Search Results (511)

Optogenetic gene therapy-based treatment offers a unique approach to bypass dysfunctional or degenerated photoreceptors in retinal degenerative disorders. Ambient light-activatable multi-characteristic opsin (MCO) targeted to bipolar cells of the retina has demonstrated partial vision restoration in animal models of retinitis pigmentosa (RP). Here, we describe the potential therapeutic efficacy of intravitreally delivered AAV-carried MCO-010 in a mouse model of Stargardt disease. MCO-010 treatment led to significantly improved behavioral outcomes in the visually guided radial arm water maze. Furthermore, longitudinal optical coherence tomographic imaging showed that the MCO-010 treatment led to no notable change in the retina thickness. Furthermore, the MCO-010-treated mice exhibited higher electrophysiological responses compared to the control group. Together, these findings demonstrate potential vision-restoring and disease-modifying aspects of ambient light-activatable intravitreal MCO-010 therapy. Full article

Background/Objectives: Retinitis pigmentosa (RP) is characterized by progressive degeneration of photoreceptors, with increasing evidence supporting the involvement of inflammation in disease progression. Aqueous humor (AH) reflects the intraocular microenvironment and represents an accessible source for biochemical analysis. This study aimed to characterize the profile of the main inflammatory proteins and bioactive lipids in the AH of RP patients and to compare it with healthy subjects. Methods: The AH was analyzed for cytokines using multiplex immunoassays and for lipid species using liquid chromatography–mass spectrometry. The concentrations of the analyzed molecules were compared between RP patients and the control group and then correlated with age and ellipsoid zone (EZ) width in RP patients. Results: A total of 26 RP patients and 13 controls were recruited. Significantly elevated levels of the pro-inflammatory IL-6 and a significant decrease in vascular endothelial growth factor (VEGF) were found in RP patients compared to controls. In RP patients, lipidomic analysis demonstrated significant increases in medium- and long-chain sphingomyelins (SMs) and very-long-chain unsaturated phosphatidylcholines (PCs). Higher levels of Cer 16:0, PC 32:0, and PC 34:0 were significantly associated with greater EZ preservation in RP patients. Additionally, in RP patients, VEGF and GM-CSF levels increased significantly with age, while IL-8 showed a non-significant decreasing trend. Conclusions: By integrating proteomic and, for the first time, lipidomic analyses of AH, we identified significant alterations in pro-inflammatory cytokines and bioactive lipid species in RP patients compared to controls, further highlighting a link between inflammatory activity, patient age, and disease stage. These preliminary findings need further validation in larger longitudinal cohorts to confirm the clinical utility of these bioactive mediators as potential disease biomarkers. Full article

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal degenerations with primary degeneration of rod photoreceptors followed by secondary cone loss. We investigated whether downregulating Nrl (neural retina leucine zipper), a key transcription factor specifying rod fate, can reprogram rods into a more resilient state. In a transgenic Nrl^N/N mouse in which Nrl was markedly downregulated, the rod phenotype became more like a rod precursor, particularly in the inferior retina. Crossing Nrl^N/N mice with two rod degeneration models, rd1 (Pde6b^rd1/rd1) and rhodopsin P23H knock-in (Rho^P23H/P23H) mice, showed significantly improved photoreceptor survival in double-mutant mice. In addition, AAV-mediated delivery of shRNA targeting Nrl mRNA substantially enhanced photoreceptor survival in rd10 (Pde6b^rd10/rd10) mice. These findings demonstrate that downregulation of Nrl reprograms rods and confers broad resistance to degeneration across multiple RP models. AAV-mediated Nrl knockdown represents a promising mutation-independent therapeutic strategy for autosomal recessive and dominant forms of RP. Full article

Background: Retinal and optic nerve disorders remain major causes of visual morbidity worldwide. Ocular fundus flavoprotein fluorescence (FPF) imaging has emerged as a potential noninvasive biomarker of mitochondrial dysfunction for earlier detection and evaluation of disease severity. Methods: We conducted a Systematic Scoping Review of the diagnostic and correlational utility of quantitative FPF parameters in retinal and optic nerve diseases compared with healthy controls. Following PRISMA-ScR guidelines, we searched MEDLINE, Web of Science, Scopus, and CENTRAL for peer-reviewed human studies available online before 31 December 2025. Results: Seventeen studies were included, encompassing 1914 eyes and 1339 participants, and were predominantly cross-sectional. In healthy eyes, mean macular and optic nerve head FPF intensity were reported as 24.1 ± 12.2 gsu and 30.6 ± 14.6 gsu, respectively. Higher signals were reported in several disorders, including diabetes mellitus (76.0 [67.0–92.0] gsu), neovascular age-related macular degeneration (67.47 ± 17.77 gsu), and retinitis pigmentosa (50.5 ± 12.2 gsu). However, lower, unchanged, or stage-dependent signals were also observed within the same disease categories. Interpretation across studies was limited by substantial heterogeneity in patient selection, disease definitions, imaging protocols, control groups, and FPF outcome metrics. The precise cellular and sublayer origin of the detected signal also remains challenging to determine. Conclusions: Ocular fundus FPF imaging provides promising metabolic insight into retinal and optic nerve diseases. However, current evidence remains heterogeneous and largely cross-sectional, limiting clinical interpretability and generalizability. Longitudinal studies, technical standardization, and multimodal integration are needed to define reproducible disease-specific FPF profiles and improve translational applicability. Full article

Inherited retinal dystrophies (IRDs) comprise a diverse group of genetic disorders that frequently result in irreversible vision loss due to photoreceptor dysfunction or degeneration. Among them, retinitis pigmentosa (RP) and achromatopsia (ACHM) are, in some cases, associated with pathogenic variants in PDE6A and PDE6C, respectively, which are key components of the phototransduction cascade. As most of IRDs still lack effective therapies, retinal organoids (ROs) provide a valuable in vitro model for the investigation of disease-associated mechanisms. Here, we generated induced pluripotent stem cell (iPSC)-derived ROs from an RP patient carrying compound heterozygous PDE6A mutations and from a patient with ACHM harboring a homozygous PDE6C mutation, along with their corresponding CRISPR/Cas9-corrected isogenic controls, which, to our knowledge, represent the first patient-derived RO models reported for the PDE6A and PDE6C genes. The mutant PDE6A line exhibited impaired neuroretinal vesicle formation and RO differentiation; however, a subset of RP-derived ROs matured appropriately and retained photoreceptor features. Moreover, the specific isoform expression pattern detected in retinal tissues reflected differences across developmental maturation stages that could influence disease severity. In contrast, the PDE6C_mutant ROs displayed normal structure and maturation, although cGMP hydrolysis within photoreceptors was likely compromised. In both models, CRISPR/Cas9-mediated correction restored the disease-associated phenotype resembling wild-type ROs. Collectively, these findings provide new insights into PDE6-associated pathogenesis, underscore the utility of patient-specific and gene-corrected ROs for elucidating IRD mechanisms, and support gene editing as a promising therapeutic strategy. Full article

Purpose: To evaluate the safety and feasibility of repeated subtenon administration of autologous platelet-rich plasma (PRP) in patients with degenerative retinal diseases and to explore preliminary, hypothesis-generating functional observations in retinitis pigmentosa (RP) and extensive macular atrophy with pseudodrusen-like appearance (EMAP). Methods: This prospective, open-label, uncontrolled pilot study included 13 patients (6 RP, 7 EMAP) who received three subtenon PRP injections (1.5 mL each) at baseline, Month 2, and Month 4, with follow-up through Month 6. The study was designed primarily to assess safety and feasibility and was not powered or intended to evaluate efficacy. The primary outcome was safety, including adverse events and intraocular pressure changes. Exploratory secondary outcomes included best-corrected visual acuity (BCVA, logMAR), visual field mean deviation (MD), and structural optical coherence tomography (OCT) parameters. Electrophysiological outcomes were analyzed descriptively due to incomplete paired data. Analyses were conducted within diagnostic groups, and no between-group comparisons were performed. Results: All 13 patients completed the study. No serious adverse events or permanent ocular morbidity were observed. Two transient and self-limited adverse events occurred (anterior uveitis and intraocular pressure elevation), both resolving without sequelae. In the overall cohort, BCVA remained stable without statistically significant change. In the RP subgroup, a small exploratory change in BCVA was observed (mean ΔlogMAR −0.09; nominal p = 0.048), corresponding to approximately 4–5 ETDRS letters; however, this finding was associated with wide confidence intervals and limited statistical power and should be interpreted cautiously. In the EMAP subgroup, functional stability was observed without evidence of consistent improvement. Visual field mean deviation and OCT findings were consistent with absence of short-term deterioration across available paired data. Electrophysiological outcomes showed no consistent directional change. Conclusions: Repeated subtenon PRP administration appeared feasible and well tolerated in this small, uncontrolled pilot cohort. Any observed functional changes are preliminary and hypothesis-generating only and do not establish efficacy. Larger, adequately powered controlled studies with standardized endpoints are required to determine the potential role of PRP in degenerative retinal diseases. Full article

Background: Non-syndromic retinitis pigmentosa (RP) is characterized by rod–cone degeneration, resulting in night blindness, visual field constriction, and eventual blindness. Recessively inherited RP is predominantly exacerbated in consanguineous populations, such as Pakistan. This study aimed to perform the genetic analysis of sixteen non-syndromic RP segregating Pakistani families, and to summarize the mutation spectrum of non-syndromic RP in our population by reviewing related literature. Methods: We screened 16 non-syndromic RP families using targeted capture panel sequencing of 344 genes related to inherited retinal dystrophies. Variants were prioritized based on rarity (minor allele frequency (MAF) < 0.001 in the gnomAD South Asian subset), pathogenicity assessments using ACMG/AMP criteria, and REVEL scores (>0.5). Candidate variants were validated for familial segregation through Sanger sequencing. Results: We identified 15 distinct variants across 14 genes associated with non-syndromic retinitis pigmentosa, comprising 6 missense, 7 nonsense, 1 frameshift, and 2 splice-site variants, including 4 novel variants, i.e., p.(Val220Met) and p.(Pro1282SerfsTer2) in RP1, 1 each in PDE6B (c.2021+5G>A), and PRCD p.(Ser38Ter). Homozygosity predominated, underscoring the impact of consanguinity on the burden of autosomal recessive disease in the present cohort, while the CERKL disease-causing mutation, i.e., p.(Arg257Ter), recurred in two families. Conclusions: This study expands Pakistan’s non-syndromic RP mutational spectrum by identifying novel variants in RP1, PDE6B, and PRCD, alongside recurrent CERKL and RHO mutations of the local population. The literature review suggests that RP1, TULP1, and PDE6B are among the most mutated genes in our population, supporting the value of population-specific genetic panels to enhance diagnostics and carrier screening. Full article

Coenzyme Q10 (CoQ10), a natural antioxidant produced by the human body, has strong anti-inflammatory properties, reduces oxidative stress, and improves mitochondrial function. It is also known for its strong neuroprotective effects. With age, endogenously produced CoQ10 levels decline, contributing to the development of chronic diseases, including eye disorders. Irreversible ocular diseases that result in blindness present a significant challenge in contemporary medicine, as no fully effective cure exists; current treatments primarily aim to decelerate disease progression, manage symptoms, and preserve residual vision. Our study reviews research on the use of CoQ10 in eye diseases like age-related macular degeneration (AMD), retinitis pigmentosa (RP), and glaucoma, which can cause permanent vision loss and are linked to oxidative stress and mitochondrial dysfunction. This article explores whether CoQ10 can be a safe and effective addition to treatment for these conditions. We also outline directions for future research and explain how CoQ10 functions in the studies discussed in this review. Full article

Background/Objectives: To describe retinal imaging characteristics and the natural history of rhodopsin (RHO)-associated autosomal dominant retinitis pigmentosa (ADRP) by evaluating ellipsoid zone (EZ) width loss and measuring the degree of constriction of the area within and including the hyperautofluorescent ring. Methods: Eighteen patients with molecularly confirmed RHO variants were retrospectively evaluated. EZ width on spectral-domain optical coherence tomography (SD-OCT) and the area within and including the hyperfluorescent ring on fundus autofluorescence (FAF) were measured. The correlation between EZ width and hyperfluorescent ring area was assessed using a linear mixed-effects model. Results: Mean best corrected visual acuity (BCVA) (logMAR) was 0.21 at baseline and 0.29 at last visit over a mean follow-up of 5 years. Nine patients presented with sectoral RP, eight with typical RP, and one with unilateral RP. The mean EZ width constriction rate was −93.43 µm/year (SD = 130.58), and the area within and including the hyperautofluorescent ring decreased by −0.54 mm²/year (SD = 0.50). A strong positive association was observed between the EZ width and hyperfluorescent ring area at baseline (β = 151.7 ± 17.9, p < 0.001) and at the final visit (β = 185.7 ± 18.2, p < 0.001). Conclusions: In this study, patients with RHO-associated ADRP appeared to show a relatively slow rate of progression. Quantitative imaging markers, such as EZ width and the area within and including the hyperautofluorescent ring, may offer potentially reproducible measures of disease progression. These imaging biomarkers could be useful as outcome measures in future natural history studies and therapeutic trials, pending further validation. Full article

Objectives: To evaluate the long-term effects on retinal structure and visual function of oral bromelain and curcumin supplementation in patients with inherited retinal dystrophies (IRD) complicated by persistent cystoid macular oedema (CMO). Methods: We retrospectively studied 20 eyes with genetically confirmed IRD complicated by CMO, with refractory to systemic or local treatments performed for 6 months. We collected baseline (V1) and follow-up (V2) data from these IRD-CMO patients, who were continuously supplemented with oral bromelain and curcumin for 12 months. Outcome measures were the Snellen best-corrected visual acuity (BCVA) and central macular thickness (CMT) values, collected by spectral-domain optical coherence tomography (OCT). Based on OCT scans, we classified IRD-CMO as microcystic or macrocystic, performing this sub-grouping in two eye cohorts (n = 10). Baseline median BCVA and CMT differences in both groups were verified (Mann–Whitney test). For both CMO groups, changes from V1 to V2 in median BCVA and CMT values were evaluated (Friedman test). Results: At baseline, both the median BCVA and CMT values were significantly different in both groups (p < 0.01 and p < 0.001). Between V1 and V2, in the microcystic CMO group, a slightly improved median BCVA was found, whereas the median CMT was reduced; however, this did not reach statistical significance (p = 0.6 and p = 0.2, respectively). In the macrocystic CMO group, a significant stable median BCVA was found from V1 to V2, with concomitant significant reduction in median CMT (p < 0.05 for both comparisons). Conclusions: Retinal structural improvement and visual function preservation were observed after oral bromelain and curcumin supplementation in macrocystic IRD-CMO. It is likely that the vasogenic component in macrocystic CMO is more responsive to nutraceutical molecules than the degenerative microcystic component. Full article

Fibroblast growth factor 2 (FGF2) is expressed in retinal Müller glia cells, and its expression increases in response to photoreceptor degeneration. To investigate the physiological relevance of FGF2, we analyzed retinal morphology and cellular responses in Fgf2-deficient (Fgf2^−/−) mice. Loss of FGF2 did not affect photoreceptor survival, retinal vasculature, or retinal pigment epithelium (RPE) integrity. To further understand its role in retinal degeneration, Fgf2^−/− mice were crossed with Pde6b^STOP/STOP mice, a model of retinitis pigmentosa (RP). We then analyzed outer nuclear layer thickness, cone number, rod outer segments length, RPE morphology, and microglia number in Fgf2^−/− Pde6b^STOP/STOP and Pde6b^STOP/STOP mice. Although FGF2 was upregulated in degenerating photoreceptor cells in the Pde6b^STOP/STOP retina, its absence did not accelerate photoreceptor loss in Fgf2^−/− Pde6b^STOP/STOP mice. Interestingly, microglia numbers were significantly changed at early disease stages in Fgf2^−/− Pde6b^STOP/STOP retinas compared with Pde6b^STOP/STOP controls, suggesting that FGF2 modulates inflammatory signaling. Together, these results show that loss of FGF2 does not alter photoreceptor degeneration kinetics or retinal morphology, but may contribute to the regulation of early microglial accumulation during degeneration. Full article

Background/Objectives: To investigate the volume of the lateral geniculate nucleus (LGN) in patients with advanced retinitis pigmentosa (RP). Methods: Nineteen patients with advanced RP (mean age 52 years and mean duration of illness 357 months) and twenty-one age-matched normal subjects have been examined using 7 Tesla MRI of the brain. Brain segmentation was carried out with the “recon-all” function in the FreeSurfer software (version 7.4.1) package. Results: The volumes of the left and right LGN were significantly smaller in those patients with RP, in comparison to the controls. We found a significant positive correlation between the volume of the left LGN and the right eye best-corrected visual acuity in the RP group. Conclusions: Late-stage RP leads to a significant reduction in LGN volume, as measured with 7 Tesla MRI. The volume of the left LGN was correlated with the visual function of the right eye in patients with late-stage RP. The statistical power of the results is limited by there being a low number of RP patients included in this study, which is due to the low prevalence of this rare eye disease. Full article

Background: Senior–Loken syndrome (SLS) is a rare autosomal recessive ciliopathy classically defined by the concurrence of nephronophthisis, frequently progressing to end-stage renal disease (ESRD), and retinal dystrophy, most commonly presenting as retinitis pigmentosa (RP). Given its phenotypic overlap with other renal–retinal syndromes, establishing a definitive diagnosis necessitates integrated clinical evaluation and molecular confirmation. Case Presentation: A 28-year-old Chinese female presented with a two-month history of binocular floaters. Her medical history was significant for ESRD of five years’ duration, managed with maintenance hemodialysis. Ophthalmic assessment revealed retinal pigment mottling along the inferior temporal arcades and generalized arterial attenuation. Spectral-domain optical coherence tomography demonstrated outer retinal thinning with loss of the ellipsoid zone at corresponding locations. Perimetry confirmed visual field constriction, and full-field electroretinography showed severely reduced rod- and cone-mediated responses. Genetic testing was performed and a pathogenic variant in the NPHP1 gene was identified. Segregation studies confirmed both parents as heterozygous carriers, consistent with autosomal recessive inheritance. Collectively, these findings established a diagnosis of SLS. Conclusions: This case reinforces that SLS should be considered in the differential diagnosis of any young patient exhibiting RP alongside chronic kidney disease, particularly in the setting of early-onset ESRD. It also illustrates the essential role of a coordinated, multidisciplinary approach—encompassing nephrology, ophthalmology, and genetics—in diagnosing complex ciliopathies. Genetic confirmation not only validates the clinical diagnosis but also provides a foundation for family counseling, prognostic stratification, and future eligibility for gene-specific therapeutic trials. Full article

Retinitis pigmentosa (RP) comprises a heterogeneous group of inherited retinal dystrophies characterized by the progressive degeneration of photoreceptors, leading to night blindness and gradual loss of peripheral vision. RP is characterized by a substantial genetic heterogeneity, with more than 85 genes implicated across autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have identified mutations in the ARL3 gene as a causative factor in both syndromic and non-syndromic forms of RP, including autosomal dominant and recessive cases. ARL3 encodes a small GTPase that plays a crucial role in intracellular trafficking, particularly within photoreceptors. This process is critical for maintaining ciliary function and phototransduction. Here, we investigate the pathogenic mechanisms of the ARL3 c.199G>C (p.Asp67His) variant identified in individuals from a four-generation family. We show that mutant ARL3 disrupts normal protein expression and affects ciliogenesis. Clinically affected individuals showed a non-syndromic retinal degenerative RP phenotype, with marked intrafamilial heterogeneity, ranging from extensive retinal atrophy to the absence of clinical manifestation, independent of age. This report highlights the incomplete penetrance and variable expressivity associated with the ARL3 variant and emphasizes the value of combining molecular diagnostics with functional validation to expedite molecular diagnosis. Full article

Chronic neuroinflammation is increasingly implicated in the progression of neurodegenerative diseases, yet the mechanisms linking metabolic stress, innate immune activation, and neuronal vulnerability remain incompletely defined. Retinitis pigmentosa (RP), despite its genetic heterogeneity, exhibits convergent inflammatory and metabolic alterations during disease progression, providing a useful model for studying immune-mediated neurodegeneration. This review summarizes current evidence from experimental models of retinal degeneration and human retinal studies to examine how sustained neuroinflammation is established in RP. We focus on the coordinated roles of retinal microglia and Müller glia in sensing photoreceptor stress and shaping the inflammatory microenvironment. Microglia are activated early in disease and contribute to progression through inflammatory signaling, phagoptosis, metabolic adaptation, and inflammasome-associated pathways. Müller glia, in turn, modulate metabolic homeostasis and propagate inflammatory signals across retinal layers. We also discuss how stress-responsive regulatory pathways, including p53-associated signaling, influence redox balance, iron handling, and inflammatory persistence without acting as primary apoptotic drivers. Together, these findings support a model in which chronic immunometabolic dysregulation contributes to retinal degeneration and highlight inflammation-related processes as potential targets for mutation-independent therapeutic strategies. Full article