Search Results (92)

11-cis-retinal, the indispensable chromophore of photoreceptor opsins, is fundamental for light detection and the initiation of visual signal transduction. Its synthesis and regeneration through the visual cycle are critical not only for phototransduction but also for maintaining retinal homeostasis. Disruption of key enzymes, such as retinal pigment epithelium (RPE)65 and retinol dehydrogenases, results in toxic retinoid accumulation, oxidative stress, and progressive photoreceptor degeneration. These pathological mechanisms contribute to inherited and acquired retinal diseases, including Stargardt disease type 1, age-related macular degeneration, Leber congenital amaurosis, retinitis pigmentosa, and fundus albipunctatus. Recent therapeutic advances, ranging from gene replacement therapy with RPE65 (voretigene neparvovec, Luxturna^®) to small-molecule modulators and antioxidant strategies, underscore the translational potential of targeting chromophore metabolism. This review outlines molecular processes underlying chromophore synthesis and regeneration, elucidates how disruptions in these processes contribute to inherited and acquired retinal pathologies, and evaluates existing and emerging therapeutic strategies that target chromophore metabolism. We highlight ongoing challenges and critical knowledge gaps to guide future investigations on basic science, translational research, and clinical practice. This review provides a comprehensive overview of the molecular mechanisms, current therapeutic approaches, and outstanding challenges, with a focus on future intervention directions. Full article

Stargardt disease (STGD1), the most common inherited juvenile macular degeneration, is caused by biallelic mutations in the ABCA4 gene. Currently, there is no approved treatment. In this study, we investigated early-stage epigenomic changes in the retinal pigment epithelium (RPE) of Abca4^-/- mice, a well-established model of STGD1. Reduced representation bisulfite sequencing (RRBS) revealed hypermethylation of gene regions associated with disease-related pathways, implicating methyl-CpG-binding protein 2 (MeCP2) and RE1-silencing transcription factor (REST) as potential regulators. Notably, DNA methylation of a subset of genes preceded their transcriptional change and disease phenotypes in Abca4^-/- RPE. Together with the detected age-dependent increase in MeCP2 levels in Abca4^-/- RPE, these findings suggest that early DNA methylation changes may contribute to RPE dysfunction and eventual cell loss in STGD1. Full article

Inherited retinal dystrophies (IRDs) represent a diverse group of disorders caused by mutations in genes essential for retinal function and maintenance. Traditional bulk RNA sequencing techniques provide valuable information for deciphering disease pathogenesis but lack the resolution to capture variation among specific cell clusters during disease progression. In contrast, single-cell transcriptomics, including single-cell RNA sequencing (scRNA-seq), enables detailed examination of distinct retinal clusters in both healthy and diseased states, uncovering unique gene expression signatures and early molecular changes preceding photoreceptor cell death in IRDs. These insights not only deepen our understanding of the complex pathogenesis of IRDs but also highlight potential targets for novel therapeutic interventions. In this review, we examine the recent literature on the application of single-cell transcriptomics in IRDs to explore how these techniques enhance our understanding of disease mechanisms and contribute to the identification of new therapeutic targets. Full article

Purpose: To investigate genotype–phenotype correlations in PRPH2-retinopathies in a cohort of 36 patients from the Oxford Eye Hospital and report on novel pathogenic variants. Methods: Clinical data, including best corrected visual acuities (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) imaging, were analysed. Genetic testing was performed using next-generation sequencing (NGS). Results: In this cohort, 26 different PRPH2 variants, including 8 novel variants, were identified. Variants were clustered in the D2 loop of the protein. A diverse range of phenotypes were observed: pseudo-Stargardt pattern dystrophy (PSPD) (47.2%), adult-onset vitelliform macular dystrophy (AVMD) (22.2%), pattern dystrophy (PD) (25.0%), atypical macular dystrophy (2.8%), and retinitis pigmentosa (RP) (2.8%). The mean age of symptom onset was 44.0 ± 14.4 years. Mean BCVA was 0.20 ± 0.54 logMAR OD and 0.14 ± 0.29 logMAR OS at baseline and 0.33 ± 0.40 logMAR OD and 0.32 ± 0.40 logMAR OS after a mean follow up duration of 6.0 ± 3.2 years (range 1–11 years). A thickened ellipsoid zone (EZ) was noted in 34/36 patients with a mean EZ thickness of 44.3 ± 11.3 µm OD and 42.7 ± 11.6 µm OS. No clear genotype–phenotype correlations were observed. Conclusions: The significant phenotypic range described in this study is consistent with the previously reported phenotypic variability in PRPH2 retinopathy and emphasises the complexity of establishing genotype–phenotype correlations in this disease. The thickness of the EZ on OCT may serve as a useful biomarker in distinguishing PRPH2 retinopathy from other phenocopies. These findings contribute to improved understanding of PRPH2 retinopathy and help inform diagnosis and genetic counselling. Full article

Replacement of the retinal pigment epithelium (RPE) is emerging as a promising approach to treat degenerative retinal diseases, including age-related macular degeneration and Stargardt disease, in which RPE function cannot otherwise be restored. Despite the limitations of existing treatments, advances in cell sourcing and surgical methods have enabled initial human trials of RPE transplantation, with early results indicating potential efficacy. This review comprehensively examines the evolution of RPE transplantation in recent decades, highlighting the advantages and limitations of different cell sources and delivery methods. Current clinical trial data are analyzed with a particular focus on immune rejection risks, surgical complications, and long-term safety. Despite encouraging safety profiles, achieving consistent and sustained visual improvement remains a challenge, as vision outcomes might be influenced by factors such as disease stage at intervention, transplantation site, number of cells transplanted, and duration of follow-up. Key challenges, such as cell or graft survival and integration with the host retina, are discussed in depth, as overcoming these obstacles is essential for achieving stable and effective RPE replacement. Future research directions, including innovations in biomaterials, molecular modification strategies, and personalized approaches, hold promise for enhancing the efficacy and durability of RPE transplantation for retinal disease. Full article

Background/Objectives: To quantitatively assess lateral geniculate nucleus (LGN) volume using 7 Tesla MRI in patients with Stargardt disease (STGD). Methods: A total of 18 patients with STGD and 15 healthy volunteers were examined with a 7 Tesla MRI of the brain. Measures of LGN volume were performed manually by three independent investigators (radiologists) using ITK-SNAP software, version 4.0.0-rc.2. The volume of the thalamus was evaluated using the open-source automated software package FreeSurfer. Before 7 Tesla MRI, patients underwent ophthalmic examination and 1.5 Tesla MRI. Results: The average LGN volume in both hemispheres was significantly smaller in patients with STGD (right, −111.2 mm³; left, 107.4 mm³) than in the control group (right, −128.7 mm³; left, 123.6 mm³, respectively) (p < 0.0001). The ratio of LGN to thalamus in the right hemisphere was significantly lower (p = 0.024) in the group of patients with STGD (0.014) than in the control group (0.017). Conclusions: The right and left LGN volumes in MR 7T imaging, as well as the right LGN/thalamus ratio, were reduced in patients with STGD compared to controls. 7T MRI using the 3D MT-weighted SILENT protocol provides new insight into structural changes in the brain in retinal dystrophies and offers a possible marker of the response to future therapies in STGD. Full article

The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller glial cells, which are essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by the upregulation of the glial fibrillary acidic protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood–retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD). Extracellular vesicles (EVs) play a crucial role in intercellular communication, protein homeostasis, and immune modulation, and have emerged as promising diagnostic and therapeutic tools. Understanding the role of extracellular vesicles’ (EVs’) signaling machinery of glial cells and the retinal pigment epithelium (RPE) is critical for developing effective treatments for retinal degeneration. In this study, we investigated the bidirectional EV-mediated crosstalk between RPE and Müller cells under hypoxic conditions and its impact on cellular metabolism and retinal cell integrity. Our findings demonstrate that RPE-derived extracellular vesicles (RPE EVs) induce time-dependent metabolic reprogramming in Müller cells. Short-term exposure (24 h) promotes pathways supporting neurotransmitter cycling, calcium and mineral absorption, and glutamate metabolism, while prolonged exposure (72 h) shifts Müller cell metabolism toward enhanced mitochondrial function and ATP production. Conversely, Müller cell-derived EVs under hypoxia influenced RPE metabolic pathways, enhancing fatty acid metabolism, intracellular vesicular trafficking, and the biosynthesis of mitochondrial co-factors such as ubiquinone. Proteomic analysis revealed significant modulation of key regulatory proteins. In Müller cells, hypoxic RPE-EV exposure led to reduced expression of Dyskerin Pseudouridine Synthase 1 (DKc1), Eukaryotic Translation Termination Factor 1 (ETF1), and Protein Ser/Thr phosphatases (PPP2R1B), suggesting alterations in RNA processing, translational fidelity, and signaling. RPE cells exposed to hypoxic Müller cell EVs exhibited elevated Ribosome-binding protein 1 (RRBP1), RAC1/2, and Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 (GNAI1), supporting enhanced endoplasmic reticulum (ER) function and cytoskeletal remodeling. Functional assays also revealed the compromised barrier integrity of the outer blood–retinal barrier (oBRB) under hypoxic co-culture conditions. These results underscore the adaptive but time-sensitive nature of retinal cell communication via EVs in response to hypoxia. Targeting this crosstalk may offer novel therapeutic strategies to preserve retinal structure and function in ischemic retinopathies. Full article

Stargardt’s disease (STGD1) is an autosomal recessive juvenile macular degeneration caused by mutations in the ABCA4 gene, impairing clearance of toxic retinoid byproducts in the retinal pigment epithelium (RPE). This leads to lipofuscin accumulation, oxidative stress, photoreceptor degeneration, and central vision loss. Over 1200 pathogenic/likely pathogenic ABCA4 variants highlight the genetic heterogeneity of STGD1, which manifests as progressive central vision loss, with phenotype influenced by deep intronic variants, modifier genes, and environmental factors like light exposure. ABCA4 variants also show variable penetrance and geographical prevalence. With no approved treatment, investigational therapies target different aspects of disease pathology. Small-molecule therapies target vitamin A dimerization (e.g., ALK-001), inhibit lipofuscin accumulation (e.g., soraprazan), or modulate the visual cycle (e.g., emixustat hydrochloride). Gene therapy trials explore ABCA4 supplementation including strategies like RNA exon editing (ACDN-01) and bioengineered ambient light-activated OPSIN. RORA gene therapy (Phase 2/3) addresses oxidative stress, inflammation, lipid metabolism, and complement system dysregulation. Trials like DRAGON (Phase 3, tinlarebant), STARLIGHT (phase 2, bioengineered OPSIN) show promise, but optimizing efficacy remains challenging. With the key problem of establishing genotype–phenotype correlations, the future of STGD1 therapy may rely on approaches targeting oxidative stress, lipid metabolism, inflammation, complement regulation, and genetic repair. Full article

Gene therapy has emerged as a promising treatment for several eye diseases since it may restore vision and stop blindness. Many eye diseases, including retinitis pigmentosa and macular degeneration, have historically been rather difficult to treat and usually cause permanent vision loss. However, thanks to advances in gene therapy, many disorders can now be effectively targeted and genetically changed, providing a safer, more direct, maybe even curative approach. By introducing, altering, or repairing specific genes inside the eye, gene therapy seeks to fix the defective genes causing these disorders, thereby improving general eye health and visual ability. Voretigene neparvovec is one FDA- and EMA-approved treatment for RPE65 mutations. Retinitis pigmentosa, age-related macular degeneration, X-linked retinoschisis, choroideremia, and Stargardt disease are among the several eye disorders still under clinical trials, and experimental treatment is in progress. As research on gene therapy develops, it opens the path for groundbreaking treatments that could fundamentally change the ophthalmic care scene. Full article

Fundus autofluorescence (FAF) is a non-invasive retinal imaging technique that helps visualize naturally occurring fluorophores, such as lipofuscin, and provides valuable insight into retinal diseases—particularly inherited retinal diseases (IRDs). FAF is especially useful in detecting subclinical or early-stage IRDs and in monitoring disease progression over time. In Stargardt disease, areas of decreased autofluorescence correlate with disease progression and have been proposed as a biomarker for future clinical trials. FAF can also help differentiate Stargardt disease from other macular dystrophies. In retinitis pigmentosa, hyperautofluorescent rings are a common feature on FAF and serve as an important marker for disease monitoring, especially as changes align with those seen on other imaging modalities. FAF is valuable in tracking progression of choroideremia and may help identify disease carrier status. FAF has also improved the characterization of mitochondrial retinopathies such as maternally inherited diabetes and deafness. As a rapid and widely accessible imaging modality, FAF plays a critical role in both diagnosis and longitudinal care of patients with IRDs. Full article

Pupil cycle time (PCT) estimates the dynamics of a biofeedback loop established between pupil size and stimulus luminance, size or colour. The PCT is useful for probing the functional integrity of the retinopupillary circuits, and is therefore potentially applicable for assessing the effects of damage due to retinopathies or neuropathies. In previous studies, PCT was measured by manually counting the number of pupil oscillations during a fixed period to calculate the PCT. This method is scarce, requires a good expertise and cannot be used to estimate several PCT parameters, such as the oscillation amplitude or variability. We have developed a computerised setup based on eye-tracking that expands the possibilities of characterising PCT along several dimensions: oscillation frequency and regularity, amplitude and variability, which can be used with a large palette of stimuli (different colours, sizes, shapes or locations), and further allows measuring blinking frequency and eye movements. We used this method to characterise the PCT in young control participants as well as in patients with several pathologies, including age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), Stargardt disease (SD), and Leber hereditary optic neuropathy (LHON). We found that PCT is very regular and stable in young healthy participants, with little inter-individual variability. In contrast, several PCT features are altered in older healthy participants as well as in ocular diseases, including slower dynamics, irregular oscillations, and reduced oscillation amplitude. The distinction between patients and healthy participants based on the calculation of the area under the curve of the receiver operating characteristics (AUC of ROC) were dependent on the pathologies and stimuli (0.7 < AUC < 1). PCT nevertheless provides relevant complementary information to assess the physiopathology of ocular diseases and to probe the functioning of retino-pupillary circuits. Full article

Dark adaptometry is a non-invasive functional test that assesses the retina’s ability to recover sensitivity in low-light conditions following photobleaching. This review explores the physiological mechanisms underlying dark adaptation (DA), including photopigment regeneration and the critical role of the retinal pigment epithelium in the visual cycle. We detail clinical protocols for dark adaptometry using modern instruments such as the AdaptDx, highlighting methodological advances that improve testing efficiency and reproducibility. The clinical utility of dark adaptometry is examined across a range of inherited and acquired retinal disorders, including age-related macular degeneration (AMD), retinitis pigmentosa (RP), Stargardt disease, diabetic retinopathy (DR), cone–rod dystrophy (CRD), vitamin A deficiency, and congenital stationary night blindness (CSNB). Dark adaptometry has emerged as a sensitive biomarker capable of detecting functional deficits before structural changes are evident, making it a valuable tool for early diagnosis and monitoring disease progression. However, limitations such as age-related variability, patient compliance, and lack of standardization remain challenges to broader clinical adoption. Continued refinement of dark adaptometry protocols and instrumentation is essential to maximize its diagnostic potential in ophthalmic practice. Full article

Retinal degeneration, characterized by the progressive loss of photoreceptors, retinal pigment epithelium cells, and/or ganglion cells, is a leading cause of vision impairment. These diseases are generally classified as inherited (e.g., retinitis pigmentosa, Stargardt disease) or acquired (e.g., age-related macular degeneration, diabetic retinopathy, glaucoma) ocular disorders that can lead to blindness. Available treatment options focus on managing symptoms or slowing disease progression and do not address the underlying causes of these diseases. However, recent advancements in regenerative medicine offer alternative solutions for repairing or protecting degenerated retinal tissue. Stem and progenitor cell therapies have shown great potential to differentiate into various retinal cell types and can be combined with gene editing, extracellular vesicles and exosomes, and bioactive molecules to modulate degenerative cellular pathways. Additionally, gene therapy and neuroprotective molecules play a crucial role in enhancing the efficacy of regenerative approaches. These innovative strategies hold the potential to halt the progression of retinal degenerative disorders, repair or replace damaged cells, and improve visual function, ultimately leading to a better quality of life for those affected. Full article

Stem cell therapy has emerged as a promising approach for treating various retinal diseases, particularly degenerative retinal diseases such as geographic atrophy in age-related macular degeneration (AMD), retinitis pigmentosa (RP), and Stargardt disease. A wide variety of imaging techniques have been employed in both preclinical and clinical settings to assess the efficacy and safety of stem cell therapy for retinal diseases. These techniques can be classified into two categories: methods for imaging stem cells and those for the overall morphology and function of the retina. The techniques employed for stem cell imaging include optical imaging, magnetic resonance imaging (MRI), and radionuclide imaging. Additional imaging techniques include fundus photography, fluorescein angiography, and fundus autofluorescence. Each technique has its own advantages and disadvantages, and thus, the use of multimodal imaging can help to overcome the shortcomings and achieve a more comprehensive evaluation of stem cell therapy in retinal disease. This review discusses the characteristics of the main techniques and cell-labeling techniques applied in stem cell therapy, with a particular focus on the applications of multimodal imaging. Furthermore, this review discusses the challenges and prospects of multimodal imaging in stem cell therapy for retinal disease. Full article

Stargardt disease (STGD1), the most common retinal dystrophy caused by pathogenic variants of the biallelic ABCA4 gene, results in irreversible vision loss. This cross-sectional case series study analyzes 18 unrelated Stargardt disease (STGD1) patients from southeast China, examining clinical and genetic features. Ophthalmological assessments included BCVA, ophthalmoscopy, fundus photography, and autofluorescence, with ultra-widefield OCT angiography carried out on one patient. Genetic testing uses targeted exome sequencing for eye disease genes. The mean age of onset was 44.3 years for adult onset (6 patients) and 9.6 years for childhood/adolescent onset (12 patients). The mean logMAR visual acuity was 0.96 (right eye) and 0.91 (left eye). Eight novel ABCA4 variants were found, including two nonsense, two frameshift deletions, one copy number variant, one splice-site alternation, and two deep intronic variants. The genotypes are as follows: 77.8% (14/18) biallelic heterozygous, 16.7% (3/18) homozygous, and one patient with three variants. The study underscores STGD1’s phenotypic and genotypic diversity, expands the ABCA4 mutation spectrum, and offers insights into therapeutic strategies. Full article