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Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50 000, 100 000, and 150 000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration). There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16–25 points 3–12 months after transplantation in patients with atrophic age-related macular degeneration and 8–20 points in patients with Stargardt's macular dystrophy. The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. Advanced Cell Technology.

BackgroundTo assess the anatomical and functional outcomes in eyes with persistent diabetic macular oedema (pDME) on chronic anti-vascular endothelial growth factor therapy switched to intravitreal faricimab.MethodsPatients with pDME on chronic anti-vascular endothelial growth factor therapy that were switched to faricimab and received at least three injections at our institution between April 2022 and May 2023 were included in this study. Patients were excluded if they had complete response to previous treatment but were switched to extend treatment intervals if they had steroid or laser treatment for DME within 6 months prior to switch. Clinical and imaging data were extracted from the electronic medical record. Central foveal thickness (CFT) and Snellen visual acuity (VA) were obtained before and after three intravitreal faricimab injections. Generalised estimating equations were used to analyse the change in CFT and VA.ResultDuring the study period, 69 eyes of 53 patients met inclusion criteria. The mean age was 68.6±9.0 years. The mean number of injections prior to switch was 18.1±16.0. Pre-switch mean logarithm of the minimal angle of resolution VA was 0.40±0.30 (Snellen equivalent 20/50) and 0.38±0.27 (Snellen equivalent 20/48) after three faricimab injections (p=0.397). Mean CFT improved from 380±155 microns to 323±147 microns (p<0.001). No ophthalmic or systemic adverse events occurred during the study period.ConclusionsIntravitreal faricimab can improve anatomic outcomes while maintaining visual acuity in eyes with pDME previously treated with anti-VEGF therapy.

To investigate potential biomarkers and biological processes associated with diabetic retinopathy (DR) using transcriptomic and proteomic data. The OmicsPred PheWAS application was interrogated to identify genes and proteins associated with DR and diabetes mellitus (DM) at a false discovery rate (FDR)-adjusted p-value of <0.05 and also <0.005. Gene Ontology PANTHER analysis and STRING database analysis were conducted to explore the biological processes and protein interactions related to the identified biomarkers. The interrogation identified 49 genes and 22 proteins associated with DR and/or DM; these were divided into those uniquely associated with diabetic retinopathy, uniquely associated with diabetes mellitus, and the ones seen in both conditions. The Gene Ontology PANTHER and STRING database analyses highlighted associations of several genes and proteins associated with diabetic retinopathy with adaptive immune response, valyl-TRNA aminoacylation, complement activation, and immune system processes. Our analyses highlight potential transcriptomic and proteomic biomarkers for DR and emphasize the association of known aspects of immune response, the complement system, advanced glycosylation end-product formation, and specific receptor and mitochondrial function with DR pathophysiology. These findings may suggest pathways for future research into novel diagnostic and therapeutic strategies for DR.

Correspondence to Ashish Sharma, Lotus Eye Hospital and Institute, Avinashi Road, Civil Aerodrome Post, Peelamedu, Coimbatore, Tamil Nadu 641014, India; drashish79@hotmail.com The management and outcome of retinal disorders was revolutionised with the advent of ocular anti-vascular endothelial growth factor (VEGF) therapies including US Food and Drug Administration (FDA)-approved ranibizumab (Lucentis; Genentech, South San Francisco, CA, USA) and aflibercept (Eylea; Regeneron, Tarrytown, NY, USA) and off-label bevacizumab (Avastin; Genentech). 1 The real-world studies though have highlighted a few restrictions to the approved regimens, primarily the required monthly injections and follow-up visits. 2 Multiple treatment regimens have been introduced in recent years to reduce the frequency of anti-VEGF agent dosing while attempting to maintain efficacy comparable to monthly or bimonthly fixed treatment protocols by individualising therapy. Based on the clinical trial data from HAWK and HARRIER, brolucizumab demonstrated superior anatomic results with greater fluid resolution and similar best-corrected visual acuity compared to aflibercept with the possibility to extend the dosing regimen to q12-week intervals potentially reducing treatment burden. 4 Brolucizumab is the first humanised single-chain antibody fragment to be approved for therapeutic use across the field of medicine. Earlier trials such as Comparision of Age-Related Macular Degeneration Treatment Trials (CATT) and Efficacy and Safety of Ranibizumab in Subjects with Subfoveal and CNV secondary to AMD (EXCITE) have demonstrated that the presence of IRF is an indicator of a later decline in visual acuity. 8 The better control of IRF with brolucizumab might have contributed to the >50% proportion of patients maintaining q12w dosing through 1 year of follow-up. 4 The FDA has approved a q8/q12 dosing schedule for the molecule after three monthly loading doses.

PurposeTo evaluate the association between subfoveal choroidal thickness (SFCT) and branch retinal vein occlusion (BRVO) eyes treated with antivascular endothelial growth factor (anti-VEGF) therapy.MethodsRetrospective cohort study of treatment naïve BRVO eyes treated with 3 monthly anti-VEGF injections. All patients received enhanced depth imaging spectral-domain optical coherence tomography scans to determine SFCT and central macular thickness (CMT). Baseline predictors (particularly SFCT) for functional response (best-corrected visual acuity (BCVA) gain ≥2 lines) were assessed at 3 months using univariate and multivariate analyses.ResultsForty eyes from 39 patients were included. Mean baseline SFCT was higher in functional responders (240.4±73.1 µm), compared with both non-responders (193.3±63.6 µm; p=0.036) and their corresponding fellow eye (202.2±67.1 µm; p=0.022). A higher baseline SFCT (for every 100 µm increase in SFCT) was found to be a positive predictor for functional response (regression coefficient: 1.1; p=0.03) on univariate analysis but not multivariate analysis. A worse baseline BCVA (for every 0.1 logMAR increase) was a positive predictor for visual improvement with an adjusted OR of 1.30 (95% CI 1.03 to 1.63; p=0.0009) on multivariate analysis.ConclusionsPatients with BRVO with a worse initial BCVA are most likely to achieve visual improvement following anti-VEGF therapy. Additionally, baseline SFCT may also help predict which patients with BRVO have favourable visual outcomes. Patients with an initial choroidal thickness thicker than their fellow eye are more likely to have short-term visual improvement following treatment.

The last decade has seen a paradigm shift in the management of neovascular age-related macular degeneration (nAMD) with the introduction of biologicals that inhibit vascular endothelial growth factor (VEGF). These agents, similar to biologicals have imposed a major burden on all healthcare systems. Patients are not only financially strained by the cost of intravitreal injections that require repeated administrations but multiple visits to the hospital compromise quality of life. The recognition of this burden has to some extent led to a shift in the dosing strategy from fixed monthly (of ranibizumab) or 8-weekly dosing (of aflibercept) to pro-re-nata and treat-and-extend (T&E) protocols. 1 After the three initial loading doses, re-injection decisions are made based on the presence of fluid on optical coherence tomography (OCT). The OCT is a tool that demonstrates structural changes in the macular retina arising from leakage in the nAMD lesion or occurring as part of the sequelae of chronicity of the pathology. Leakage of fluid and blood constituents representing lesion activity is interpreted by detecting signs (biomarkers) seen on OCT. The presence of clear hypo-reflective regions within the intraretinal layers is considered to represent fluid accumulation. Depending on the location of these regions of hypo-reflectivity, they can be compartmentalised into intraretinal fluid (IRF), subretinal fluid (SRF) and subretinal pigment epithelial fluid.

Newly approved treatments for patients with geographic atrophy are changing the treatment paradigm, highlighting the need for eye care providers (ECPs) to have a set of recommendations on how to best manage GA patients. Here, we outline how to identify various stages of age-related macular degeneration including geographic atrophy (GA) by examining optimal management scenarios implicating various ECPs and reviewing treatment considerations for patients with GA. Early identification of GA will lead to optimal patient outcomes, while a standardized management scenario will reduce clinical burden among ECPs treating patients with GA.

Neovascular age-related macular degeneration (nAMD) leads to irreversible central vision loss if untreated. Frequent administration of anti-vascular endothelial growth factor (anti-VEGF) injections inhibits disease activity with excellent functional and morphological benefits. However, these injections pose a heavy therapeutic burden, and treatment discontinuation is common. Although current anti-VEGF treatment paradigms, such as treat-and-extend, mitigate treatment burden while still leading to acceptable vision outcomes, they fail to sustain initial vision gains for many. Novel longer-acting anti-VEGF therapies may reduce the overall burden on nAMD patients. Gene therapy might offer a paradigm shift by providing continuous expression of anti-VEGF, potentially decreasing treatment requirements and improving long-term vision outcomes. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:654–659.]