Search Results (259)

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy (prevalence ~1:4000) and a leading Mendelian cause of working-age blindness. Despite marked genetic heterogeneity, its progression converges on a common secondary cascade of outer-retinal hyperoxia, increased reactive oxygen species (ROS), and mitochondrial dysfunction that drives cone degeneration and central vision loss. Because this oxidative cascade is largely genotype-independent and pharmacologically tractable, oxidative stress is a cross-cutting therapeutic target. Within it, mitochondrial DNA (mtDNA) is a key element: once released from damaged photoreceptors—free or within exosomes—it may act as a damage-associated molecular pattern (DAMP), engaging TLR9, cGAS–STING, and the NLRP3 inflammasome and sustaining chronic neuroinflammation. Extracellular mtDNA is therefore a potential integrative marker, simultaneously reflecting oxidative stress, mitochondrial dysfunction, cell death, and innate-immune activation. A central knowledge gap, however, remains: the mechanistic steps linking mtDNA to inflammation and to photoreceptor death have not been demonstrated in RP itself, and extracellular mtDNA has never been quantified in the ocular fluids of RP patients. In this review we appraise oxidative biomarkers in RP, propose extracellular mtDNA as a candidate biomarker of disease activity, and examine antioxidant and redox-modulating therapies—from N-acetylcysteine and elamipretide trials to DAMP-sensor inhibition—across experimental and clinical models. Finally, we propose extracellular mtDNA as a candidate pharmacodynamic endpoint and outline a path toward its validation. Full article

Full-field stimulus threshold (FST) testing is a psychophysical method used to assess global retinal function, particularly in patients with severe visual impairment where conventional perimetry is unreliable. This review explores the development, clinical protocols, and applications of FST in retinal diseases, with a focus on its role in inherited retinal dystrophies (IRDs) such as Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). FST has emerged as a key functional outcome measure in clinical trials, particularly in evaluating novel gene therapies for IRDs. Its fixation-independent nature and ability to detect residual visual function make it valuable for assessing disease progression and treatment efficacy. However, challenges remain regarding standardization and test variability. Ongoing efforts seek to standardize and optimize FST protocols and establish it as a standardized metric in both clinical and research settings. Full article

Background/Objectives: To describe the genetic resolution rate, molecular findings, and genotype–phenotype correlations of non-ABCA4 and non-BEST1 inherited macular dystrophies (IMDs) within an Irish inherited retinal disease (IRD) registry. Methods: Retrospective review of individuals with a clinical diagnosis of macular or cone dystrophy. Comprehensive phenotyping (dilated ocular biomicroscopy, multimodal retinal imaging, visual electrophysiology) and genetic testing (panel-based next-generation sequencing, single-gene testing, whole exome/genome sequencing, WES/WGS). Variants were interpreted using ACMG AMP criteria, and genotype-phenotype match was confirmed through multidisciplinary review. Results: 232 patients with macular/cone dystrophies were identified. ABCA4 and BEST1 accounted for most molecular diagnoses (47.4%). Removing ABCA4 and BEST1, 59.0% of IMDs were genetically unresolved, higher than the rate in general IRD cohorts. Deep phenotyping enabled diagnostic reclassification in 13/72 (18.1%), namely achromatopsia, congenital stationary night blindness, and oculocutaneous albinism. Further genetic testing resolved 35/72 (48.6%) of those unresolved on first-line testing, with PRPH2 being most prevalent (n = 12), followed by GUCY2D, CRB1, PROM1, and CRX. Characteristic phenotypic signatures—such as CRB1-associated retinal thickening and retinoschisis or PROM1-associated Stargardt-like changes—supported known genotype–phenotype correlations. Conclusions: Genetic resolution rates for rare IMDs remain lower than pan-retinal IRD phenotypes. Beyond ABCA4 and BEST1, IMDs exhibit substantial genetic and phenotypic heterogeneity (24 genotypes in this cohort), with low molecular diagnostic rates despite comprehensive sequencing approaches. Detailed multimodal phenotyping (i.e., structural, functional and extra-ocular) is essential to refine diagnosis, guide genetic testing and interpret candidate variants. Genetic testing is challenging when the retinal phenotype is advanced (i.e., atrophy) or lacks pathognomonic features. Meticulous phenotyping (functional, structural and systemic) and broader genomic strategies (e.g., WES/WGS) may further increase diagnostic yield, though gene panel content is constantly improving. Consistently improving molecular diagnostic rates will ensure equitable access to emerging gene-specific therapies. Full article

Bietti crystalline dystrophy like retinal degeneration (BCD) is an inherited retinal degenerative disease caused by defects in the CYP4V2 gene. Recombinant AAV-based gene replacement therapy holds promise for this disease, yet reliable enzymatic activity assays for product potency evaluation remain urgently needed. This study established and validated a method for determining the enzymatic activity of CYP4V2 based on the bioluminescent substrate Luciferin-MultiCYP.HEK293-AAVR cells were seeded at 1 × 10⁴ cells/well and transduced with rAAV-hCYP4V2 across an MOI gradient (1.17 × 10³–2.4 × 10⁶). After incubating at 37 °C for 72 h, medium was replaced with Opti-MEM containing 20 µM Luciferin-MultiCYP and incubated for 90 min ± 30 min. Next, cell supernatants were mixed with luciferase reagent, and bioluminescence was measured. Methodological validation results revealed that the method has good specificity, with an accuracy recovery rate of 100.94% ± 2.84% (RSD = 2.81%). Repeatability (GCV%) was 4.21%, and intermediate precision (RSD) was 6.16%. Linearity was good within the MOI range of 1.17 × 10³ to 2.4 × 10⁶ (R² = 0.9902 ± 0.0061, n = 9). Lastly, the method was successfully applied to activity testing the products of three AAV serotypes (AAV8, AAV2/8, and AAV2). This bioluminescent method meets regulatory potency assay requirements and serves as an effective QC tool for process development, batch release, and stability evaluation of rAAV-hCYP4V2 products. Full article

Background: To assess how historical patterns in retinitis pigmentosa (RP) gene inheritance, functional category, and phenotypic onset may inform the remaining unsolved RP discovery space. Methods: We manually reviewed PubMed-indexed primary reports in the RetiGene database, supplemented with PubMed-indexed human studies where necessary to improve extractable phenotype data. Gene-level variables extracted included age of symptom onset, inheritance pattern, functional category and syndromic association. Gene-level associations between earliest year of RP gene discovery and mean age of symptom onset were assessed, alongside temporal analyses for functional category, inheritance, and syndromic patterns. Results: Later year of gene discovery was associated with later mean age of symptom onset, both in the primary analysis restricted to genes with at least 5 extractable onset cases (n = 83, p < 0.001) and in a stricter sensitivity analysis restricted to genes with at least 10 onset cases (n = 66, p = 0.00525). Year of discovery differed significantly across functional categories (p < 0.001). No significant temporal association was observed for AR versus non-AR inheritance or syndromic status. Conclusions: This hypothesis-generating analysis suggests that observed patterns likely reflect a combination of biological detectability, study design, and publication dynamics rather than intrinsic gene–phenotype relationships alone; within this context, future RP-solving efforts may benefit from greater attention to less obvious biological pathways (such as ciliary, transport, and metabolic categories), along with later-presenting or less conspicuous phenotypes. Full article

Intracellular retinoid-binding proteins, including cellular retinol-binding proteins (CRBPs) and cellular retinoic acid-binding proteins (CRABPs), belong to the intracellular lipid-binding protein (iLBP) family, whereas cellular retinaldehyde-binding protein (CRALBP) is a structurally distinct retinoid-binding protein belonging to the CRAL-TRIO protein family and functions as an active regulator of retinoid trafficking, metabolism, and signaling. Although these proteins are directly implicated in inherited retinal dystrophies, retinoid-dependent cancers, and neurodegenerative diseases, they have received comparatively little attention as pharmacological targets relative to the extracellular carrier Retinol-Binding Protein 4 (RBP4). High-resolution structural studies, including atomic-resolution X-ray co-crystal structures of protein–ligand complexes, have defined the binding pocket architecture of each protein and established a basis for structure-guided drug discovery. This review critically evaluates the druggability of CRBP, CRALBP, and CRABP by integrating structural, biochemical, and pharmacological evidence. We discuss known small-molecule modulators, including the first-in-class CRBP1 inhibitor abn-CBD and next-generation non-retinoid scaffolds, alongside gene therapy strategies targeting CRALBP deficiency. We further address the selectivity challenges inherent to the conserved iLBP fold and identify future directions for the development of isoform-selective therapeutics for retinal degeneration, oncology, and neurodegeneration. Full article

Background: Optical coherence tomography (OCT) and OCT angiography (OCTA) retinal imaging in inherited retinal dystrophies (IRD) has been limited to the posterior pole and central midperiphery (up to about 16.5 × 16.5 mm). Two novel commercially available swept-source (SS) OCT/-OCTA devices provide the possibility of wide-field (WF) evaluation of retinal and choroidal structures, including the vasculature, in a single examination. Methods: A limited consecutive series of 16 IRD patients were examined with a BMizar (400 kHz, 24 × 20 mm scan width) and a Dream OCT (200 kHz, 26 × 21 mm scan width) in addition to the normal clinical examination protocol. This series included patients with retinitis pigmentosa, cone-rod dystrophy, macular dystrophy and autosomal recessive bestrophinopathy. In addition, 12 healthy probands were examined. Results: WF-SS-OCT/-OCTA enabled the detection of retinal, choroidal and choriocapillaris alterations in the macular and midperiphery in a short, single examination session of up to 15 s. Even small foveal lesions and a small silent macular neovascularization were detected on WF screening. Regional alterations of choroidal and choriocapillaris flow patterns were identified. These were mostly in correspondence with areas that appeared clinically affected, but unexpected lesions were identified as well. Occlusion of peripheral retinal vessels was seen in retinitis pigmentosa, though flow was detected in retinal vessels, which were difficult to distinguish on fundus images. In one patient with nystagmus, WF-SS-OCT/-OCTA was performed, whereas standard OCT volume scan could not be obtained. The most frequent artifact were horizontal lines of misalignment, which did not interfere with the detection of pathologies. Conclusions: Both WF-SS-OCT/-OCTA devices provide detailed insights in structural and vascular retinal and choroidal alterations in a single, short examination. Larger series of IRD patients examined with WF-SS-OCT/-OCTA promise to provide novel insights into the pathology of IRDs. Full article

ROSAH syndrome is a rare autosomal dominant autoinflammatory disorder caused by gain-of-function mutations in the ALPK1 gene, characterized by retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis, and headache. We present three related female patients (two sisters and their aunt) with a long-standing history of decreased visual acuity, recurring macular oedema, and progressive retinal dystrophy, as well as systemic involvement including anhidrosis, splenomegaly, headache, and arthritis. All our patients come from one family, with a total of 11 people suffering from ophthalmologic diseases with profound vision loss. Described three patients had confirmed pathogenic variant c.710C>T; p.Thr237Met in the ALPK1 gene and extensive ophthalmic assessment. This case series highlights the importance of genetic testing and multimodal imaging in unexplained familial retinal dystrophies and underlines intrafamilial phenotypic variability. Moreover, it emphasizes ROSAH syndrome as an important differential diagnosis for inherited inflammatory vitreoretinopathies. Full article

Background and Clinical Significance: Biallelic pathogenic variants in the PCARE gene (photoreceptor cilium actin regulator), also known as C2orf71 (chromosome 2 open reading frame 71), are typically associated with retinitis pigmentosa type 54 (RP54) and, less frequently, with cone–rod dystrophy (CORD23). Case Presentation: A 52-year-old man presented with an eight-year history of progressive visual loss, without photophobia or nyctalopia. He underwent a comprehensive ophthalmological evaluation, including multimodal retinal imaging, automated perimetry, and full electrophysiological testing, in accordance with International Society for Clinical Electrophysiology of Vision (ISCEV)’s standards. Genetic testing was performed using next-generation sequencing (NGS) with an inherited retinal dystrophy gene panel, and findings were confirmed by Sanger sequencing. Clinical examination revealed bilateral macular atrophy with minimal foveal sparing and a central scotoma. Optical coherence tomography (OCT) showed disruption of the outer retinal layers and retinal pigment epithelium (RPE) abnormalities. Fundus autofluorescence (FAF) demonstrated central hypoautofluorescence surrounded by a hyperautofluorescent ring. Electrophysiological testing revealed severely reduced rod- and cone- mediated responses on full-field electroretinography (ERG), absent pattern ERG responses, and markedly reduced multifocal ERG responses, indicating widespread retinal dysfunction with significant macular involvement. Genetic analysis identified a homozygous pathogenic nonsense variant in PCARE [c.3289C>T; p.(Gln1097*)], confirming the diagnosis of an autosomal recessive inherited retinal dystrophy. Conclusions: Biallelic PCARE variants can cause late-onset severe retinal dystrophy, with predominant macular involvement and cone–rod dysfunction. Given its phenotypic overlap with other inherited retinal diseases, accurate diagnosis requires the integration of multimodal retinal imaging, electrophysiological testing, and comprehensive genetic analysis. Full article

Mitochondrial dysfunction and oxidative stress are increasingly recognized as key contributors to the development and progression of retinal degenerative diseases, including age-related macular degeneration and inherited retinal dystrophies. Growing evidence suggests that alterations in mitochondrial function, excessive production of reactive oxygen species, defective mitophagy, and chronic inflammatory responses are closely interconnected processes that contribute to retinal cell damage and degeneration. This review provides an overview of the current understanding of the molecular mechanisms linking mitochondrial dysfunction to retinal degeneration, with particular emphasis on the impact of oxidative stress, mitochondrial quality-control pathways, and inflammatory signaling. Available evidence indicates that mitochondrial DNA damage, impaired bioenergetics, and dysregulated mitochondrial dynamics play a crucial role in the degeneration of photoreceptors and retinal pigment epithelium cells. In turn, oxidative stress further exacerbates mitochondrial impairment, creating a self-sustaining cycle that promotes disease progression. Recent advances have also highlighted the therapeutic potential of targeting mitochondrial pathways. Although several mitochondria-directed strategies have shown encouraging results in experimental models, their translation into clinical practice remains at an early stage. Overall, the available data identify mitochondria as a promising therapeutic target and support the development of precision medicine approaches aimed at preserving retinal function and slowing disease progression in patients with retinal degenerative disorders. 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

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

Prominin-1 (Prom1/CD133) has long been recognized as a structural determinant of photoreceptor outer segment (OS) morphogenesis, yet rapidly accumulating evidence extends its role to retinal pigment epithelium (RPE) homeostasis, encompassing autophagy–lysosomal flux, outer segment phagocytosis, mitochondrial function, and regulation of inflammatory stress. This review synthesizes mechanistic and transcriptomic insights that position PROM1 as a central regulator of photoreceptor and RPE integrity, reframing Prom1 disease as a multi-compartment retinal disorder relevant to both inherited retinal dystrophies (IRDs) and atrophic age-related macular degeneration (aAMD). We develop a dual-axis conceptual model in which Prom1 dysfunction can initiate pathology in either the photoreceptors (OS morphogenesis failure) or the RPE, including impaired autophagic flux, lysosomal activity, defective phagocytosis, and Epithelial-Mesenchymal Transition (EMT)-like de-differentiation, with secondary cross-compartmental degeneration. Clinically, autosomal-dominant missense variants associate with macular or cone-rod dystrophy, whereas biallelic truncating/splice-site mutations drive early-onset rod–cone disease and panretinal/RPE atrophy, illustrating genotype–phenotype diversity. By integrating recent high-resolution transcriptomic data from Prom1-deficient RPE cells with long-standing insights into photoreceptor biology, we highlight converging pathways of degeneration that challenge a photoreceptor-centric view and unify disparate phenotypes within a single molecular framework. These insights broaden the therapeutic landscape, advancing gene augmentation and pathway-targeted strategies to preserve RPE integrity, sustain photoreceptor function, and modify disease course in PROM1-associated IRDs and atrophic AMD. 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

Background: Retinal and optic nerve disorders are a leading cause of irreversible visual impairment worldwide. Advances in molecular genetics—including next-generation sequencing, genome-wide association studies, and gene-based therapeutic technologies—have reshaped understanding of both inherited and complex retinal diseases. However, translating genetic discovery into sustained clinical benefit remains biologically and practically constrained. Methods: A structured literature search was conducted using PubMed and Scopus to identify relevant studies published between 2015 and 2025. The search focused on molecular genetics, epigenetic modulation, mitochondrial biology, and translational applications in inherited retinal dystrophies and selected complex retinal diseases, prioritizing high-impact original research and systematic reviews addressing diagnostic innovation and therapeutic development. Results: Inherited retinal dystrophies represent the most advanced model of precision ophthalmology, with diagnostic yields approaching 70–80% in well-characterized cohorts. Gene augmentation and genome-editing strategies have demonstrated proof-of-concept efficacy, yet clinical benefit depends on residual cellular viability, delivery efficiency, and durability of expression. Emerging platforms include AAV-mediated gene transfer, in vivo CRISPR-based editing, RNA-directed splice modulation, and mitochondrial-targeted approaches. Persistent barriers include unresolved non-coding and structural variants, variant interpretation uncertainty, and endpoint selection in clinical trials. In contrast, complex retinal diseases such as glaucoma, age-related macular degeneration, and pathological myopia reflect polygenic susceptibility interacting with environmental and aging-related factors. Although polygenic risk scores refine probabilistic prediction, their utility is limited by ancestry bias and incomplete predictive performance. Epigenetic and mitochondrial mechanisms further modulate disease expression but remain largely non-actionable in routine practice. Conclusions: Retinal genetics has progressed from gene discovery to early therapeutic implementation. Future advances will depend on improved variant detection, functional validation, biomarker-guided staging, and integration of genomics with imaging and longitudinal modeling to achieve durable and equitable precision ophthalmology. Full article