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.

Purpose Branch retinal vein occlusion (BRVO) is the second most common retinal vascular disorder. This study evaluates the real-world visual and anatomical outcomes of intravitreal aflibercept in BRVO, addressing the gap between clinical trials and daily practice, and aims to identify distinct response phenotypes that predict functional decline. Methods This retrospective analysis included 96 BRVO patients receiving aflibercept monotherapy over 12 months. Patients were stratified into three groups based on anatomical response: Resolved (sustained dry macula), Recurrent (fluid recurrence after initial resolution), and Persistent (incomplete resolution). The primary outcome was change in best-corrected visual acuity (BCVA). Results At 12 months, eyes were Resolved (52%), Recurrent (27%), or Persistent (21%). The Resolved group achieved the best visual outcomes (-0.29 logMAR; 95% CI, -0.38 to -0.20), whereas the Recurrent group showed the least improvement (-0.05 logMAR; 95% CI, -0.22 to 0.12; p=0.021 vs. Resolved). Despite achieving complete fluid resolution at month 3, this group experienced significant rebound by month 6. Total injections (p=0.808) and the distribution of treatment strategies did not differ among groups. Baseline BCVA (β=0.411, 95% CI: 0.202 to 0.619; p=0.001) and treat-and-extend (T&E) regimen (β=0.244, 95% CI: 0.033 to 0.454; p=0.025) significantly predicted visual improvement, whereas baseline central macular thickness (CMT) and systemic factors were not. Conclusion In a real-world setting, nearly half of BRVO patients exhibit unstable phenotypes. Despite comparable treatment intensity, cumulative damage from fluid fluctuations causes irreversible visual loss in the Recurrent group. This supports a stratified intervention strategy: evaluating month-3 response to establish strict T&E intervals or early treatment modifications, mitigating preventable vision loss.

Macular disease is the leading cause of vision loss in the United Kingdom, affecting nearly 1.5 million people. Vascular endothelial growth factor (VEGF) has a major role in the onset and progression of vision-threatening macular conditions such as neovascular age-related macular degeneration, diabetic macular oedema and retinal vein occlusion. Anti-VEGF treatments, given by intravitreal injection, can prevent vision loss and may improve vision but must be started quickly before sight loss is irreversible. Informed by an observational study using Hospital Episode Statistics and the Emergency Care Data Set in England and a Costed Integrated Patient Scenario, we identify issues within the current pathway in England. Our key recommendations to optimise care and improve patient outcomes include: (1) increasing public awareness of macular disease to reduce late presentation; (2) ensuring the right patients are seen in the right place at the right time by improving quality and priority of optometrist referrals and by specialists directing patients with conditions such as diabetes and hypertension to community optometrists in the first instance; (3) planning for current and future demand and capacity using innovative solutions to manage expected increases in medical retina conditions and (4) ensuring patient-centred care. Our evidence should encourage National Health Service organisations at all levels to review macular disease pathways to address immediate issues and plan for the future. A shift in care delivery is needed, embracing scalable sustainable solutions, earlier diagnosis and treatment, improved access to more durable therapies, wider adoption of digital technologies and care closer to home.

Vein occlusion (VO), including deep venous thrombosis (DVT) and retinal vein occlusion (RVO), is a common cause of multiple diseases that severely compromise the quality of life of affected individuals. Epidemiological evidence indicates that VO prevalence increases in cold seasons, yet the underlying mechanism remains unknown. Here, we show that cold exposure markedly elevates peripheral platelet counts, thereby aggravating VO in mouse models. Cold-augmented thrombocytopoiesis depends on the activation of adipose thermogenesis and subsequent increase in circulating free fatty acid (FFA) levels. Mechanistically, FFA-β-oxidation promotes acetyl-CoA production, which upregulates and stabilizes C/EBPα by shifting the balance between p300 acetyltransferase and SIRT1 deacetylase. Acetyl-C/EBPα transcriptionally upregulates GATA-1 and NF-E2 for megakaryocyte maturation and platelet production. Depletion of adipose triglyceride lipase PNPLA2, megakaryocyte-specific knockout of key β-oxidation enzyme CPT1α, or pharmacological inhibition of CPT1α and p300 abolishes cold-augmented thrombocytopoiesis and alleviates DVT and RVO in mouse models. In healthy volunteers, tolerable cold exposure activates adipose thermogenesis, increases circulating FFA levels, and increases platelet counts. Moreover, a retrospective cohort study of 425 patients reveals elevated platelet counts and higher DVT incidence during cold seasons. Similarly, increased platelet counts are observed in 448 patients with RVO at the time of diagnosis in cold seasons. Our study provides novel mechanistic insights into the increased VO risk induced by cold exposure and proposes a new therapeutic paradigm for VO by targeting megakaryocyte metabolism.