Lions Eye Institute

Abstract Voltage-gated (Kv) potassium channels are critical for neuronal physiology, and their dysfunction can lead to serious consequences. For example, mutations in the silent modulatory Kv8.2 subunit are known to cause irreversible inherited blindness ( KCNV2 retinopathy). This is a currently incurable condition that causes lifelong visual loss, reduced visual acuity, photoaversion, night blindness and abnormal colour vision, alongside a distinctive supernormal electrophysiological (ERG) retinal response to light. In this study, we demonstrate that AAV-mediated gene replacement therapy delivering a codon-optimised human KCNV2 gene subretinally into Kv8.2 knock-out mice significantly restores retinal function. Treated mice exhibited improved ERG responses and correct expression of KCNV2 and its encoded Kv8.2 protein in photoreceptors. Recovery of visually guided scotopic and photopic optomotor responses to wildtype levels was achieved at lower vector doses, highlighting dose-dependent efficacy. Furthermore, treatment of human retinal organoids derived from a KCNV2 patient iPSC line resulted in substantial Kv8.2 protein rescue. This work provides the first preclinical proof-of-concept for the safety and therapeutic potential of gene therapy for KCNV2 retinopathy, laying a strong foundation for future clinical trials.

Retinal degenerative diseases are a major cause of vision loss worldwide, with oxidative stress being a key pathological driver. This study aimed to develop and evaluate probucol-lithocholic acid (LCA) nanoparticles for targeted retinal protection. Nanoparticles were formulated via spray drying of a mixture containing probucol, low-viscosity sodium alginate, polyethylene glycol, and LCA, followed by detailed physicochemical characterization. In vitro studies using human retinal pigment epithelial (ARPE-19) cells exposed to oxidative (H₂O₂) and hyperglycaemic stress demonstrated that the probucol-LCA nanoparticles significantly improved cell viability, reduced reactive oxygen species (ROS), restored glutathione (GSH) levels, and enhanced mitochondrial bioenergetics compared with non-functionalized formulations. In vivo, a single intravitreal injection of the nanoparticles in wild-type and retinal degeneration 1 (rd1) mice confirmed their biocompatibility and safety, showing no adverse effects on retinal structure or function. These findings establish the probucol-LCA nanoparticle system as a safe and effective antioxidant platform for intravitreal delivery. Its demonstrated in vitro efficacy and favourable safety profile highlight its potential for translation into therapeutic interventions for oxidative stress related retinal diseases.

The Consortium for Refractive Error and Myopia (CREAM) was established in 2011, bringing together an international team of researchers studying more than 30 cohorts. Since its establishment, CREAM has played a pivotal role in research investigating the genetics of myopia and other refractive errors, serving as a key driver of progress in the field. The aim of this review is to highlight the latest advances and insights from CREAM, with a focus on research carried out in the past 5 years. We performed a literature review of journal articles authored by the CREAM consortium since the year 2020, when the last review of CREAM consortium findings was published. Key discoveries from recent CREAM studies were the identification of SIX6, CRX, PER3, PDCD6IP, MAPT, CHST6, GRHL2, USH2A, P4HTM, COL4A4 and ATM as high-confidence candidate genes associated with myopia development. Variants in enhancers and lncRNA regions were shown to have potential regulatory effects on refractive error; the DDIT4 gene was highlighted as a potential hotspot for future analyses. A polygenic risk score for predicting high myopia with an area under the curve (AUC) accuracy of 0.78 was made openly available; prediction accuracy was close to that required for clinical use. A shared genetic architecture for refractive error and axial length was confirmed. Novel findings were the identification of rare, large-effect gene variants through targeted and whole exome sequencing and the development of a polygenic risk score for predicting children at risk of developing high myopia. Large-scale multi-ancestry genome-wide association studies of the myopia endophenotypes axial length and corneal curvature doubled the number of common genetic variants known to be associated with these traits. Nevertheless, much remains to be done to fulfil the promise of myopia genetics research for improving the detection of children at above-average risk of high myopia, and the prevention and treatment of myopia.

Glaucoma surgery remains a cornerstone of care for patients with advanced disease or those uncontrolled on medications and laser [1] and [2]. Yet, despite decades of refinement, the major barrier to long-term success has not changed: postoperative conjunctival scarring [3, 4]. Whether in trabeculectomy or more recent minimally invasive bleb surgery (MIBS) procedures, the biological tendency of Tenon's fibroblasts to initiate and propagate fibrosis undermines surgical outcomes [5]. For all the ingenuity invested in new devices, the real battle continues to be fought in the microscopic wound-healing pathways of the conjunctiva. The burden of fibrosis is starkly illustrated in experimental models, particularly the rabbit eye, which is characterised by a highly aggressive scarring response. This exaggerated biology has often been seen as a limitation, yet it also creates a powerful platform for testing novel antifibrotic approaches under the most hostile conditions. A therapy that demonstrates efficacy in this setting may hold even greater potential in the more permissive environment of the human conjunctiva. Thus, advances in experimental wound modulation remain central to the future of surgical glaucoma care. Currently, mitomycin C (MMC) is the most widely used adjunct to control postoperative scarring [6]. Its use has undeniably improved the success of filtering procedures, but it comes at a price. MMC is a potent, nonspecific cytotoxic agent that can occassionally result in the formation of thin, avascular blebs prone to leakage and infection [7]. In this respect, MMC represents more of a blunt instrument than a tailored solution. The search for safer, more selective wound-modulating strategies has therefore become one of the most important unmet needs in glaucoma surgery. Potential targets include oxidative stress, inflammation, angiogenesis, and fibroblast activation, all of which contribute to the cascade of conjunctival fibrosis. In this issue, the study “Inhibitory Effects of 3’,4’-Dihydroxyflavonol in a Rabbit Model of Minimally Invasive Glaucoma Surgery with PreserFlo MicroShunt” adds important new insights [8]. The authors evaluated the antioxidant flavonoid 3′,4′-dihydroxyflavonol (DiOHF) in a rabbit model of bleb-forming MIBS. Animals were randomised to receive topical vehicle, topical DiOHF, or intraoperative MMC. Remarkably, daily topical DiOHF inhibited postoperative fibrosis by reducing collagen accumulation, angiogenesis, inflammation, and fibroblast expression in the bleb. This antifibrotic effect was accompanied by restoration of redox balance, as demonstrated by reduced staining for the oxidative stress biomarker 3-nitrotyrosine. Importantly, blebs treated with DiOHF were smaller and less ischaemic than those exposed to MMC, suggesting healthier long-term tissue architecture. These findings not only strengthen the evidence that oxidative stress is a central driver of conjunctival fibrosis but also identify DiOHF as a potential candidate for clinical translation. By providing a safer, more targeted method of modulating wound healing, such approaches could shift the paradigm away from reliance on nonspecific cytotoxins like MMC. Another emerging approach is modulation of lymphangiogenesis [9]. In a similar rabbit trabeculectomy model, subconjunctival VEGF-C promoted lymphatic vessel growth, reduced fibrosis and inflammation, and lowered IOP compared with controls. Unlike the thin avascular blebs seen with MMC, VEGF-C encouraged more physiological remodelling by enhancing fluid drainage and potentially increasing the function of the bleb—highlighting the potential of harnessing, rather than suppressing, wound-healing pathways. Direct translation of these findings is challenging, as rabbits are not primates; while they share similar conjunctival volume, they tend to scar more aggressively than human eyes. Still, the demanding rabbit model provides strong proof-of-concept [4, 10]. Complementing these recent innovations, Yu-Wai-Man and colleagues performed the first genome-wide RNA sequencing analysis of human conjunctival fibrosis after glaucoma surgery, identifying a distinct gene signature that could differentiate fibrotic from non-fibrotic conjunctival cell lines [11]. Validated by quantitative PCR and with more than 200 genes dysregulated, these findings create a molecular roadmap for novel antifibrotic therapies, potentially moving the field beyond empirical use of cytotoxics and towards rational drug development. In this light, the future of glaucoma surgery may lie less in hardware innovation and more in biological modulation. Recent laboratory research highlights multiple promising directions and the development of targeted antifibrotic therapies—whether antioxidants, cytokine blockers, or fibroblast-specific inhibitors—has the potential to transform surgical outcomes. Safer alternatives to MMC are urgently needed, and the work presented here highlights a promising pathway [12, 13]. With continued investment in translational science and careful clinical testing, agents such as DiOHF may help realise the true potential of trabeculectomy surgery and other minimally invasive filtering procedures. In conclusion, the high failure rates of glaucoma surgery reflect a persistent challenge: the conjunctiva's innate tendency to scar. While devices continue to evolve, it is our ability to modulate wound healing that will ultimately determine surgical success. Studies such as these underscore that the future of glaucoma surgery is not only about engineering new stents or shunts but also about engineering the wound-healing response. The author declares no conflicts of interest.

Both age-related macular degeneration (AMD) and inherited retinal disease (IRD) can present with outer retinal atrophy at the macula. Distinguishing between IRD and geographic atrophy (GA) secondary to AMD is important for appropriate management, particularly as disease-specific treatments become available. This study investigates the utility of genetic testing for suspected IRDs in individuals with atypical macular atrophy. Twenty-four participants aged over 50, presenting with macular atrophy atypical for AMD, underwent clinical assessments, multimodal retinal imaging and exome-based sequencing covering known IRD genes. Three retinal ophthalmologists reviewed genetic and clinical data to reach a consensus for the underlying cause of macular atrophy and identified a set of features that challenge an AMD diagnosis and suggest a higher likelihood of an IRD. The panel judged 58% of atypical atrophy cases as likely being an IRD. Of these suspected cases, 57% (33% of the entire cohort) received IRD genetic confirmation (PRPH2, ABCA4 or MT-TL1 [m.3243A>G]-related IRD). The remaining cases were classified as GA (29%) or did not reach consensus on the likely diagnosis (13%). Clinical features aiding in the differentiation of IRD from GA included symptom onset before age 50, family history, distinctive autofluorescence patterns (speckled, reticular or widespread), extensive atrophy and absence of subretinal drusen. IRD genetic testing is valuable if a positive identification is achieved, but negative results neither rule out IRD nor confirm AMD. Limitations in our ability to robustly differentiate IRD-related atrophy from GA, especially in advanced lesions, need further research to improve diagnostic accuracy.

ABSTRACTBackgroundEye injuries are a significant cause of monocular blindness, contributing to individual morbidity and substantial healthcare costs. Despite this burden, eye injury prevention remains underrepresented in Australian public health initiatives. This systematic review (PROSPERO ID: CRD42024551054) aims to provide the first comprehensive nationwide synthesis of eye injury epidemiology in Australia.MethodsThree databases (MEDLINE, Embase, Web of Science) were searched to identify Australian studies on eye injuries from 1 January 2000 to 1 May 2024. Studies were excluded per the following criteria: not in English; did not exclusively evaluate eye injury (e.g., evaluated all causes of blindness); only evaluated outcomes after injury; sample size < 25; conference abstracts, editorials, letters to the editor/other review articles. Critical appraisals of included texts were performed using the Joanna Briggs Institute Checklist for Analytical Cross‐Sectional Studies. Results were synthesised using the International Globe and Adnexal Trauma Epidemiology Study (IGATES) as a framework.ResultsIn total, 30 studies were included, ranging from statewide audits to nationwide surveys. Eye injuries were commonest among young males in occupational settings and older adults experiencing falls at home. Paediatric eye injuries frequently occurred during sport or at home. Rural Australians and First Nations women were disproportionately affected by assault‐related injuries, including domestic violence.ConclusionsThis review highlights key demographic and contextual risk factors for eye injury in Australia and establishes a robust evidence base to inform targeted, data‐driven national prevention strategies. The main limitation of this review is the heterogeneity of included studies, which emphasises the importance of using international, standardised registries such as IGATES.

Purpose: To determine the long-term functional and structural outcomes of intravitreal anti-VEGF therapy for macular neovascularization (MNV) in PRPH2-associated retinopathy. Methods: Multicenter retrospective case series including patients with molecularly confirmed PRPH2-associated retinopathy complicated by unilateral MNV. Best-corrected visual acuity (BCVA) and central subfield thickness (CST) were selected as outcome measures and compared between eyes with MNV undergoing anti-VEGF therapy and fellow eyes. Results: Six patients affected by PRPH2-associated retinopathy developed MNV at a median age of 55 years (range, 34 to 71). Two novel PRPH2 variants were found [c.499del p.(Cys150Phefs*3) and c.660dup p.(Pro221Alafs*80)]. In all patients, the phenotype was characterized by a pattern dystrophy with multifocal flecks. At baseline, eyes with MNV had a median BCVA (logMAR) of 0.2 (range, 0.2 to 0.7), corresponding to 20/32 Snellen, while the median CST was 320 µm (range, 228 to 362). After a median follow-up of 6.2 years and 5.5 injections per patient, 5 eyes (83%) retained a BCVA of at least 20/32 Snellen, while CST decreased by a median of −69 µm (range, −117 to +15). No additional CST thinning was observed in eyes with MNV compared with their fellow eyes. In 4 eyes (67%), OCT angiography revealed large neovascular networks growing below the retinal pigment epithelium that persisted after resolution of exudation. Conclusion: A favorable long-term outcome can be obtained in PRPH2-associated retinopathy complicated by MNV when timely intravitreal anti-VEGF therapy is administered. Further research is needed to understand the significance of subretinal pigment epithelium neovascular networks.

Natural killer (NK) cell homeostasis and effector functions require context-dependent signaling via numerous receptors, including the interleukin-15 receptor (IL-15R). Post-translational modifications can regulate receptor signaling, impacting receptor turnover and trafficking. Core fucosylation is one such modification known to impact receptor expression and is uniquely mediated by fucosyltransferase 8 (FUT8). We identified FUT8 as an essential gene required for IL-15R responsiveness in a human NK cell genome-wide CRISPR screen. To further validate core fucosylation in IL-15R signaling and NK cell biology, mice lacking Fut8 in NK cells (Fut8fl/flNcr1cre/+) were generated. The loss of core fucose in murine NK cells resulted in severe NK cell lymphopenia, with a reduction in IL-15Rβ (IL-2RB/CD122) expression, impairing in vivo homeostatic proliferation. The loss of FUT8 also decreased NK cell cytotoxicity, tumor immunity, and early viral immunity. Taking these results together, we have identified FUT8 as a key modulator of NK cell biology by regulating their development, IL-15R expression, and signaling.

Inherited retinal diseases (IRDs) are a diverse group of genetic disorders that lead to progressive vision loss and are a major cause of blindness in working-age adults. The complexity and heterogeneity of IRDs pose significant challenges in diagnosis, prognosis, and management. Recent advancements in artificial intelligence (AI) offer promising solutions to these challenges. However, the rapid development of AI techniques and their varied applications have led to fragmented knowledge in this field. This review consolidates existing studies, identifies gaps, and provides an overview of AI's potential in diagnosing and managing IRDs. It aims to structure pathways for advancing clinical applications by exploring AI techniques like machine learning and deep learning, particularly in disease detection, progression prediction, and personalized treatment planning. Additionally, the integration of explainable AI is discussed, emphasizing its importance in clinical settings to improve transparency and trust in AI-based systems. The review addresses the need to bridge existing gaps in focused studies on AI's role in IRDs, offering a structured analysis of current AI techniques and outlining future research directions. It concludes with an overview of the challenges and opportunities in deploying AI for IRDs, highlighting the need for interdisciplinary collaboration and the continuous development of robust, interpretable AI models to advance clinical applications.