08 mL, followed by OCT-guided pro re nata retreatment. Best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP), reinjection need, and adverse events were assessed over 24 weeks. Results: Mean BCVA improved from 1.32 ± 0.36 to 0.85 ± 0.29 logMAR, with a significant overall change across follow-up visits (F(4,32)=17.87, p<0.001). Mean CMT decreased from 612.78 ± 190.60 to 322.44 ± 87.07 µm, with a significant Greenhouse–Geisser-corrected overall change (F(2.40,19.24)=7.14, p=0.003). Mean baseline-to-24-week CMT reduction was 290.33 µm (95% CI, 139.23–441.43). Mean IOP remained stable (F(4,32)=1.19, p=0.336). Three eyes required additional injections after loading. No ocular, systemic, or injection-related complications were recorded. Conclusions: Intravitreal ziv-aflibercept was associated with favorable short-term visual and anatomical outcomes, stable IOP, and no recorded short-term safety concerns in this pilot series. Larger studies with longer follow-up are needed.
2026-06-19 | Real-world outcomes of naïve, early switch and late switch eyes treated with dexamethasone intravitreal implant for retinal vein occlusion.
PurposeTo evaluate functional and anatomical outcomes after intravitreal dexamethasone implant (DEXI) in macular edema secondary to retinal vein occlusion (ME-RVO), comparing treatment-naïve eyes with early-switch (ES) and late-switch (LS) eyes previously treated with anti-VEGF, to explore the optimal therapeutic window for switching.MethodsA retrospective real-world study including 71 eyes with ME-RVO treated with DEXI and followed for 12 months. Patients were classified as naïve (no prior intravitreal therapy), ES (≤3 anti-VEGF injections before switching), and LS (>3 anti-VEGF injections before switching). Functional outcomes were assessed by best-corrected visual acuity (BCVA), and anatomical outcomes by central macular thickness (CMT) using spectral-domain optical coherence tomography.ResultsBCVA improved significantly at month 2 in treatment-naïve and ES eyes (p < 0.05), whereas no significant change was observed in LS eyes. A ≥ 2-line gain occurred in 50% of naïve eyes, markedly higher than in previously treated eyes. Naïve patients maintained functional and anatomical improvement throughout follow-up. All groups demonstrated an early reduction in CMT at month 2 (p < 0.05). Multivariate analysis identified baseline BCVA, but not switching timing, as the main predictor of functional improvement.ConclusionsWhile DEXI improved anatomical outcomes across all subgroups, functional recovery was more frequently observed in naïve and ES eyes. However, baseline BCVA emerged as the main independent determinant of functional response, suggesting that visual outcomes are primarily driven by initial visual status rather than switching timing. By including a naïve comparison group, this study provides novel insights into the management of ME-RVO in patients with suboptimal anti-VEGF response.
2026-04-21 | CD5L promotes efferocytosis and resolution of retinal ischemic injury.
Ischemia-induced retinopathy is a defining feature of prevalent ocular conditions, including diabetic retinopathy and central retinal artery or vein occlusion. Therapeutic interventions for ischemic retinopathies show limited efficacy and adverse effects, highlighting the need to thoroughly investigate the underlying mechanisms. Histone deacetylase 3 (HDAC3), a member of the histone deacetylase family, plays a central role in regulating gene expression in myeloid cells (microglia and macrophages). We recently showed that myeloid HDAC3 deletion promotes tissue repair and functional recovery after retinal ischemia-reperfusion (IR) injury via efferocytosis, a process by which myeloid cells engulf and clear apoptotic cells. Here, we investigated the mechanism by which myeloid HDAC3 deletion enhances efferocytosis. Employing an in vitro efferocytosis assay coupled with RNA sequencing on HDAC3 KO macrophages revealed that the secreted protein, CD5 molecule-like (CD5L), was the most upregulated among other pro-efferocytic genes. In vivo, we found that CD5L levels markedly increased in the retinas of myeloid HDAC3 KO mice subjected to IR injury, and its expression colocalized with myeloid cells. Co-immunoprecipitation experiments showed that HDAC3 represses CD5L expression in a liver X receptor (LXRα)-dependent manner. Additionally, we found that CD36, a receptor for CD5L that facilitates the clearance of apoptotic cells, was upregulated in retinal myeloid cells after IR. In vitro, CD5L treatment enhanced efferocytosis via CD36. We then evaluated the role of CD5L in retinal IR injury using in vivo neuronal, vascular, structural, and functional endpoints. CD5L KO mice showed worsened outcomes after IR, whereas treatment with recombinant CD5L was protective against retinal ischemic injury. Collectively, our findings suggest that deleting HDAC3 enhances macrophage efferocytosis by upregulating the CD5L/CD36 axis. CD5L may serve as a promising therapeutic target to improve outcomes in ischemic retinopathy.
2026-03-12 | Efficacy and safety of intravitreal Ziv-Aflibercept for the treatment of macular edema: A systematic review and meta-analysis.
Intravitreal Ziv-Aflibercept (ZA-IV) is a recombinant fusion protein used to treat macular diseases. Several studies have demonstrated its efficacy and safety. The objective was to evaluate the efficacy and safety of ZA-IV in the treatment of diabetic macular edema (DME) and macular edema secondary to retinal vein occlusion (RVO). Systematic review with meta-analysis (PROSPERO: CRD42024542788), with searches in PubMed, EMBASE, and Web of Science up to April 2024. Observational studies and randomized controlled trials (RCTs) were included. Efficacy was determined by best-corrected visual acuity (BCVA) and central macular thickness (CMT). Safety was assessed based on the reports in the studies. Risk of bias was assessed using the Robins-I and Cochrane RoB 2.0 tools. Of 503 studies, 8 observational studies and 5 RCTs were included. In DME, RCTs showed a reduction in CMT (-105 μm; 95% CI: -129.8 to -80.3; I2: 0%) and in BCVA a LogMAR reduction (-0.29; 95% CI: -0.36 to -0.21; I2: 0%). Observational studies in DME showed a reduction in CMT (-108 μm; 95% CI: -133 to -83.1; I2: 34%) and in BCVA a LogMAR reduction (-0.2; 95% CI: -0.26 a -0.14; I2: 0%). In RVO, RCTs showed a reduction in CMT (-230 μm; 95% CI: -367 to -94; I2: 46%). Observational studies in EMSOV showed a reduction in GMC (-160 μm; 95% CI: -257 to -64; I2: 74%) and in BCVA (best corrected visual acuity) a reduction in LogMAR (-0.2; 95% CI: -0.26 to -0.14; I2: 50%). No serious ocular or systemic adverse effects were reported. ZA-IV demonstrated efficacy and is potentially safe for the treatment of EMD and EMSOV.
2026-01-21 | Prosaposin is a dual-action therapeutic target for vascular stabilization and neuroprotection.
The disruption of vascular homeostasis is a key pathological feature of fundus abnormal vascular diseases, including wet age-related macular degeneration, diabetic macular edema, and retinal vein occlusion. While anti-vascular endothelial growth factor therapies are widely used, many patients exhibit limited or suboptimal responses. Through proteomic analysis of 173 aqueous humor samples from fundus abnormal vascular disease patients, followed by validation in an independent cohort of 70 samples, this study identifies prosaposin as a potential therapeutic candidate. In vitro, prosaposin mitigated endothelial dysfunction and reduced vascular permeability, while in vivo, it demonstrated anti-angiogenic and anti-inflammatory effects comparable to aflibercept, effectively reducing vascular leakage and retinal edema. Additionally, prosaposin provided neuroprotection by preserving photoreceptor cells. These findings highlight the dual role of prosaposin in maintaining vascular homeostasis and protecting neural tissues, suggesting its potential as an alternative treatment for patients unresponsive to anti-vascular endothelial growth factor therapies.
cell therapies
2026-05-31 | Stem cell therapy in retinal disease.
Stem cell therapy presents a new solution to cure degenerative diseases of the retina, which normally have limited ability to regenerate after injury. Stem cells are cells capable of self-renewal and differentiation into more specialized cells, and can be derived from both embryonic and adult sources. This definition encompasses a heterogeneous group of cells possessing varied potency and characteristics. Current attempts in applying stem cell technology to the retina have primarily focused on regenerating the retinal pigment epithelium (RPE) and light-sensing photoreceptor cells. They have not only shown the ability to prevent the death of host photoreceptors, but they can also differentiate into all major retinal cell types to replace lost cells. In vivo experiments, primarily performed in mice, have found that stem cell-derived RPE cells, photoreceptors, and their precursors can survive long-term in animal models without tumorigenicity or immune rejection. Following transplantation, these cells were able to integrate and mature in vivo, forming synapse-like structures with host retinal cells. Furthermore, transplants in mice were able to rescue visual function at a cellular and behavioral level. These promising preclinical results have led to clinical trials testing cell therapy in numerous diseases, including Stargardt macular dystrophy, age-related macular degeneration, retinitis pigmentosa, and central retinal vein occlusion. These trials have demonstrated the safety of cell therapy and have improved visual function in some patients. Scientific advances in the culturing of retinal organoids and the understanding of cell redifferentiation are informing the development of better stem cell therapies, which hold great potential for restoring vision to patients with retinal dystrophies.
2026-01-26 | Corrigendum to "Randomized Study of Intravitreal Autologous CD34+ Stem Cells in Central Retinal Vein Occlusion (Treatment of Retinal vein occlusion Using STem cells [TRUST] Report 1): Safety and Feasibility. Ophthalmol Sci. 2026;6:100905".
[This corrects the article DOI: 10.1016/j.xops.2025.100905.].
2025-08-05 | Randomized Study of Intravitreal Autologous CD34+ Stem Cells in Central Retinal Vein Occlusion (Treatment of Retinal vein occlusion Using STem cells [TRUST] Report 1): Safety and Feasibility
Purpose: To assess the safety and feasibility of intravitreal injection of autologous CD34+ bone marrow stem cells (BMSCs) in eyes with vision loss from central retinal vein occlusion (CRVO). Design: Phase I/II single-center, prospective, randomized, sham-controlled, double-masked study. Participants: Participants with CRVO of 6 to 42 months duration, best-corrected visual acuity (VA) of 20/40 to 20/400, and no concurrent retinopathy or optic neuropathy contributing to vision loss in the study eye. The exclusion criteria include any concurrent systemic condition that would alter bone marrow components. Methods: Participants were randomized to immediate cell injection followed by sham injection at month 6 or immediate sham injection followed by cell injection at month 6. Cell injection consisted of a bone marrow aspiration and intravitreal injection of autologous CD34+ BMSCs. CD34+ BMSCs were isolated from the mononuclear cell fraction of bone marrow using Miltenyi CliniMACS system under current good manufacturing practices. Isolated cells were released for intravitreal injection if they passed the release criteria for quantity, sterility, and viability accepted by the US Food and Drug Administration. Sham injection consisted of a sham bone marrow aspiration and intravitreal injection without entering bone or eye. Eye examination, microperimetry, fundus photography, fluorescein angiography, electroretinography, OCT, and OCT angiography were performed at baseline and during study follow-up of 12 months. Main Outcome Measures: Adverse events (AEs) associated with study treatment, number of CD34+ BMSCs injected intravitreally. Results: Sixteen participants (16 eyes) were randomized to 1 of 2 study groups. All received intravitreal injection of autologous CD34+ BMSCs (mean 4.3 million cells) and completed the study follow-up. Rubeosis with vitreous hemorrhage occurred in 1 study eye, <1 month after sham injection and 7 months after cell injection, attributed to normal progression of CRVO. There were no other serious ocular AEs. The most common AE related to the study cell injection was new floaters (15/16, 93%). Other ocular AEs were similarly noted after sham injection. No eye had persistent VA loss of ≥15 letters after cell injection. Conclusions: Intravitreal injection of autologous CD34+ BMSCs appears well-tolerated and feasible in eyes with vision loss from CRVO. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
2024-05-23 | Pericyte in retinal vascular diseases: A multifunctional regulator and potential therapeutic target.
Retinal vascular diseases (RVDs), in particular diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, are leading contributors to blindness. The pathogenesis of RVD involves vessel dilatation, leakage, and occlusion; however, the specific underlying mechanisms remain unclear. Recent findings have indicated that pericytes (PCs), as critical members of the vascular mural cells, significantly contribute to the progression of RVDs, including detachment from microvessels, alteration of contractile and secretory properties, and excessive production of the extracellular matrix. Moreover, PCs are believed to have mesenchymal stem properties and, therefore, might contribute to regenerative therapy. Here, we review novel ideas concerning PC characteristics and functions in RVDs and discuss potential therapeutic strategies based on PCs, including the targeting of pathological signals and cell-based regenerative treatments.
2023-09-11 | Enhanced therapeutic effect of PEDF-loaded mesenchymal stem cell-derived small extracellular vesicles against oxygen-induced retinopathy through increased stability and penetrability of PEDF.
Several common retinal diseases that cause blindness are characterised by pathological neovascularisation accompanied by inflammation and neurodegeneration, including retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinal vein occlusion (RVO). The current treatment strategies for these diseases have limited benefits. Thus, safer and more effective alternative approaches are required. In this study, we loaded small extracellular vesicles (sEVs) derived from mesenchymal stem cell (MSC) with pigment epithelium-derived factor (PEDF), and tested the therapeutic effect of PEDF-loaded sEVs (PEDF-sEVs) using an oxygen induced retinopathy (OIR) mouse model, aiming to establish a new therapy strategy for the treatment of retinal pathological angiogenesis. We formulated PEDF-loaded sEVs (PEDF-sEVs) containing high concentrations of PEDF and evaluated their effects through in vivo and in vitro experiments. In OIR mice, PEDF-sEVs showed significantly better effects on retinal avascular areas, inflammation, and neuronal degeneration compared with the anti-vascular endothelial growth factor (VEGF) drug, which may indicate a possible advantage of PEDF-sEVs over anti-VEGF drugs in the treatment of pathological neovascularisation. In vitro, PEDF-sEVs greatly inhibited endothelial cell (EC) proliferation, migration, and tube formation by suppressing the VEGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) and AKT (also known as Protein Kinase B). All experiments and analyses were performed in triplicate. PEDF-sEVs were more effective than PEDF or sEVs alone, both in vitro and in vivo. Furthermore, to determine the distribution of PEDF-sEVs, we used DiD-labelled sEVs and FITC-labelled PEDF to track the sEVs and PEDF, respectively. We found that PEDF-sEVs effectively reduced the degradation of PEDF. Loading PEDF on sEVs effectively enhanced the anti-angiogenic, anti-inflammatory, and neuroprotective effects of PEDF by increasing the stability and penetrability. These results suggest a potential role for PEDF-sEVs in retinal pathological neovascularisation.
other
2025-09-24 | Nanomaterial-Based Anti-Angiogenic Gene Therapy for Retinal Neovascular Diseases: Mechanistic Insights and Preclinical Advances.
Retinal neovascular diseases (RNVs) are the leading cause of preventable vision loss worldwide, including diabetic retinopathy, age related macular degeneration, retinopathy of prematurity, and retinal vein occlusion. Anti-VEGF therapy remains central to current clinical management, while emerging molecular targets, including ANG-2, PDGF, Sema4D, integrins, and inflammatory mediators, are gaining therapeutic relevance. The current standard anti-VEGF intravitreal injection (administered every 4-8 weeks) regimen significantly increases the risk of complications such as endophthalmitis and elevated intraocular pressure, which has driven interest in one-time gene therapy approaches. However, traditional viral delivery systems for gene therapy are limited by limited drug loading and poor biocompatibility. This review systematically investigated nanomaterial mediated gene therapy options for anti-angiogenesis in RNVs, focusing on six distinct nanomaterial categories: metal nanoparticles, carbon/silicon nanostructures, lipid nanoparticles, polymers, dendrimers, and nanocomposites. The advantages and limitations of various nanomaterials in terms of gene-loading capacity, controlled release profiles, biocompatibility, and transfection efficiency in the preclinical application of anti-angiogenic gene therapy for RNV diseases were compared. It also provides unique insights into the future multi-target therapy of nanomaterials and hybrid nanomaterial delivery.
2024-12-14 | Multiple gene therapy as a tool for regulating the expression of molecules involved in neovascular age-related macular degeneration.
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.
2024-07-02 | Tetrahedral framework nucleic acids-based delivery of MicroRNA-22 inhibits pathological neovascularization and vaso-obliteration by regulating the Wnt pathway.
The objective of this study was to investigate the effects and molecular mechanisms of tetrahedral framework nucleic acids-microRNA22 (tFNAs-miR22) on inhibiting pathological retinal neovascularization (RNV) and restoring physiological retinal vessels. A novel DNA nanocomplex (tFNAs-miR22) was synthesised by modifying microRNA-22 (miR22) through attachment onto tetrahedral frame nucleic acids (tFNAs), which possess diverse biological functions. Cell proliferation, wound healing, and tube formation were employed for in vitro assays to investigate the angiogenic function of cells. Oxygen-induced retinopathy (OIR) model was utilised to examine the effects of reducing pathological neovascularization (RNV) and inhibiting vascular occlusion in vivo. In vitro, tFNAs-miR22 demonstrated the ability to penetrate endothelial cells and effectively suppress cell proliferation, tube formation, and migration in a hypoxic environment. In vivo, tFNAs-miR22 exhibited promising results in reducing RNV and promoting the restoration of normal retinal blood vessels in OIR model through modulation of the Wnt pathway. This study provided a theoretical basis for the further understanding of RNV, and highlighted the innovative and potential of tFNAs-miR22 as a therapeutic option for ischemic retinal diseases.
2024-04-26 | Role of mRNA-binding proteins in retinal neovascularization.
Retinal neovascularization (RNV) is a pathological process that primarily occurs in diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion. It is a common yet debilitating clinical condition that culminates in blindness. Urgent efforts are required to explore more efficient and less limiting therapeutic strategies. Key RNA-binding proteins (RBPs), crucial for post-transcriptional regulation of gene expression by binding to RNAs, are closely correlated with RNV development. RBP-RNA interactions are altered during RNV. Here, we briefly review the characteristics and functions of RBPs, and the mechanism of RNV. Then, we present insights into the role of the regulatory network of RBPs in RNV. HuR, eIF4E, LIN28B, SRSF1, METTL3, YTHDF1, Gal-1, HIWI1, and ZFR accelerate RNV progression, whereas YTHDF2 and hnRNPA2B1 hinder it. The mechanisms elucidated in this review provide a reference to guide the design of therapeutic strategies to reverse abnormal processes.
2023-05-27 | BCL6B Contributes to Ocular Vascular Diseases via Notch Signal Silencing.
Endothelial cell activation is tightly controlled by the balance between VEGF (vascular endothelial cell growth factor) and Notch signaling pathway. VEGF destabilizes blood vessels and promotes neovascularization, which are common features of sight-threatening ocular vascular disorders. Here, we show that BCL6B (B-cell CLL/lymphoma 6 member B protein), also known as BAZF, ZBTB28, and ZNF62, plays a pivotal role in the development of retinal edema and neovascularization. The pathophysiological physiological role of BCL6B was investigated in cellular and animal models mimicking 2 pathological conditions: retinal vein occlusion and choroidal neovascularization. An in vitro experimental system was used in which human retinal microvascular endothelial cells were supplemented with VEGF. Choroidal neovascularization cynomolgus monkey model was generated to investigate the involvement of BCL6B in the pathogenesis. Mice lacking BCL6B or treated with BCL6B-targeting small-interfering ribose nucleic acid were examined for histological and molecular phenotypes. In retinal endothelial cells, the BCL6B expression level was increased by VEGF. BCL6B-deficient endothelial cells showed Notch signal activation and attenuated cord formation via blockage of the VEGF-VEGFR2 signaling pathway. Optical coherence tomography images showed that choroidal neovascularization lesions were decreased by BCL6B-targeting small-interfering ribose nucleic acid. Although BCL6B mRNA expression was significantly increased in the retina, BCL6B-targeting small-interfering ribose nucleic acid suppressed ocular edema in the neuroretina. The increase in proangiogenic cytokines and breakdown of the inner blood-retinal barrier were abrogated in BCL6B knockout (KO) mice via Notch transcriptional activation by CBF1 (C promotor-binding factor 1) and its activator, the NICD (notch intracellular domain). Immunostaining showed that Müller cell activation, a source of VEGF, was diminished in BCL6B-KO retinas. These data indicate that BCL6B may be a novel therapeutic target for ocular vascular diseases characterized by ocular neovascularization and edema.
small molecules
2026-09-30 | Effect of Topical Bromfenac 0.09% on Pain Following Intravitreal Antivascular Endothelial Growth Factor Injections.
To evaluate the effect of topical bromfenac 0.09% on pain following intravitreal (IVT) injection of antivascular endothelial growth factor (anti-VEGF) medications in patients diagnosed as having choroidal neovascularization secondary to age-related macular degeneration or other etiologies, diabetic macular edema, diabetic retinopathy, or macular edema associated with retinal vein occlusion. A total of 78 adult patients scheduled to receive bilateral anti-VEGF IVT injections were randomized to receive topical bromfenac 0.09% in 1 eye and artificial tears in the fellow eye (control) immediately before the anti-VEGF treatment at 2 academic institutions from March 2021 to June 2022. Pain was evaluated using the Wong-Baker FACES Pain Rating Scale (score range, 0-10) and the Short-Form McGill Pain Questionnaire (score range, 0-5) at baseline (preinjection) and 5 minutes, 6 hours, and 24 hours following injection. Wilcoxon signed-rank sum test was used for statistical comparisons. In total, 156 eyes were analyzed. Mean baseline pain scores were similar between the bromfenac 0.09% and control groups. Five minutes after injection, eyes randomized to receive bromfenac 0.09% had significantly less pain compared with control eyes receiving artificial tears, on both the Wong-Baker FACES scale (mean raw score, 2.29 vs 2.79; P = .0275) and the McGill Pain Questionnaire (mean raw score, 1.13 vs 2.36; P = .0135). No significant difference in pain scores was noted at 6 hours or 24 hours post-IVT injection. Bromfenac 0.09% solution administered to the study eye before IVT anti-VEGF injection reduced pain 5 minutes after injection in comparison with artificial tears. There was no difference in pain between the 2 groups at 6 hours or 24 hours post-IVT injection.
2026-09-25 | Potential protective associations of antidiabetic and lipid-lowering therapies with retinal vein occlusion risk: a systematic review and meta-analysis.
Retinal vein occlusion (RVO) shares key pathophysiological pathways with metabolic and atherothrombotic disorders. Emerging evidence suggests that statins and antidiabetic drugs may be associated with lower RVO incidence, yet their potential to modify RVO risk remains uncertain. A systematic search of MEDLINE, Embase, Scopus, and Web of Science was performed from inception through June 11, 2025, for studies evaluating the association between systemically administered antidiabetic or lipid-lowering agents and RVO. Risk of bias was assessed using the Newcastle-Ottawa Scale. Association between antidiabetic or lipid-lowering therapy and RVO risk was the primary outcome, and drug-class-specific associations, differences by RVO subtype, and related retinal outcomes were the secondary outcomes. Certainty of evidence was appraised. Protocol registered in PROSPERO (CRD420251077729). Ten good-quality studies (six cohorts and four case-control) involving over 2 million adults met eligibility criteria. Meta-analysis results suggest that statin use consistently reduced RVO risk; pooled effect odds ratio (OR) = 0.65 (95% CI = 0.53-0.79; I² = 29%) with moderate certainty. Studies suggest metformin monotherapy halved risk [hazard ratio (HR) = 0.46, 0.30-0.73], and glucagon-like peptide-1(GLP-1) receptor agonists were associated with reduced risk compared to dipeptidyl-peptidase-4 (DPP-4) inhibitors (HR = 0.73, 0.54-0.98). Findings for sodium-glucose cotransporter-2 (SGLT-2) inhibitors were inconsistent, showing harm versus other oral glucose-lowering drugs in 1 Korean study (HR = 1.26, 1.06-1.51) but benefit versus DPP-4 inhibitors in a Taiwanese study (HR = 0.76, 0.59-0.98). Other conventional agents (repaglinide, thiazolidinediones, sulfonylureas, α-glucosidase inhibitors, insulin) yielded imprecise or null estimates. Only statins met criteria for meta-analysis; findings for other drug classes were narratively synthesised from single studies. Statins show moderate evidence of an association with reduced RVO risk. Signals of benefit for metformin and GLP-1 receptor agonists arise from single large cohorts and require independent replication. Additionally, the role of SGLT-2 inhibitors remains uncertain. These indicators warrant confirmation in prospective studies and may inform tailored retinal vascular risk reduction strategies in patients with diabetes and dyslipidaemia.
2026-09-19 | Microglia in retinal vascular diseases: inflammatory mechanism and therapeutic target.
Retinal vascular diseases (RVDs) are leading causes of vision impairment and blindness, often associated with systemic diseases such as diabetes and hypertension. Despite treatment advancements, managing RVDs, particularly retinal vein occlusion (RVO), remains challenging due to the lack of a definitive cure and reliance on controlling complications. Microglia, the retina's resident immune cells, play a crucial role in maintaining retinal health, regulating inflammation, and modulating angiogenesis. In pathological conditions, microglia adopt heterogeneous and context-dependent activation states, contributing to both inflammatory injury and vascular repair. Studies suggest that modulating microglial activation and their secreted cytokines may provide novel therapeutic strategies for RVDs. This review examines the role of microglia in RVDs and their potential as therapeutic targets, exploring strategies such as inhibiting microglial activation, regulating pro-angiogenic factor secretion, and targeting specific signaling pathways. Future research should focus on understanding the specific roles of microglial subtypes, their contributions to disease progression, and developing targeted therapies for early diagnosis and treatment of RVDs.
2026-08-27 | Baicalin Protects ARPE-19 Cells Against BRVO-Related Hypoxic Injury by Preserving Mitochondrial Function and Inhibiting Ferroptosis.
Branch retinal vein occlusion (BRVO) is a retinal vascular disorder characterized by ischemia and hypoxia. These pathological conditions contribute to retinal pigment epithelial (RPE) cell injury through oxidative stress and ferroptosis. However, whether baicalin (BC) protects against hypoxia-induced RPE injury remains unclear. CoCl2-induced hypoxic ARPE-19 cells were used to evaluate the protective effects and potential mechanisms of BC. BC improved cell viability and reduced LDH release under hypoxic conditions. BC markedly suppressed hypoxia-induced inflammatory responses, as evidenced by reduced p65 and ICAM-1 expression and decreased release of pro-inflammatory cytokines. Moreover, BC alleviated oxidative stress by reducing ROS and MDA accumulation and restoring SOD and GSH activity. BC attenuated mitochondrial dysfunction, accompanied by restoration of mitochondrial membrane potential, oxygen consumption rate (OCR), and ATP production. Transmission electron microscopy (TEM) results further confirmed the protective effect of BC on mitochondrial integrity. Mechanistically, BC suppressed ferroptosis by reducing intracellular Fe2+ accumulation and lipid peroxidation, accompanied by downregulation of TFR1, ACSL4, and p53, as well as upregulation of SLC7A11 and GPX4. These findings suggest that BC protects ARPE-19 cells against hypoxia-induced injury through preservation of mitochondrial function and inhibition of ferroptosis.
2026-08-13 | Wnt Pathway Agonism as a Therapeutic Strategy for Retinal Vascular Diseases: A Narrative Review of Evidence to Date.
Breakdown of the blood-retinal barrier (BRB) is implicated in many blinding retinal diseases, including diabetic macular edema, neovascular age-related macular degeneration, and retinal vein occlusion. Anti-vascular endothelial growth factor (anti-VEGF) therapies or laser photocoagulation are currently the standard of care for retinal diseases that are characterized by breakdown of the vascular barrier function and vascular hyperpermeability. However, inadequate response to anti-VEGF therapy is seen in a substantial proportion of patients and laser photocoagulation does not restore vision loss and can lead to collateral damage of the retina. Thus, new therapeutic targets are needed. The β-catenin-dependent wingless-related integration site (Wnt) signaling pathway plays a critical role in inner BRB development and maintenance. There are several potential therapeutics for retinal vascular diseases targeting the Wnt/β-catenin pathway under investigation, including several in preclinical development and one (MK-3000; also known as Restoret and formerly EYE103) with early clinical trial results advancing to late-stage clinical development. In this narrative review we examine the role of Wnt/β-catenin signaling in inner BRB maintenance and in retinal vascular diseases, as well as the potential for Wnt pathway agonism as a therapeutic approach.
antibodies
2026-09-27 | Comparative Analysis of Systemic Complications of Antivascular Endothelial Growth Factor Therapies in Retinal Diseases.
Purpose: To compare the systemic safety profiles of antivascular endothelial growth factor (anti-VEGF) agents using a large real-world dataset. Methods: The TriNetX Research Network database was used to identify adults with macular edema secondary to diabetes, retinal vein occlusion, or age-related macular degeneration who received bevacizumab, ranibizumab, or aflibercept (2012-2022) or faricimab (2022-2024). The bevacizumab cohort was matched with the other cohorts using propensity score matching to account for demographic characteristics and comorbidities. Outcomes included stroke, venous thromboembolism, myocardial infarction, hypertension, brain hemorrhage, and renal function. Results: In the propensity score-matched cohorts comparing outcomes between bevacizumab and aflibercept (each n = 9538), bevacizumab was associated with higher mean blood urea nitrogen level (28.07 mg/dL vs 26.89 mg/dL; P = .017), higher mean serum creatinine level (1.86 mg/dL vs 1.72 mg/dL; P = .004), and lower mean estimated glomerular filtration rate (55.64 mL/min vs 58.01 mL/min; P = .003) at 1 to 6 months' follow-up. Compared with the faricimab cohort, the bevacizumab cohort (each n = 3500) showed increased risk of stroke (risk ratio [RR], 1.71, 95% CI, 1.19-2.48), venous thromboembolism (RR, 1.80, 95% CI, 1.11-2.93), myocardial infarction (RR, 1.72, 95% CI, 1.19-2.49), and hypertension (RR, 1.47, 95% CI, 1.19-1.83) within 2 years of follow-up. No significant differences were found between the bevacizumab and ranibizumab cohorts (each n = 2211). Conclusions: Bevacizumab may confer an increased risk of cardiovascular events and differences in renal function parameters compared with aflibercept and faricimab, but not ranibizumab. This underscores the importance of tailoring anti-VEGF therapy to patient-specific profiles, particularly in patients with underlying cardiovascular and renal comorbidities. Further studies in lower-comorbidity populations are needed to clarify these associations.
2026-09-20 | Real-World Analysis of Switching Between Ranibizumab Biosimilars: Safety and Results - a Multicenter Retrospective Observational Study.
To describe disease-specific visual, anatomical, treatment-exposure, and documented safety outcomes over 24 weeks among eyes undergoing availability-driven switching between ranibizumab biosimilars in routine retinal practice in India. This multicenter retrospective observational cohort study reviewed records from January to December 2024. Baseline was the index-switch visit, before administration of the substituted ranibizumab biosimilar. Only one eye per patient was included; when both eyes were eligible, the right eye was selected by convention. Eligible eyes had at least one documented availability-driven biosimilar-to-biosimilar switch and complete 24-week follow-up. Outcomes were summarized descriptively because there was no non-switch comparator group. Of 742 screened eyes, 595 eyes from 595 patients met the inclusion criteria and received 1625 intravitreal ranibizumab biosimilar injections over 24 weeks (mean, 2.73 injections per eye). One switch was recorded in 466 eyes (78.3%) and two switches in 129 eyes (21.7%). Mean BCVA improved from 0.57 logMAR at baseline to 0.26 at 12 weeks and 0.32 at 24 weeks; the early visual improvement therefore attenuated modestly by week 24 but remained better than baseline. Mean central macular thickness decreased from 490.4 micrometers at baseline to 273.6 micrometers at 24 weeks. At final follow-up, 369 eyes (62.0%) gained at least two lines and 488 eyes (82.0%) maintained or improved vision. No endophthalmitis, retinal detachment, or treatment-related systemic adverse event was documented in the available clinical records. Eyes exposed to availability-driven switching between ranibizumab biosimilars showed favorable short-term visual and anatomical outcomes over 24 weeks. Because this retrospective study lacked a non-switch comparator and protocol-mandated safety or immunogenicity surveillance, it cannot establish an effect attributable to switching, comparative safety, equivalence, or formal interchangeability.
2026-09-17 | Early Macular Leakage Resolution Is Associated with Extended Faricimab Dosing in Retinal Vein Occlusion: A BALATON/COMINO Post Hoc Analysis.
Macular leakage (ML) is a biomarker of disease activity and, in retinal vein occlusion (RVO), is associated with poor vision outcomes. Faricimab, a dual angiopoietin-2 (Ang-2)/vascular endothelial growth factor (VEGF)-A inhibitor, has demonstrated efficacy and durability in RVO. This post hoc analysis of BALATON/COMINO examined the association between week 24 ML resolution and extended faricimab dosing intervals and vision outcomes achieved at week 68 in patients with RVO. BALATON and COMINO (NCT04740905/NCT04740931) were identically designed, phase 3, randomized trials that evaluated the efficacy and safety of faricimab in patients with branch or central/hemiretinal RVO, respectively. Patients initially received faricimab 6 mg every 4 weeks (Q4W) or aflibercept 2 mg Q4W; then from weeks 24-72, all patients received faricimab 6 mg up to Q16W according to a modified treat-and-extend regimen. This analysis included patients who remained in the study at week 68 and had a fluorescein angiography ML reading at week 24. Among 989 patients, 502 had ML resolution (≤ 1 mm2) and 143 had high ML (≥ 10 mm2) at week 24. The proportion of patients who achieved ≥ Q12W faricimab dosing at week 68 was higher among those with ML resolution at week 24 versus those with high ML at week 24 (56.1% vs 38.0%, p = 0.0001). The odds of patients receiving ≥ Q12W faricimab dosing at week 68 were higher among those with ML resolution than among those with high ML at week 24 (odds ratio 2.46, p < 0.001). Patients with ML resolution experienced greater vision gains at week 68 versus patients with high ML at week 24 (18.8 vs 15.0 letters, p = 0.0036). ML resolution at week 24 was associated with extended faricimab dosing intervals and improved vision at week 68 in patients with RVO in the BALATON/COMINO clinical trials. NCT04740905, NCT04740931.
2026-09-15 | Molecular Determinants of Intravitreal Anti-VEGF Durability: Drug Architecture, Intraocular Pharmacokinetics, Target Biology and Treatment Resistance.
Intravitreal inhibition of vascular endothelial growth factor (VEGF) has transformed the management of neovascular age-related macular degeneration, diabetic macular oedema and macular oedema secondary to retinal vein occlusion, but frequent monitoring and retreatment remain major burdens. Ocular half-life is often used as shorthand for durability, although the clinical interval is produced by a wider molecular and biological system. This narrative review examines how dose, molecular format, hydrodynamic size, binding affinity, valency, ligand spectrum, target turnover, tissue distribution and delivery architecture determine the time for which an eye remains controlled. Human ocular pharmacokinetic and pharmacodynamic evidence is interpreted according to compartment, assay and model provenance, with particular attention to the distinction between drug elimination, free-ligand suppression, anatomical control and protocol-assigned treatment interval. Trial evidence for ranibizumab, aflibercept, conbercept, brolucizumab and faricimab shows that extended dosing can arise from greater starting exposure, altered binding architecture or pathway expansion without a proportionate change in intrinsic ocular half-life. Patient phenotype and retreatment rules further modify the observed interval. Refillable reservoirs, biodegradable depots and ocular gene therapy change the governing kinetics from bolus elimination to controlled release or sustained local production, thereby increasing the importance of reversibility and cumulative safety. We propose that durability be defined as a time-to-threshold phenotype integrating active target-site exposure, biological demand, anatomical recurrence, all treatment-related procedures and safety. Standardised estimands, longitudinal human ocular sampling, spatial exposure methods and externally validated mechanism-informed models are needed to make molecular durability comparable and clinically actionable.
2026-09-07 | Faricimab in the Treatment of Retinal Disease: A Narrative Review.
Retinal and choroidal diseases, including diabetic macular edema, neovascular age-related macular degeneration, retinal vein occlusion, and polypoidal choroidal vasculopathy, remain a significant cause of visual impairment around the world, especially among elderly . Although anti-vascular endothelial growth factor (anti-VEGF) therapy remains the standard of care, it is limited by its side effect profile, resistance, and high injection burden. This underscores the need for a more optimal and possible replacement. Faricimab is an emerging bispecific antibody targeting VEGF-A and angiopoietin-2, addressing both angiogenesis and vascular permeability by modulating the tyrosine kinase with immunoglobulin-like domains-2 pathway. This literature review synthesizes information from preclinical studies and randomized controlled trials. It focuses on the molecular reasoning behind the use of faricimab and the safety profile compared with anti-VEGF monotherapy.
proteins
2026-08-15 | Short-term Anatomical and Functional Outcomes of Intravitreal Ziv-aflibercept for Macular Edema Secondary to Central Retinal Vein Occlusion: A Prospective Pilot Interventional Case Series
Background: Central retinal vein occlusion (CRVO) may cause substantial central visual impairment, particularly when macular edema develops. This study evaluated the 24-week visual, anatomical, and safety outcomes of intravitreal ziv-aflibercept in eyes with CRVO-related macular edema. Methods: Nine eyes of nine patients were prospectively evaluated in this pilot interventional case series between September 2024 and March 2025. Patients received three monthly intravitreal injections of ziv-aflibercept 2 mg/0.08 mL, followed by OCT-guided pro re nata retreatment. Best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP), reinjection need, and adverse events were assessed over 24 weeks. Results: Mean BCVA improved from 1.32 ± 0.36 to 0.85 ± 0.29 logMAR, with a significant overall change across follow-up visits (F(4,32)=17.87, p<0.001). Mean CMT decreased from 612.78 ± 190.60 to 322.44 ± 87.07 µm, with a significant Greenhouse–Geisser-corrected overall change (F(2.40,19.24)=7.14, p=0.003). Mean baseline-to-24-week CMT reduction was 290.33 µm (95% CI, 139.23–441.43). Mean IOP remained stable (F(4,32)=1.19, p=0.336). Three eyes required additional injections after loading. No ocular, systemic, or injection-related complications were recorded. Conclusions: Intravitreal ziv-aflibercept was associated with favorable short-term visual and anatomical outcomes, stable IOP, and no recorded short-term safety concerns in this pilot series. Larger studies with longer follow-up are needed.
2026-06-19 | Real-world outcomes of naïve, early switch and late switch eyes treated with dexamethasone intravitreal implant for retinal vein occlusion.
PurposeTo evaluate functional and anatomical outcomes after intravitreal dexamethasone implant (DEXI) in macular edema secondary to retinal vein occlusion (ME-RVO), comparing treatment-naïve eyes with early-switch (ES) and late-switch (LS) eyes previously treated with anti-VEGF, to explore the optimal therapeutic window for switching.MethodsA retrospective real-world study including 71 eyes with ME-RVO treated with DEXI and followed for 12 months. Patients were classified as naïve (no prior intravitreal therapy), ES (≤3 anti-VEGF injections before switching), and LS (>3 anti-VEGF injections before switching). Functional outcomes were assessed by best-corrected visual acuity (BCVA), and anatomical outcomes by central macular thickness (CMT) using spectral-domain optical coherence tomography.ResultsBCVA improved significantly at month 2 in treatment-naïve and ES eyes (p < 0.05), whereas no significant change was observed in LS eyes. A ≥ 2-line gain occurred in 50% of naïve eyes, markedly higher than in previously treated eyes. Naïve patients maintained functional and anatomical improvement throughout follow-up. All groups demonstrated an early reduction in CMT at month 2 (p < 0.05). Multivariate analysis identified baseline BCVA, but not switching timing, as the main predictor of functional improvement.ConclusionsWhile DEXI improved anatomical outcomes across all subgroups, functional recovery was more frequently observed in naïve and ES eyes. However, baseline BCVA emerged as the main independent determinant of functional response, suggesting that visual outcomes are primarily driven by initial visual status rather than switching timing. By including a naïve comparison group, this study provides novel insights into the management of ME-RVO in patients with suboptimal anti-VEGF response.
2026-04-21 | CD5L promotes efferocytosis and resolution of retinal ischemic injury.
Ischemia-induced retinopathy is a defining feature of prevalent ocular conditions, including diabetic retinopathy and central retinal artery or vein occlusion. Therapeutic interventions for ischemic retinopathies show limited efficacy and adverse effects, highlighting the need to thoroughly investigate the underlying mechanisms. Histone deacetylase 3 (HDAC3), a member of the histone deacetylase family, plays a central role in regulating gene expression in myeloid cells (microglia and macrophages). We recently showed that myeloid HDAC3 deletion promotes tissue repair and functional recovery after retinal ischemia-reperfusion (IR) injury via efferocytosis, a process by which myeloid cells engulf and clear apoptotic cells. Here, we investigated the mechanism by which myeloid HDAC3 deletion enhances efferocytosis. Employing an in vitro efferocytosis assay coupled with RNA sequencing on HDAC3 KO macrophages revealed that the secreted protein, CD5 molecule-like (CD5L), was the most upregulated among other pro-efferocytic genes. In vivo, we found that CD5L levels markedly increased in the retinas of myeloid HDAC3 KO mice subjected to IR injury, and its expression colocalized with myeloid cells. Co-immunoprecipitation experiments showed that HDAC3 represses CD5L expression in a liver X receptor (LXRα)-dependent manner. Additionally, we found that CD36, a receptor for CD5L that facilitates the clearance of apoptotic cells, was upregulated in retinal myeloid cells after IR. In vitro, CD5L treatment enhanced efferocytosis via CD36. We then evaluated the role of CD5L in retinal IR injury using in vivo neuronal, vascular, structural, and functional endpoints. CD5L KO mice showed worsened outcomes after IR, whereas treatment with recombinant CD5L was protective against retinal ischemic injury. Collectively, our findings suggest that deleting HDAC3 enhances macrophage efferocytosis by upregulating the CD5L/CD36 axis. CD5L may serve as a promising therapeutic target to improve outcomes in ischemic retinopathy.
2026-03-12 | Efficacy and safety of intravitreal Ziv-Aflibercept for the treatment of macular edema: A systematic review and meta-analysis.
Intravitreal Ziv-Aflibercept (ZA-IV) is a recombinant fusion protein used to treat macular diseases. Several studies have demonstrated its efficacy and safety. The objective was to evaluate the efficacy and safety of ZA-IV in the treatment of diabetic macular edema (DME) and macular edema secondary to retinal vein occlusion (RVO). Systematic review with meta-analysis (PROSPERO: CRD42024542788), with searches in PubMed, EMBASE, and Web of Science up to April 2024. Observational studies and randomized controlled trials (RCTs) were included. Efficacy was determined by best-corrected visual acuity (BCVA) and central macular thickness (CMT). Safety was assessed based on the reports in the studies. Risk of bias was assessed using the Robins-I and Cochrane RoB 2.0 tools. Of 503 studies, 8 observational studies and 5 RCTs were included. In DME, RCTs showed a reduction in CMT (-105 μm; 95% CI: -129.8 to -80.3; I2: 0%) and in BCVA a LogMAR reduction (-0.29; 95% CI: -0.36 to -0.21; I2: 0%). Observational studies in DME showed a reduction in CMT (-108 μm; 95% CI: -133 to -83.1; I2: 34%) and in BCVA a LogMAR reduction (-0.2; 95% CI: -0.26 a -0.14; I2: 0%). In RVO, RCTs showed a reduction in CMT (-230 μm; 95% CI: -367 to -94; I2: 46%). Observational studies in EMSOV showed a reduction in GMC (-160 μm; 95% CI: -257 to -64; I2: 74%) and in BCVA (best corrected visual acuity) a reduction in LogMAR (-0.2; 95% CI: -0.26 to -0.14; I2: 50%). No serious ocular or systemic adverse effects were reported. ZA-IV demonstrated efficacy and is potentially safe for the treatment of EMD and EMSOV.
2026-01-21 | Prosaposin is a dual-action therapeutic target for vascular stabilization and neuroprotection.
The disruption of vascular homeostasis is a key pathological feature of fundus abnormal vascular diseases, including wet age-related macular degeneration, diabetic macular edema, and retinal vein occlusion. While anti-vascular endothelial growth factor therapies are widely used, many patients exhibit limited or suboptimal responses. Through proteomic analysis of 173 aqueous humor samples from fundus abnormal vascular disease patients, followed by validation in an independent cohort of 70 samples, this study identifies prosaposin as a potential therapeutic candidate. In vitro, prosaposin mitigated endothelial dysfunction and reduced vascular permeability, while in vivo, it demonstrated anti-angiogenic and anti-inflammatory effects comparable to aflibercept, effectively reducing vascular leakage and retinal edema. Additionally, prosaposin provided neuroprotection by preserving photoreceptor cells. These findings highlight the dual role of prosaposin in maintaining vascular homeostasis and protecting neural tissues, suggesting its potential as an alternative treatment for patients unresponsive to anti-vascular endothelial growth factor therapies.
cell therapies
2026-05-31 | Stem cell therapy in retinal disease.
Stem cell therapy presents a new solution to cure degenerative diseases of the retina, which normally have limited ability to regenerate after injury. Stem cells are cells capable of self-renewal and differentiation into more specialized cells, and can be derived from both embryonic and adult sources. This definition encompasses a heterogeneous group of cells possessing varied potency and characteristics. Current attempts in applying stem cell technology to the retina have primarily focused on regenerating the retinal pigment epithelium (RPE) and light-sensing photoreceptor cells. They have not only shown the ability to prevent the death of host photoreceptors, but they can also differentiate into all major retinal cell types to replace lost cells. In vivo experiments, primarily performed in mice, have found that stem cell-derived RPE cells, photoreceptors, and their precursors can survive long-term in animal models without tumorigenicity or immune rejection. Following transplantation, these cells were able to integrate and mature in vivo, forming synapse-like structures with host retinal cells. Furthermore, transplants in mice were able to rescue visual function at a cellular and behavioral level. These promising preclinical results have led to clinical trials testing cell therapy in numerous diseases, including Stargardt macular dystrophy, age-related macular degeneration, retinitis pigmentosa, and central retinal vein occlusion. These trials have demonstrated the safety of cell therapy and have improved visual function in some patients. Scientific advances in the culturing of retinal organoids and the understanding of cell redifferentiation are informing the development of better stem cell therapies, which hold great potential for restoring vision to patients with retinal dystrophies.
2026-01-26 | Corrigendum to "Randomized Study of Intravitreal Autologous CD34+ Stem Cells in Central Retinal Vein Occlusion (Treatment of Retinal vein occlusion Using STem cells [TRUST] Report 1): Safety and Feasibility. Ophthalmol Sci. 2026;6:100905".
[This corrects the article DOI: 10.1016/j.xops.2025.100905.].
2025-08-05 | Randomized Study of Intravitreal Autologous CD34+ Stem Cells in Central Retinal Vein Occlusion (Treatment of Retinal vein occlusion Using STem cells [TRUST] Report 1): Safety and Feasibility
Purpose: To assess the safety and feasibility of intravitreal injection of autologous CD34+ bone marrow stem cells (BMSCs) in eyes with vision loss from central retinal vein occlusion (CRVO). Design: Phase I/II single-center, prospective, randomized, sham-controlled, double-masked study. Participants: Participants with CRVO of 6 to 42 months duration, best-corrected visual acuity (VA) of 20/40 to 20/400, and no concurrent retinopathy or optic neuropathy contributing to vision loss in the study eye. The exclusion criteria include any concurrent systemic condition that would alter bone marrow components. Methods: Participants were randomized to immediate cell injection followed by sham injection at month 6 or immediate sham injection followed by cell injection at month 6. Cell injection consisted of a bone marrow aspiration and intravitreal injection of autologous CD34+ BMSCs. CD34+ BMSCs were isolated from the mononuclear cell fraction of bone marrow using Miltenyi CliniMACS system under current good manufacturing practices. Isolated cells were released for intravitreal injection if they passed the release criteria for quantity, sterility, and viability accepted by the US Food and Drug Administration. Sham injection consisted of a sham bone marrow aspiration and intravitreal injection without entering bone or eye. Eye examination, microperimetry, fundus photography, fluorescein angiography, electroretinography, OCT, and OCT angiography were performed at baseline and during study follow-up of 12 months. Main Outcome Measures: Adverse events (AEs) associated with study treatment, number of CD34+ BMSCs injected intravitreally. Results: Sixteen participants (16 eyes) were randomized to 1 of 2 study groups. All received intravitreal injection of autologous CD34+ BMSCs (mean 4.3 million cells) and completed the study follow-up. Rubeosis with vitreous hemorrhage occurred in 1 study eye, <1 month after sham injection and 7 months after cell injection, attributed to normal progression of CRVO. There were no other serious ocular AEs. The most common AE related to the study cell injection was new floaters (15/16, 93%). Other ocular AEs were similarly noted after sham injection. No eye had persistent VA loss of ≥15 letters after cell injection. Conclusions: Intravitreal injection of autologous CD34+ BMSCs appears well-tolerated and feasible in eyes with vision loss from CRVO. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
2024-05-23 | Pericyte in retinal vascular diseases: A multifunctional regulator and potential therapeutic target.
Retinal vascular diseases (RVDs), in particular diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, are leading contributors to blindness. The pathogenesis of RVD involves vessel dilatation, leakage, and occlusion; however, the specific underlying mechanisms remain unclear. Recent findings have indicated that pericytes (PCs), as critical members of the vascular mural cells, significantly contribute to the progression of RVDs, including detachment from microvessels, alteration of contractile and secretory properties, and excessive production of the extracellular matrix. Moreover, PCs are believed to have mesenchymal stem properties and, therefore, might contribute to regenerative therapy. Here, we review novel ideas concerning PC characteristics and functions in RVDs and discuss potential therapeutic strategies based on PCs, including the targeting of pathological signals and cell-based regenerative treatments.
2023-09-11 | Enhanced therapeutic effect of PEDF-loaded mesenchymal stem cell-derived small extracellular vesicles against oxygen-induced retinopathy through increased stability and penetrability of PEDF.
Several common retinal diseases that cause blindness are characterised by pathological neovascularisation accompanied by inflammation and neurodegeneration, including retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinal vein occlusion (RVO). The current treatment strategies for these diseases have limited benefits. Thus, safer and more effective alternative approaches are required. In this study, we loaded small extracellular vesicles (sEVs) derived from mesenchymal stem cell (MSC) with pigment epithelium-derived factor (PEDF), and tested the therapeutic effect of PEDF-loaded sEVs (PEDF-sEVs) using an oxygen induced retinopathy (OIR) mouse model, aiming to establish a new therapy strategy for the treatment of retinal pathological angiogenesis. We formulated PEDF-loaded sEVs (PEDF-sEVs) containing high concentrations of PEDF and evaluated their effects through in vivo and in vitro experiments. In OIR mice, PEDF-sEVs showed significantly better effects on retinal avascular areas, inflammation, and neuronal degeneration compared with the anti-vascular endothelial growth factor (VEGF) drug, which may indicate a possible advantage of PEDF-sEVs over anti-VEGF drugs in the treatment of pathological neovascularisation. In vitro, PEDF-sEVs greatly inhibited endothelial cell (EC) proliferation, migration, and tube formation by suppressing the VEGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) and AKT (also known as Protein Kinase B). All experiments and analyses were performed in triplicate. PEDF-sEVs were more effective than PEDF or sEVs alone, both in vitro and in vivo. Furthermore, to determine the distribution of PEDF-sEVs, we used DiD-labelled sEVs and FITC-labelled PEDF to track the sEVs and PEDF, respectively. We found that PEDF-sEVs effectively reduced the degradation of PEDF. Loading PEDF on sEVs effectively enhanced the anti-angiogenic, anti-inflammatory, and neuroprotective effects of PEDF by increasing the stability and penetrability. These results suggest a potential role for PEDF-sEVs in retinal pathological neovascularisation.
other
2025-09-24 | Nanomaterial-Based Anti-Angiogenic Gene Therapy for Retinal Neovascular Diseases: Mechanistic Insights and Preclinical Advances.
Retinal neovascular diseases (RNVs) are the leading cause of preventable vision loss worldwide, including diabetic retinopathy, age related macular degeneration, retinopathy of prematurity, and retinal vein occlusion. Anti-VEGF therapy remains central to current clinical management, while emerging molecular targets, including ANG-2, PDGF, Sema4D, integrins, and inflammatory mediators, are gaining therapeutic relevance. The current standard anti-VEGF intravitreal injection (administered every 4-8 weeks) regimen significantly increases the risk of complications such as endophthalmitis and elevated intraocular pressure, which has driven interest in one-time gene therapy approaches. However, traditional viral delivery systems for gene therapy are limited by limited drug loading and poor biocompatibility. This review systematically investigated nanomaterial mediated gene therapy options for anti-angiogenesis in RNVs, focusing on six distinct nanomaterial categories: metal nanoparticles, carbon/silicon nanostructures, lipid nanoparticles, polymers, dendrimers, and nanocomposites. The advantages and limitations of various nanomaterials in terms of gene-loading capacity, controlled release profiles, biocompatibility, and transfection efficiency in the preclinical application of anti-angiogenic gene therapy for RNV diseases were compared. It also provides unique insights into the future multi-target therapy of nanomaterials and hybrid nanomaterial delivery.
2024-12-14 | Multiple gene therapy as a tool for regulating the expression of molecules involved in neovascular age-related macular degeneration.
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.
2024-07-02 | Tetrahedral framework nucleic acids-based delivery of MicroRNA-22 inhibits pathological neovascularization and vaso-obliteration by regulating the Wnt pathway.
The objective of this study was to investigate the effects and molecular mechanisms of tetrahedral framework nucleic acids-microRNA22 (tFNAs-miR22) on inhibiting pathological retinal neovascularization (RNV) and restoring physiological retinal vessels. A novel DNA nanocomplex (tFNAs-miR22) was synthesised by modifying microRNA-22 (miR22) through attachment onto tetrahedral frame nucleic acids (tFNAs), which possess diverse biological functions. Cell proliferation, wound healing, and tube formation were employed for in vitro assays to investigate the angiogenic function of cells. Oxygen-induced retinopathy (OIR) model was utilised to examine the effects of reducing pathological neovascularization (RNV) and inhibiting vascular occlusion in vivo. In vitro, tFNAs-miR22 demonstrated the ability to penetrate endothelial cells and effectively suppress cell proliferation, tube formation, and migration in a hypoxic environment. In vivo, tFNAs-miR22 exhibited promising results in reducing RNV and promoting the restoration of normal retinal blood vessels in OIR model through modulation of the Wnt pathway. This study provided a theoretical basis for the further understanding of RNV, and highlighted the innovative and potential of tFNAs-miR22 as a therapeutic option for ischemic retinal diseases.
2024-04-26 | Role of mRNA-binding proteins in retinal neovascularization.
Retinal neovascularization (RNV) is a pathological process that primarily occurs in diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion. It is a common yet debilitating clinical condition that culminates in blindness. Urgent efforts are required to explore more efficient and less limiting therapeutic strategies. Key RNA-binding proteins (RBPs), crucial for post-transcriptional regulation of gene expression by binding to RNAs, are closely correlated with RNV development. RBP-RNA interactions are altered during RNV. Here, we briefly review the characteristics and functions of RBPs, and the mechanism of RNV. Then, we present insights into the role of the regulatory network of RBPs in RNV. HuR, eIF4E, LIN28B, SRSF1, METTL3, YTHDF1, Gal-1, HIWI1, and ZFR accelerate RNV progression, whereas YTHDF2 and hnRNPA2B1 hinder it. The mechanisms elucidated in this review provide a reference to guide the design of therapeutic strategies to reverse abnormal processes.
2023-05-27 | BCL6B Contributes to Ocular Vascular Diseases via Notch Signal Silencing.
Endothelial cell activation is tightly controlled by the balance between VEGF (vascular endothelial cell growth factor) and Notch signaling pathway. VEGF destabilizes blood vessels and promotes neovascularization, which are common features of sight-threatening ocular vascular disorders. Here, we show that BCL6B (B-cell CLL/lymphoma 6 member B protein), also known as BAZF, ZBTB28, and ZNF62, plays a pivotal role in the development of retinal edema and neovascularization. The pathophysiological physiological role of BCL6B was investigated in cellular and animal models mimicking 2 pathological conditions: retinal vein occlusion and choroidal neovascularization. An in vitro experimental system was used in which human retinal microvascular endothelial cells were supplemented with VEGF. Choroidal neovascularization cynomolgus monkey model was generated to investigate the involvement of BCL6B in the pathogenesis. Mice lacking BCL6B or treated with BCL6B-targeting small-interfering ribose nucleic acid were examined for histological and molecular phenotypes. In retinal endothelial cells, the BCL6B expression level was increased by VEGF. BCL6B-deficient endothelial cells showed Notch signal activation and attenuated cord formation via blockage of the VEGF-VEGFR2 signaling pathway. Optical coherence tomography images showed that choroidal neovascularization lesions were decreased by BCL6B-targeting small-interfering ribose nucleic acid. Although BCL6B mRNA expression was significantly increased in the retina, BCL6B-targeting small-interfering ribose nucleic acid suppressed ocular edema in the neuroretina. The increase in proangiogenic cytokines and breakdown of the inner blood-retinal barrier were abrogated in BCL6B knockout (KO) mice via Notch transcriptional activation by CBF1 (C promotor-binding factor 1) and its activator, the NICD (notch intracellular domain). Immunostaining showed that Müller cell activation, a source of VEGF, was diminished in BCL6B-KO retinas. These data indicate that BCL6B may be a novel therapeutic target for ocular vascular diseases characterized by ocular neovascularization and edema.
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Drug Discovery Landscape
1 orphan drug designation for Central retinal vein occlusion.
1 orphan drug designation for Central retinal vein occlusion.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Aganirsen | oligonucleotides | EMA | Gene Signal SAS |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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