2026-08-14 | Development of an antisense oligonucleotide targeting EFEMP1 in models relevant to macular degeneration.
Antisense oligonucleotides (ASOs) are RNA-targeting therapeutics with broad potential for genetically defined and complex ocular diseases. The eye is particularly well suited for ASO delivery because of its compartmentalized anatomy, accessibility, and capacity for sustained intraocular drug retention. Autosomal dominant drusen (ADD), an inherited retinal dystrophy characterized by early drusen formation and secondary choroidal neovascularization (CNV), is caused by the EFEMP1 R345W mutation. Mutant EFEMP1 accumulates within the retinal pigment epithelium (RPE) and extracellular matrix, contributing to disease pathology. EFEMP1 is also elevated in the serum and RPE/choroid of patients with age-related macular degeneration (AMD), although its functional role in AMD remains incompletely defined. Here, we developed a biallelic EFEMP1-targeted ASO that achieved potent knockdown and modulated disease-relevant pathways in iPSC-derived RPE, human microvascular retinal endothelial cells (HMRECs), ex vivo human choroidal explants, and in vivo mouse models. EFEMP1 protein levels were increased in AMD tissue, and ASO-mediated EFEMP1 knockdown reduced complement factor 3 (C3), suppressed HMREC proliferation and migration, and inhibited angiogenic sprouting in choroidal explants. These findings support EFEMP1 as a pathogenic regulator of retinal degeneration and vascular dysfunction and establish EFEMP1-directed ASOs as a promising therapeutic strategy for ADD and AMD.
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2026-08-12 | From food to function: Nutraceutical-based modulation of mitochondrial, inflammatory and epigenetic networks in retinal neurodegeneration.
Retinal neurodegenerative diseases, such as age-related macular degeneration, diabetic retinopathy, glaucoma, and inherited retinal dystrophies, are major causes of irreversible vision loss worldwide. Although they originate from different causes, these disorders increasingly appear to share a network of cellular stress pathways, including impaired mitochondrial function, oxidative stress, endoplasmic reticulum proteostasis collapse, chronic neuroinflammation, epigenetic dysregulation, and activation of regulated cell death pathways. The interactions among these processes create an integrated stress network that gradually disrupts retinal homeostasis and promotes neuronal degeneration, which explains the failure of therapies targeting single molecular pathways. Nutraceutical compounds found in food are gaining interest as potential agents to support retinal health because many exhibit pleiotropic biological activities that influence mitochondrial function, inflammatory signaling, antioxidant defenses, and transcriptional regulation. Herein, we consolidate knowledge of the molecular mechanisms underlying retinal neurodegeneration and how major classes of nutraceuticals (polyphenols, carotenoids, omega-3 fatty acids, and metabolic modulators) may interact with these pathways. We also discuss key translational challenges in developing therapies, including poor bioavailability and differences between human phenotypes and model systems. Additionally, we highlight emerging concepts such as microbiome-dependent metabolism of nutraceuticals, personalized nutrition strategies, and advanced ocular drug-delivery technologies. Collectively, these findings support a systems-level framework in which selected nutraceuticals may influence multiple nodes of retinal stress biology, although clinical validation remains limited.
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2026-08-11 | Efficacy and safety of AAV RPGR gene therapy in X-linked retinitis pigmentosa: a systematic review and meta-analysis.
X-linked retinitis pigmentosa (XLRP) represents a severe inherited retinal dystrophy associated with pathogenic variants in the retinitis pigmentosa GTPase regulator (RPGR) gene. Adeno-associated virus (AAV)-mediated RPGR gene augmentation is designed to preserve photoreceptor structure and function. The purpose of this study was to critically appraise and quantitatively synthesize the efficacy and safety evidence for AAV-RPGR gene therapy in X-linked retinitis pigmentosa. Scopus, PubMed, the Cochrane Library, ScienceDirect, and Google Scholar were searched from inception through July 11, 2026. Two reviewers independently screened records, two reviewers assessed risk of bias, and extracted data were verified by a second reviewer. Proportions were synthesized using inverse-variance fixed-effect logit models with a 0.5 continuity correction for zero or all-event cells; DerSimonian-Laird random-effects models were used as sensitivity analyses. Cohort linkage, dose-stratified safety, and overlap-adjusted analyses were performed. The search identified 571 records and included 12 clinical reports. Pooled retinal sensitivity improvement was 73.8% (95% confidence interval, 56.0%-86.1%; 25/33 participants), and pooled visual function improvement was 52.3% (95% confidence interval, 38.0%-66.2%; 28/52 participants). The pooled adverse-event proportion was 42.6% (95% confidence interval, 27.2%-59.5%; 42/90 participants), intraocular inflammation was 45.5% (95% confidence interval, 34.6%-56.8%; 36/81 participants), and intraocular-pressure elevation was 34.9% (95% confidence interval, 24.2%-47.4%; 22/63 participants). Product-specific dose analyses showed greater inflammatory or ocular serious adverse-event frequencies at higher vector exposure. AAV-RPGR gene therapy demonstrates clinically relevant functional signals across multiple outcome domains with a structured and monitorable ocular safety profile. Cohort-linked synthesis, dose-specific interpretation, standardized outcome definitions, and long-term multinational follow-up provide a rigorous framework for subsequent clinical development.
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2026-08-10 | Defining a Novel RPGR Phenotype of Sector Retinitis Pigmentosa With Cone Dystrophy.
RPGRORF15-associated retinal degeneration is characterized by clinical and genetic heterogeneity: Proximal mutations typically result in rod-cone dystrophy, distal mutations in cone-dominated disease, and mutations within open-reading frame 15 (ORF15) in either phenotype. This study characterizes an intermediate phenotype in which patients exhibit a combination of cone dystrophy and incomplete (sectoral) rod-cone dystrophy associated with mutations in the ORF15 region and explores potential mechanistic explanations. A multinational, multicenter, observational, cross-sectional case series was conducted using databases from RPGR-related retinal dystrophy clinical trial referral centers. Patients with molecularly confirmed RPGR-related cone dystrophy or RPGR-related cone-rod dystrophy were studied. Individuals exhibiting a mixed phenotype of cone dystrophy and sectoral retinitis pigmentosa were identified. In silico analyses assessed the impact of identified mutations on RPGR transcript expression and protein structure. Fourteen patients exhibited a cone dystrophy phenotype with bilateral, symmetrical regions of outer retinal atrophy distributed along the inferior vascular arcades and extending nasally. All harbored ORF15 mutations within a defined transitional zone. All of the mutations were predicted to produce truncated proteins with partial or complete loss of function. Additionally, several were predicted to disrupt splicing regulatory elements. An intermediate phenotype consisting of a cone dystrophy with sectoral retinitis pigmentosa development was characterized. These patients may benefit from full-length RPGR gene therapy. Furthermore, we demonstrate that this rare presentation closely resembles the phenotype observed in some patients with loss-of-function TTLL5-associated cone dystrophy with sectoral involvement.
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2026-08-09 | Single-cell spatial transcriptomics reveals rewiring of RPE and Müller glia signaling toward photoreceptors following outer segment disruption in Prph2C213Y mice.
PRPH2 mutations cause inherited retinal dystrophies (IRDs), but how photoreceptor outer segment (OS) disruption reshapes the surrounding retina remains unclear. Using a heterozygous Prph2C213Y/+ mouse model generated by CRISPR/Cas9, we characterized age-related retinal pathology and responses of retinal pigment epithelium (RPE) and Müller glia. Independent age- and sex-matched cohorts were examined at 1, 3, and 6 months by electroretinography, optical coherence tomography, and fundus autofluorescence. Mutant mice showed rod dysfunction from 1 month, RPE dysfunction from 3 months, and cone dysfunction by 6 months, accompanied by progressive outer retinal thinning and hyperautofluorescent deposits. Histological and ultrastructural analyses revealed OS disorganization, shortened RPE microvilli, RPE monolayer remodeling, increased RPE autofluorescence, and reactive Müller gliosis. Single-cell spatial transcriptomics of wild-type and mutant retinas at 6 months resolved nine cell populations and identified RPE cells and Müller glia as prominently perturbed non-photoreceptor populations. RPE cells showed an epithelial-mesenchymal transition-related remodeling state linked to a candidate Nfib-Fstl1 module, whereas Müller glia showed activation of activator protein 1 (AP-1) regulons, including Fos, Fosl2, and Junb, with predicted targets Osmr, A2m, and Stat3. Cell-cell communication analyses indicated coordinated changes in neuroprotective, inflammatory, and matrix-related signaling from RPE cells and Müller glia toward photoreceptors. These findings indicate that PRPH2-associated retinal dystrophy is a multicellular process in which OS disruption drives coordinated RPE and Müller glial remodeling with potentially protective or pro-degenerative effects, and nominate the RPE Nfib-Fstl1 program, Müller glial AP-1 responses with predicted STAT3 involvement, and support-cell-derived growth factor signaling as candidate mutation-independent therapeutic targets.
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