RARE DISEASE
Inherited retinal disorder
Inherited retinal disorder
Inherited retinal disorder
Synonyms: Retinal dystrophy
Synonyms: Retinal dystrophy
Synonyms: Retinal dystrophy
Drug discovery
20
drugs
With orphan designations
Overview
Inherited retinal diseases (IRDs) are a genetically heterogeneous group of disorders characterized by progressive photoreceptor or retinal pigment epithelium degeneration, leading to visual impairment and often blindness. Over 300 genes are implicated, with phenotypes ranging from congenital blindness (e.g., Leber congenital amaurosis) to adult-onset conditions (e.g., retinitis pigmentosa). Timely genetic testing enables precise diagnosis, prognostication, and access to emerging therapies [1][6][11].
Population
Global prevalence of IRDs is ~1:3,450 individuals, with retinitis pigmentosa (1:4,500), Stargardt disease (1:17,000), and Usher syndrome (1:25,000) among the most common [7][11].
Autosomal recessive forms account for ~60% of cases, with carrier rates as high as 1:2.26 in European populations [2][12].
Burden
Annual U.S. economic costs range from $13.4–$31.8 billion, with wellbeing losses (e.g., disability-adjusted life years) comprising 63% of total burden [4][15].
Pediatric-onset IRDs cause lifelong disability, impacting education, employment, and mental health [4][16].
Genetic testing accessibility gaps delay diagnosis and counseling, exacerbating familial and societal impacts [6][15].
Therapies
Gene therapy: FDA-approved voretigene neparvovec for RPE65-related IRDs; >30 therapies in clinical trials targeting genes like ABCA4 and USH2A [8][13][18].
Supportive care: Low-vision rehabilitation, UV protection, and dietary antioxidants (e.g., vitamin A) [1][8].
Emerging approaches: CRISPR-based editing, stem cell therapies, and optogenetics to restore retinal function [3][18].
Categories: rare genetic diseases, rare ophthalmic disorders
Research Papers
2,180 drug discovery papers about Inherited retinal disorder, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,180 drug discovery papers about Inherited retinal disorder, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | Fundus albipunctatus-like retinopathy in hypovitaminosis A-related optic neuropathy with skull hyperostosis.
A young man presented with progressive night blindness, optic neuropathy and bilateral retinal flecks, initially suggestive of an inherited retinal dystrophy. Genetic testing identified a heterozygous pathogenic variant in USH2A alongside multiple variants of uncertain significance, none of which fully explained the phenotype. Further investigation revealed severe vitamin A deficiency and cranial hyperostosis with narrowing of the optic canals. Retinal findings improved following vitamin A supplementation. This case illustrates the diagnostic complexity of retinal dystrophies, emphasises the need for a multidisciplinary approach by integrating findings from various specialties, including ophthalmology, neurology, medical genetics and neurosurgery, even in patients with genetic findings of potential relevance. Moreover, it highlights vitamin A deficiency as a reversible cause of retinal pathology.
2026-09-04 | Delayed foveal atrophy following early visual improvement after voretigene neparvovec gene therapy in a child.
Voretigene neparvovec (VN) improves retinal sensitivity in biallelic RPE65-associated inherited retinal dystrophy (IRD), with greater best-corrected visual acuity (BCVA) gains reported in children. We describe a 13-year-old male with biallelic RPE65-IRD who underwent bilateral VN treatment without subretinal foveal detachment at the Manchester Royal Eye Hospital. Six weeks post-treatment, BCVA improved by four lines to 0.20 logMAR in the right eye and by three lines to 0.30 logMAR in the left eye. White full-field stimulus threshold (FST) testing showed maximal gains of -37.8 dB in the right eye and -39.1 dB in the left eye. Approximately four years later, the patient presented with marked BCVA decline (0.68 logMAR in the right eye; 0.90 logMAR in the left eye) and FST deterioration to -18.2 dB and -22.8 dB, respectively. Fundoscopy revealed chorioretinal atrophy (CRA) along the vascular arcade, and optical coherence tomography (OCT) showed foveal outer retinal atrophy with relatively preserved perifoveal layers and choroidal hyperreflective foci within the CRA. The rapid BCVA decline, foveal atrophy pattern, and presence of choroidal hyperreflective foci suggest VN-related effects or an inflammatory response as the most likely contributors to CRA development. These findings underscore the need for long-term follow-up after VN treatment to detect potential late deterioration despite early visual gains. Additionally, patients who exhibit pronounced early FST improvements may benefit from modified or extended immunosuppression to reduce the risk of CRA development.
2026-09-01 | Chemical induction and reversal of photoreceptor dystrophy in retinal organoids
Activating transcription factor 6 (ATF6) controls a signal transduction pathway of the unfolded protein response (UPR). Loss-of-function ATF6 mutations cause inherited photoreceptor diseases. Ceapin-A7 is a non-toxic, cell-permeable small molecule that selectively inhibits ATF6. We investigated how ATF6 inhibition impacts photoreceptors by treating wild-type human retinal organoids with Ceapin-A7 and evaluating the effects via single-nucleus RNA sequencing (snRNA-seq) and microscopy after 2 months. Ceapin-A7 administration effectively suppressed ATF6-dependent and UPR-related gene expression and led to fewer rod and cone inner/outer segments, malformed/stunted cone segments, and Müller gliosis, while no photoreceptor cell death was observed. When Ceapin-A7 was removed from retinal organoid media after extended exposure, photoreceptor segment quantity increased, indicating that photoreceptors were able to restore segments. These findings demonstrate that ATF6 is selectively required for photoreceptor inner/outer segment integrity. Furthermore, chemically restoring ATF6 activity promotes photoreceptor segment growth, identifying ATF6/UPR signaling as an attractive pathway to treat photoreceptor diseases.
2026-08-27 | Intracellular Retinoid-Binding Proteins (CRBP, CRALBP, CRABP) as Emerging Drug Targets in Retinal Disease.
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.
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.
proteins
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.
2026-06-29 | Retinal network dysfunction precedes structural degeneration in severe GUCA1A cone-rod dystrophy
Abstract Autosomal dominant cone-rod dystrophy caused by GUCA1A mutations is generally viewed as a disorder of phototransduction, yet the mechanisms linking photoreceptor dysfunction to progressive vision loss remain unclear. Here, using a knock-in mouse carrying the severe GCAP1 p.(E111V) variant, we show that retinal network dysfunction precedes structural degeneration. Mutant mice exhibited delayed rod photoresponses, increased light sensitivity, selective visuospatial deficits, and progressive impairment of visually evoked responses in the superior colliculus and visual cortex, demonstrating propagation of functional deficits beyond photoreceptors. Transcriptomic and ultrastructural analyses revealed early synaptic, mitochondrial and inflammatory alterations despite largely preserved retinal architecture. Acute ex vivo delivery of recombinant wild-type GCAP1 partially restored mutant rod photoresponse kinetics, indicating that these early functional deficits remain biochemically modifiable. These findings redefine severe GUCA1A -associated disease as a progressive disorder of retinal network function, identifying an early therapeutic window before structural degeneration. One-Sentence Summary Visual function breaks down long before photoreceptors are lost, opening an early window for intervention.
2026-05-10 | Genetics of the retina.
The retina is a vital component of the visual system, converting light into neural signals processed by the brain. Its structure includes photoreceptors, bipolar cells, and ganglion cells, each contributing to vision. Genetics play a critical role in retinal development and health, with mutations in over 270 genes linked to inherited retinal diseases, such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Leber congenital amaurosis (LCA). These conditions range from mild visual impairment to complete blindness, reflecting the genetic diversity underlying retinal diseases. Progress in molecular biology has improved understanding of how genetic mutations disrupt retinal function. For example, RP involves mutations in RHO, USH2A, and RPGR, leading to progressive photoreceptor degeneration. AMD is associated with variations in CFH and ARMS2, driven by both genetic and environmental factors. Next-generation sequencing and gene therapy have enabled more targeted treatments. Continued research into retinal implants, pharmacologic interventions, and mitochondrial therapies is expanding therapeutic options, providing hope for improved outcomes and preservation of vision in individuals with these genetic conditions.
2026-04-28 | Protein Inhibitor of Retinal Membrane Guanylyl Cyclase Rescues Mouse Rod Photoreceptors from GUCY2D Retinal Dystrophy.
Mutations in the GUCY2D gene coding for retinal membrane guanylyl cyclase 1 (RetGC1, or GC-E) can deregulate cGMP synthesis in photoreceptors by guanylyl cyclase-activating proteins (GCAPs) via negative Ca2+ feedback and elevate cGMP production in the dark, thus causing autosomal-dominant cone-rod dystrophy (GUCY2D adCORD). We expressed an engineered protein inhibitor of retinal guanylyl cyclase (PIGCY) in transgenic mice of either sex harboring the GUCY2D adCORD RetGC1 mutant Arg838Ser (R838ST g) in order to suppress aberrant production of cGMP in their rods and prevent their fast degeneration. PIGCY did not return the abnormal Ca2+ sensitivity of cGMP synthesis in PIGCYTgR838STg retinas to the normal physiological range, but it reduced the overall rate of cGMP production. Decelerated cGMP production strongly suppressed degeneration of functional rods. By the age of 6 months, 70% of photoreceptor nuclei remained in PIGCYTgR838STg versus 20% in R838STg Retinal response to light detected by electroretinography was preserved in PIGCYTgR838STg mice significantly better than that in R838STg. The remaining altered calcium feedback affected the shape of PIGCYTgR838STg rod photoresponses, but overall light sensitivity was not drastically different from normal. Single photon response amplitude and time-to-peak in PIGCYTgR838STg rods were increased and more variable, but were similar to wild type in fractional light sensitivity and half-saturating light intensity. Consistent with the still abnormal calcium feedback, desensitization under background light in PIGCYTgR838STg rods was increased, and their noise was elevated under moderate background illumination as compared with wild type. In summary, PIGCY effectively rescued degenerating GUCY2D adCORD rods while maintaining their functional light sensitivity.
2026-04-10 | A case of Alström syndrome with growth hormone deficiency and dyslipidemia: a novel homozygous frameshift variant of ALMS1 c.5763del.
Alström syndrome (AS, OMIM #203800) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in ALMS1, characterized by obesity, cardiomyopathy, retinal dystrophy, sensorineural hearing loss, and progressive hepatic and renal involvement. We report a pediatric case of AS complicated by growth hormone deficiency (GHD), focusing on the clinical course and potential metabolic effects of growth hormone (GH) replacement therapy. A 13-year-old girl with AS presented with severe dyslipidemia, including hypertriglyceridemia (727 mg/dL), elevated total cholesterol (251 mg/dL), and low high-density lipoprotein cholesterol (23 mg/dL), together with dilated cardiomyopathy. She was diagnosed with GHD at 3 years of age, with a height of -3.6 SD. GH replacement therapy led to sustained improvement in linear growth, reaching -1.9 SD, and was associated with long-term maintenance of lipid parameters within the normal range. Whole-exome sequencing identified a previously unreported homozygous frameshift variant in ALMS1 (NM_001378454.1:c.5763del; p.(Phe1921Leufs*18)). This case suggests that GH replacement therapy may contribute to improved lipid metabolism in patients with AS complicated by GHD. In addition, it expands the mutational spectrum of ALMS1 and highlights the potential metabolic benefits of early endocrine intervention in AS.
gene therapies
2026-09-23 | CERKL-related inherited retinal dystrophy in a Brazilian cohort: genotype-phenotype correlation
The purpose of this study was to analyze the genotype-phenotype of CERKL -related inherited retinal dystrophy in an outpatient clinic. For the study, 2841 medical records of Brazilian patients with a diagnosis of an inherited retinal dystrophy (IRD) registered at Instituto de Genética Ocular, Brazil, between January 2006 and July 2025 were retrospectively reviewed and 52 patients from 50 unrelated families with a molecular diagnosis of an IRD related to the CERKL gene were selected. Clinical data and molecular tests results were analyzed for genotype-phenotype correlation. Most patients (50/52) presented with the cone rod dystrophy (CORD) and two patients presented with the macular dystrophy (MD) phenotype. Age of presenting symptoms ranged from early childhood (7 years old) to adulthood (40 years old). BCVA Snellen measured at the first visit ranged from 20/25 to light perception, corresponding to 0.1 to 2.7 in log MAR visual acuity. Visual acuity data according to disease duration at the first visit of 37 double null (DN) alleles patients disclosed a Pearson coefficient R 2 of 0.315 for the right eye and 0.405 for the left eye, respectively. A highly significant association between disease duration and visual acuity loss was found suggesting consistent and predictable visual deterioration in patients with complete CERKL loss-of-function over time. Twenty-four different variants described in the CERKL gene were identified. The c.847C>T (p.Arg283) nonsense variant in exon 6 was the most common variant in this cohort, identified in 24 homozygous out of 52 individuals and in 12 compound heterozygous. The phenotype of CERKL -related IRD is CORD with an early age of presentation and fast decrease in visual acuity. In addition to OMIM classifying this gene as an retinitis pigmentosa IRD, we believe CERKL has CORD phenotype, in concordance with evidence described in the literature.
2026-09-23 | Nationwide epidemiology of retinitis pigmentosa in Japan, 2011-2020: a population-based cohort study.
Retinitis pigmentosa (RP) is an inherited retinal disorder with limited contemporary national epidemiological data. This study aimed to describe the nationwide epidemiology of RP in Japan using a comprehensive national health insurance claims database. This population-based longitudinal cohort study included approximately 126 million individuals covered by Japan's universal health coverage system. Data from the National Database of Health Insurance Claims from 2011 to 2020 were analysed. Patients with RP were identified as those who either had a confirmed RP diagnosis on electroretinography or had a confirmed RP diagnosis and received RP-specific treatment (e.g., helenien or vitamin A). Prevalence and incidence rates were calculated, and age-standardised rates were derived using the World Health Organization standard world population. Regional differences, mortality, and age at cataract surgery were also assessed. As of October 1, 2020, 52,964 RP cases were identified, corresponding to a prevalence of 42.0 per 100,000 persons (approximately 1:2,400). The incidence rate was 2.52 per 100,000 person-years. Incidence was higher in southwestern Japan, particularly Kyushu and Shikoku, and lower in northern regions. The mean age at death was 81.7 ± 10.9 years. The mean age at cataract surgery was 68.6 ± 11.6 years. This nationwide population-based study provides updated epidemiological data on RP in Japan, revealing higher prevalence than previously reported, geographic variation, and earlier age at the time of cataract surgery. These findings may inform clinical management, healthcare planning, and future research and clinical trials in inherited retinal diseases.
2026-09-14 | Progress in gene therapy for RPGR-associated X-linked retinitis pigmentosa.
X-linked retinitis pigmentosa (XLRP) caused by pathogenic variants in RPGR is among the most severe inherited retinal dystrophies, with childhood-onset nyctalopia followed by progressive visual-field constriction and central visual loss. The purine-rich ORF15 terminal exon has driven sustained development of adeno-associated virus-mediated gene supplementation. This review summarizes the molecular biology of RPGR, the challenge of stabilizing the ORF15 transgene, the principal clinical programs, and endpoint selection in pivotal trials. Clinical development has followed two transgene strategies: codon optimization preserving full-length RPGRORF15, or a construct containing a 126-amino-acid deletion removing approximately 36% of the Glu-Gly-rich region and 6 of 11 identified glutamylation consensus motifs. Beyond transgene design, appropriate endpoint selection is critical to demonstrating therapeutic efficacy in RPGR-XLRP. The multi-luminance mobility test was developed for RPE65-associated retinal dystrophy, where visual-cycle restoration can rapidly improve night vision, and may be less suited to slowly progressive RPGR-XLRP. Microperimetry can detect localized changes in retinal sensitivity but requires careful standardization and repeated baseline testing to minimize learning effects. Low-luminance visual acuity (LLVA) represents an attractive primary functional endpoint for: it is simple, standardized and clinically meaningful, while challenging central visual function under conditions in which RPGR-XLRP patients may be impaired despite preserved conventional acuity. Importantly, XIRIUS demonstrated treatment-related improvements in LLVA and mean microperimetry sensitivity, supporting the responsiveness of both measures to therapeutic intervention in RPGR-XLRP. LLVA and microperimetry are well suited to primary efficacy assessment in RPGR-XLRP, with endpoint selection guided by disease stage and the anticipated treatment effect and supported by complementary structural biomarkers.
2026-09-01 | Kcnv2 E151X Mouse Captures Hallmarks of KCNV2-Associated Retinal Dystrophy.
KCNV2-associated retinopathy is a rare inherited retinal dystrophy caused by variants in the KCNV2 gene, leading to disrupted photoreceptor behaviour and progressive deterioration of vision. Patients have characteristic electroretinography abnormalities, including reduced cone response, delayed and reduced rod response to low light flashes and paradoxically large rod-driven response to bright flashes of light. To model this condition, we have generated a Kcnv2 E151X mouse line and assessed its structural and functional retinal features. We have employed CRISPR/Cas 9 gene editing technology to generate a mouse line with an early stop mutation in position E151-orthologous to the commonly encountered E143X mutation in humans-and performed a combination of immunohistochemistry and Western blot to confirm the absence of the full-length KCNV2-encoded protein, Kv8.2. Next, to assess how closely it models the human disease, we have characterised the KCNV2 mutant mouse line at histological and functional levels, via immunohistochemistry and electroretinography experiments, respectively. Kcnv2 mutant mice showed markedly reduced photopic responses and reproduced the supernormal rod phenotype described in affected individuals. In the morphological context, mutant retinas demonstrated strong glial fibrillary acidic protein upregulation together with reduced cone arrestin positive cell counts and photoreceptor layers, indicating photoreceptor loss. The Kcnv2 mutant mouse line replicates key functional and structural hallmarks of KCNV2-associated retinopathy. This model provides a relevant platform for mechanistic studies and preclinical evaluation of gene-based or pharmacological therapies targeting cone and rod photoreceptor dysfunction.
2026-08-26 | The First Case Series of Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy in Türkiye Identified with EFEMP1 Gene Mutation.
This report aims to describe the clinical characteristics of the first Turkish family diagnosed with Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) associated with an EFEMP1 mutation. Four affected individuals from the same family (one male and three females; aged 25, 51, 53, and 73 years) underwent comprehensive ophthalmological evaluation. The assessment included best-corrected visual acuity, spectral-domain optical coherence tomography (OCT), color fundus photography, and OCT angiography. In addition, genetic analysis for EFEMP1 mutations was performed. The EFEMP1 variant was identified in all four patients. Clinical examination revealed numerous drusen-like deposits with a radial distribution in the posterior pole, consistent with the ML/DHRD phenotype. OCT imaging demonstrated subretinal and retinal pigment epithelium alterations, which were more advanced in the 73-year-old female patient. Visual acuity was largely preserved in the youngest patient but markedly reduced in older individuals. This case series describes the first Turkish family with genetically confirmed ML/DHRD. Structural imaging demonstrated progressive macular changes associated with aging, highlighting the value of multimodal imaging in assessing disease course.
cell therapies
2026-09-25 | Stem Cell-Based Strategies for Retinal Cell Restoration.
Retinal degenerative diseases, including age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and inherited retinal dystrophies, are among the leading causes of irreversible vision loss and blindness worldwide. Current treatments primarily slow disease progression and are unable to restore lost retinal cells or visual function, highlighting the need for regenerative therapeutic strategies. Stem cell-based therapies have emerged as a promising approach for retinal repair through multiple mechanisms, including retinal cell replacement, stimulation of endogenous regeneration, cellular reprogramming, immunomodulation, and paracrine signaling. This narrative review provides a comprehensive overview of the major stem cell sources investigated for retinal regeneration. In addition, the roles of extracellular vesicles and retinal organoids as emerging therapeutic platforms are discussed. Particular emphasis is placed on comparing the biological rationale, therapeutic potential, current preclinical and clinical evidence, and translational readiness of each approach. Despite encouraging progress, several challenges continue to limit routine clinical application, including poor survival and integration of transplanted cells, immune rejection, tumorigenicity, genomic instability, variability in differentiation efficiency, manufacturing standardization, and long-term safety. Continued advances in stem cell biology, tissue engineering, gene editing, and clinical trial design are expected to accelerate the development of safe and effective regenerative therapies for retinal diseases.
2026-09-24 | Modeling Rod and Cone Pathway Defects Of Visual Pigment Recycling in Zebrafish to Gain Insights Into the Genetics of Retinal Dystrophies
Photoreceptors are the primary light-sensitive neurons for visual perception. They are categorized into two main subgroups; the rod photoreceptors that respond to dim-light/dark and the cone photoreceptors that are responsive to bright-light. All photoreceptors require the 11-cis retinal (RAL) attached to their opsin for photon absorption and initiation of the phototransduction. The photoconverted all-trans RAL is recycled through two biochemical pathways, the RPE-mediated canonical visual cycle accessible to both photoreceptors and the MG-mediated cone-private pathway. Mutations in single components of the canonical visual cycle are known to cause severe retinopathies that ultimately lead to blindness. In contrast, components of the cone-specific visual cycle have not yet been directly associated with inherited retinal diseases, despite the fact that human vision, which largely operates under photopic conditions, relies on the sustained supply of 11-cis retinal to cone photoreceptors. Given the fact that cones comprise 3-5% of the human retina and more than 90% of our vision is generated by the cone-dominant macula. We hypothesized that cone-private pathway defects do not cause immediate vision loss and probably remain clinically undiagnosed due to the under-representation of cones. Thus, we used the cone-dominant retina of the zebrafish (Danio rerio) and the two distinct retinal mosaics in combination with light- and dark-adaptation paradigms, to investigate the dynamics of 11-cis RAL recycling and gain insights into cone pigment regeneration. In this dissertation I will introduce the photoreceptors and inherited retinal diseases (IRDs), with an emphasis on monogenic IRDs caused by components of the visual pigment recycling pathway associated with photoreceptor cell death. Chapter 2 describes the two distinct pathways responsible for the recycling of 11-cis RAL and discusses the advantages of using the cone-dominant zebrafish retina as a model system. In Chapters 3 and 4, I investigated the role of two visual cycle components, RGR and CRALBP1b, respectively, which are shared between both recycling pathways in larval and juvenile zebrafish retina, revealing novel physiological and morphological defects not previously observed in the rod-dominant models. Finally, Chapter 5 integrates the findings from these studies, discusses their limitations, and explores potential therapeutic approaches, highlighting the contribution of zebrafish models to advancing our understanding of visual cycle biology and retinal disease.
2026-07-30 | Macular holes in inherited retinal dystrophies and vitreoretinopathies.
A full-thickness macular hole is conventionally regarded as a vitreoretinal-interface disorder of later life caused by anomalous perifoveal posterior vitreous detachment, tangential traction, and failure of foveal tissue compliance. This model explains idiopathic macular holes. Secondary macular holes could occur secondary to trauma, retinal detachment and high myopia, but less is known about the nature of macular holes associated with inherited retinal dystrophies and vitreoretinopathies, in which the fovea, retinal pigment epithelium, basement membranes, or vitreous cortex may be genetically abnormal before traction is applied. We examine evidence on macular holes in inherited retinal disease, with emphasis on genotype, molecular pathology, optical coherence tomography phenotype and surgical strategy. Three mechanistic groups are clinically useful: (i) disorders of basement membrane and vitreoretinal-interface; (ii) disorders characterized by intrinsic neurosensory retinal weakness; and (iii) retinal pigment epithelium-driven outer-retinal disruption. Surgical closure is often possible, particularly when a tractional component is present and outer-retinal structure is preserved. Visual recovery, however, is limited by photoreceptor integrity, retinal pigment epithelium survival, chronicity and the extent of pre-existing degeneration. In select disorders, especially Alport syndrome, standard internal limiting membrane peeling may be impossible or inappropriate, and alternative scaffold techniques such as amniotic membrane graft may be beneficial. Genetic diagnosis helps to inform mechanism, prognosis, operative planning, counselling and eligibility for emerging gene-directed therapies. This framework may help clinicians interpret optical coherence tomography findings and consider disease-specific surgical risks;. however, the evidence base is dominated by case reports and small case series and varies substantially across diagnoses. Accordingly, the proposed classification and management considerations should be viewed as hypothesis-generating and clinically-pragmatic rather than guideline-level recommendations.
2026-07-27 | Stem cell-based therapies for neuroretinal degeneration: current landscape and future perspectives.
Retinal degenerations, comprising a heterogeneous group of disorders culminating in neuroretinal dysfunction, such as inherited retinal dystrophies (IRDs) and age-related retinal degeneration, are among the leading causes of irreversible vision loss worldwide. Restoring visual function through cell replacement therapy represents an attractive, yet challenging, strategy. Candidate retinal cell sources include retinal progenitor cells (RPCs), Müller glia, human neuroretinal stem-like cells (hNRSCs), and pluripotent stem cells (PSCs). In this review, we discuss their translational advantages and limitations, which in turn influence clinical implementation. We analyze critical manufacturing challenges, including GMP scalability, quality assurance, and ethical considerations in donor material sourcing. Experimental criteria for assessing cellular products' integration into host circuitry and their capacity to restore visual function in preclinical retinal degeneration models must account for donor maturity, host retina architecture, and immune modulation, which determine survival, synapse connectivity, and delivery requirements. Ongoing clinical trials highlight the diversity of cell replacement strategies-from fetal-derived and allogenic progenitor suspensions to laminated PSC-derived retinal sheets-with each approach presenting distinct implications for survival, true integration, and logistical complexity.
2026-07-26 | Photoreceptor replacement: a disease-agnostic approach for the treatment of advanced retinal degeneration.
Retinal dystrophies such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) affect millions of individuals worldwide and remain leading causes of irreversible blindness. Photoreceptor transplantation has emerged as a promising and disease-agnostic therapeutic approach for restoring vision in advanced degenerative retinal diseases characterised by the loss of rods and/or cones. This brief review summarises some key areas of progress and future directions for photoreceptor replacement therapy, with consideration given to translating pre-clinical findings to the clinic.
other
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.
2026-06-18 | Enhanced S-cone syndrome in a family: first long-term (12-year) follow-up and literature review.
To describe the long-term clinical course of Enhanced S-cone Syndrome (ESCS) in three siblings carrying the same NR2E3 variant, and to report therapeutic outcomes of choroidal neovascularization (CNV) and cystic macular changes during a 12-year follow-up from early childhood. This is a retrospective observational family case with literature review. Three siblings were examined periodically over 12 years beginning in early childhood. Clinical evaluation included best corrected visual acuity (BCVA), cycloplegic refraction, multimodal imaging. CNV was treated with intravitreal ranibizumab, while cystic macular changes were managed with topical carbonic anhydrase inhibitors (CAIs). The three siblings shared a homozygous splice site variant (c.119-2 A > C) in the NR2E3 gene and ERG showed ESCS pathognomonic features. In the eldest brother, acute onset esotropia secondary to visual impairment caused by CNV represented the first clinical manifestation. Following the onset of night blindness between ages 11 and 14, the older brother and sister developed macular cystic changes; however, topical CAIs were ineffective. Notably, they maintained stable visual acuity over a 12-year observation period. This family report underscores the clinical variability in ESCS and suggests that the visual acuity of young patients with ESCS remains stable, even in the presence of macular schisis. CNV was successfully treated with two intravitreal injections of ranibizumab, whilst topical CAIs proved ineffective for treating cystic patterns. Additional long-term studies are required to better understand the natural history of ESCS and improve therapeutic strategies.
2026-05-04 | Secondary punctate inner choroidopathy in an RP2 associated retinopathy female carrier.
To describe a case of punctate inner choroidopathy (PIC) occurring in a RP2 associated Retinopathy female carrier, highlighting the diagnostic contribution of multimodal imaging and the therapeutic course. Observational case report with multimodal retinal imaging, electrophysiology, and genetic testing. A 46-year-old woman with high myopia (- 8 diopters in both eyes) and a right Adie's pupil presented with a shadow-like visual disturbance in the right eye (RE). Family history was notable for X-linked retinitis pigmentosa: her brother was hemizygous for the pathogenic RP2 variant c.1 A > G (p.Met1?), and her mother was a heterozygous carrier with light perception vision in both eyes. At presentation, best-corrected visual acuity (BCVA) was 20/32 in the RE and 20/20 in the left eye (LE). Fundus examination revealed diffuse chorioretinal atrophy and multiple punched-out lesions, predominantly nasal, with some macular involvement suggestive of inactive PIC. Subtle peripheral bone spicules were also observed. Fundus autofluorescence (FAF) demonstrated hypoautofluorescent lesions corresponding to the punched-out scars and radial hyperautofluorescent streaks around the posterior pole, a characteristic pattern of X-linked RP carriers. Flash electroretinography revealed bilateral rod and cone dysfunction, more pronounced in the LE. Genetic testing confirmed the heterozygous RP2 c.1 A > G variant, establishing the patient as an X-linked RP carrier. Two years later, the patient developed a new greyish inflammatory lesion in the papillomacular bundle of the RE. OCT demonstrated hyperreflective subretinal material disrupting the RPE with posterior hypertransmission, consistent with an acute PIC lesion. She was treated with systemic corticosteroids and methotrexate. Subsequent flares required treatment escalation, including mycophenolate mofetil and later a combination of methotrexate and adalimumab due to intolerance. One year after initiating biologic therapy, the patient remains in remission with stable visual acuity (20/32 RE, 20/25 LE). Secondary PIC may occur in carriers of X-linked RP. Multimodal imaging and genetic testing are essential for accurate characterization, and immunosuppressive therapy can achieve sustained disease control.
2026-03-25 | Irreversible Ocular and Systemic Damage in ROSAH Syndrome.
This study aimed to describe the clinical, genetic, and pathophysiologic features of four Italian patients from two unrelated families with retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) syndrome, highlighting novel ocular and systemic manifestations and therapeutic considerations. We report detailed phenotypic, ophthalmologic, and systemic findings in four genetically confirmed cases (eight eyes). Special attention was given to ocular and systemic manifestations and complications, inflammatory markers, systemic complications, and treatment responses. All eyes exhibited bilateral optic disc and peripapillary involvement, cone-rod retinal dystrophy confirmed by full-field electroretinography and multimodal retinal imaging, low-grade uveitis and retinal vasculitis. Novel findings included keratoconus in one patient and dry eye in all patients. Acute angle-closure glaucoma was also observed in four eyes (two patients) with short axial lengths. Systemically, in addition to the previously described features of fever, splenomegaly, headache, dental anomalies, and anhidrosis, we report the first case of reactive amyloidosis in ROSAH syndrome, leading to severe renal failure and dialysis dependence. Splenectomy resolved recurrent fever in two patients. Conventional immunosuppressants were largely ineffective, whereas interleukin-6 inhibition provided systemic benefit but limited ocular improvement. ROSAH syndrome presents with distinctive ocular features, and recognition of ocular surface, corneal and anterior segment anomalies further broadens its phenotypic spectrum. Reactive amyloidosis is a possible complication of ROSAH syndrome, as in other autoinflammatory disorders. Early diagnosis is critical to prevent irreversible ocular and extraocular organ damage, and to guide timely, targeted therapeutic interventions.
2026-01-28 | RNA Sequencing and Targeted Knockdown Reveal miR-142a-5p as a Driver of Retinal Degeneration in rd1 Mice.
Retinitis pigmentosa (RP), an inherited retinal disorder, leads to progressive photoreceptor degeneration and irreversible blindness, with limited treatment options available. Emerging evidence implicates microRNAs (miRNAs) in the pathogenesis of retinal disease, yet understanding of their specific roles in RP remains incomplete. In this study, we employed high-throughput RNA sequencing to profile miRNA expression in a rd1 RP mouse model at postnatal day 14. Our analysis revealed 40 upregulated and 27 downregulated miRNAs in rd1 retinas compared to controls. Notably, miR-142a-5p, miR-223-3p, and miR-653-5p were significantly elevated, while miR-25-3p was downregulated. Given miR-142a-5p's established roles in apoptosis and inflammation, we investigated its contribution to retinal degeneration. Knockdown of miR-142a-5p in rd1 mice improved retinal function and preserved outer nuclear layer thickness, suggesting a protective effect against photoreceptor loss. These findings highlight miR-142a-5p as a key regulator of RP progression and a promising therapeutic target for mitigating vision loss in retinal degenerative diseases.
small molecules
2026-09-24 | Fundus albipunctatus-like retinopathy in hypovitaminosis A-related optic neuropathy with skull hyperostosis.
A young man presented with progressive night blindness, optic neuropathy and bilateral retinal flecks, initially suggestive of an inherited retinal dystrophy. Genetic testing identified a heterozygous pathogenic variant in USH2A alongside multiple variants of uncertain significance, none of which fully explained the phenotype. Further investigation revealed severe vitamin A deficiency and cranial hyperostosis with narrowing of the optic canals. Retinal findings improved following vitamin A supplementation. This case illustrates the diagnostic complexity of retinal dystrophies, emphasises the need for a multidisciplinary approach by integrating findings from various specialties, including ophthalmology, neurology, medical genetics and neurosurgery, even in patients with genetic findings of potential relevance. Moreover, it highlights vitamin A deficiency as a reversible cause of retinal pathology.
2026-09-04 | Delayed foveal atrophy following early visual improvement after voretigene neparvovec gene therapy in a child.
Voretigene neparvovec (VN) improves retinal sensitivity in biallelic RPE65-associated inherited retinal dystrophy (IRD), with greater best-corrected visual acuity (BCVA) gains reported in children. We describe a 13-year-old male with biallelic RPE65-IRD who underwent bilateral VN treatment without subretinal foveal detachment at the Manchester Royal Eye Hospital. Six weeks post-treatment, BCVA improved by four lines to 0.20 logMAR in the right eye and by three lines to 0.30 logMAR in the left eye. White full-field stimulus threshold (FST) testing showed maximal gains of -37.8 dB in the right eye and -39.1 dB in the left eye. Approximately four years later, the patient presented with marked BCVA decline (0.68 logMAR in the right eye; 0.90 logMAR in the left eye) and FST deterioration to -18.2 dB and -22.8 dB, respectively. Fundoscopy revealed chorioretinal atrophy (CRA) along the vascular arcade, and optical coherence tomography (OCT) showed foveal outer retinal atrophy with relatively preserved perifoveal layers and choroidal hyperreflective foci within the CRA. The rapid BCVA decline, foveal atrophy pattern, and presence of choroidal hyperreflective foci suggest VN-related effects or an inflammatory response as the most likely contributors to CRA development. These findings underscore the need for long-term follow-up after VN treatment to detect potential late deterioration despite early visual gains. Additionally, patients who exhibit pronounced early FST improvements may benefit from modified or extended immunosuppression to reduce the risk of CRA development.
2026-09-01 | Chemical induction and reversal of photoreceptor dystrophy in retinal organoids
Activating transcription factor 6 (ATF6) controls a signal transduction pathway of the unfolded protein response (UPR). Loss-of-function ATF6 mutations cause inherited photoreceptor diseases. Ceapin-A7 is a non-toxic, cell-permeable small molecule that selectively inhibits ATF6. We investigated how ATF6 inhibition impacts photoreceptors by treating wild-type human retinal organoids with Ceapin-A7 and evaluating the effects via single-nucleus RNA sequencing (snRNA-seq) and microscopy after 2 months. Ceapin-A7 administration effectively suppressed ATF6-dependent and UPR-related gene expression and led to fewer rod and cone inner/outer segments, malformed/stunted cone segments, and Müller gliosis, while no photoreceptor cell death was observed. When Ceapin-A7 was removed from retinal organoid media after extended exposure, photoreceptor segment quantity increased, indicating that photoreceptors were able to restore segments. These findings demonstrate that ATF6 is selectively required for photoreceptor inner/outer segment integrity. Furthermore, chemically restoring ATF6 activity promotes photoreceptor segment growth, identifying ATF6/UPR signaling as an attractive pathway to treat photoreceptor diseases.
2026-08-27 | Intracellular Retinoid-Binding Proteins (CRBP, CRALBP, CRABP) as Emerging Drug Targets in Retinal Disease.
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.
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.
proteins
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.
2026-06-29 | Retinal network dysfunction precedes structural degeneration in severe GUCA1A cone-rod dystrophy
Abstract Autosomal dominant cone-rod dystrophy caused by GUCA1A mutations is generally viewed as a disorder of phototransduction, yet the mechanisms linking photoreceptor dysfunction to progressive vision loss remain unclear. Here, using a knock-in mouse carrying the severe GCAP1 p.(E111V) variant, we show that retinal network dysfunction precedes structural degeneration. Mutant mice exhibited delayed rod photoresponses, increased light sensitivity, selective visuospatial deficits, and progressive impairment of visually evoked responses in the superior colliculus and visual cortex, demonstrating propagation of functional deficits beyond photoreceptors. Transcriptomic and ultrastructural analyses revealed early synaptic, mitochondrial and inflammatory alterations despite largely preserved retinal architecture. Acute ex vivo delivery of recombinant wild-type GCAP1 partially restored mutant rod photoresponse kinetics, indicating that these early functional deficits remain biochemically modifiable. These findings redefine severe GUCA1A -associated disease as a progressive disorder of retinal network function, identifying an early therapeutic window before structural degeneration. One-Sentence Summary Visual function breaks down long before photoreceptors are lost, opening an early window for intervention.
2026-05-10 | Genetics of the retina.
The retina is a vital component of the visual system, converting light into neural signals processed by the brain. Its structure includes photoreceptors, bipolar cells, and ganglion cells, each contributing to vision. Genetics play a critical role in retinal development and health, with mutations in over 270 genes linked to inherited retinal diseases, such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Leber congenital amaurosis (LCA). These conditions range from mild visual impairment to complete blindness, reflecting the genetic diversity underlying retinal diseases. Progress in molecular biology has improved understanding of how genetic mutations disrupt retinal function. For example, RP involves mutations in RHO, USH2A, and RPGR, leading to progressive photoreceptor degeneration. AMD is associated with variations in CFH and ARMS2, driven by both genetic and environmental factors. Next-generation sequencing and gene therapy have enabled more targeted treatments. Continued research into retinal implants, pharmacologic interventions, and mitochondrial therapies is expanding therapeutic options, providing hope for improved outcomes and preservation of vision in individuals with these genetic conditions.
2026-04-28 | Protein Inhibitor of Retinal Membrane Guanylyl Cyclase Rescues Mouse Rod Photoreceptors from GUCY2D Retinal Dystrophy.
Mutations in the GUCY2D gene coding for retinal membrane guanylyl cyclase 1 (RetGC1, or GC-E) can deregulate cGMP synthesis in photoreceptors by guanylyl cyclase-activating proteins (GCAPs) via negative Ca2+ feedback and elevate cGMP production in the dark, thus causing autosomal-dominant cone-rod dystrophy (GUCY2D adCORD). We expressed an engineered protein inhibitor of retinal guanylyl cyclase (PIGCY) in transgenic mice of either sex harboring the GUCY2D adCORD RetGC1 mutant Arg838Ser (R838ST g) in order to suppress aberrant production of cGMP in their rods and prevent their fast degeneration. PIGCY did not return the abnormal Ca2+ sensitivity of cGMP synthesis in PIGCYTgR838STg retinas to the normal physiological range, but it reduced the overall rate of cGMP production. Decelerated cGMP production strongly suppressed degeneration of functional rods. By the age of 6 months, 70% of photoreceptor nuclei remained in PIGCYTgR838STg versus 20% in R838STg Retinal response to light detected by electroretinography was preserved in PIGCYTgR838STg mice significantly better than that in R838STg. The remaining altered calcium feedback affected the shape of PIGCYTgR838STg rod photoresponses, but overall light sensitivity was not drastically different from normal. Single photon response amplitude and time-to-peak in PIGCYTgR838STg rods were increased and more variable, but were similar to wild type in fractional light sensitivity and half-saturating light intensity. Consistent with the still abnormal calcium feedback, desensitization under background light in PIGCYTgR838STg rods was increased, and their noise was elevated under moderate background illumination as compared with wild type. In summary, PIGCY effectively rescued degenerating GUCY2D adCORD rods while maintaining their functional light sensitivity.
2026-04-10 | A case of Alström syndrome with growth hormone deficiency and dyslipidemia: a novel homozygous frameshift variant of ALMS1 c.5763del.
Alström syndrome (AS, OMIM #203800) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in ALMS1, characterized by obesity, cardiomyopathy, retinal dystrophy, sensorineural hearing loss, and progressive hepatic and renal involvement. We report a pediatric case of AS complicated by growth hormone deficiency (GHD), focusing on the clinical course and potential metabolic effects of growth hormone (GH) replacement therapy. A 13-year-old girl with AS presented with severe dyslipidemia, including hypertriglyceridemia (727 mg/dL), elevated total cholesterol (251 mg/dL), and low high-density lipoprotein cholesterol (23 mg/dL), together with dilated cardiomyopathy. She was diagnosed with GHD at 3 years of age, with a height of -3.6 SD. GH replacement therapy led to sustained improvement in linear growth, reaching -1.9 SD, and was associated with long-term maintenance of lipid parameters within the normal range. Whole-exome sequencing identified a previously unreported homozygous frameshift variant in ALMS1 (NM_001378454.1:c.5763del; p.(Phe1921Leufs*18)). This case suggests that GH replacement therapy may contribute to improved lipid metabolism in patients with AS complicated by GHD. In addition, it expands the mutational spectrum of ALMS1 and highlights the potential metabolic benefits of early endocrine intervention in AS.
gene therapies
2026-09-23 | CERKL-related inherited retinal dystrophy in a Brazilian cohort: genotype-phenotype correlation
The purpose of this study was to analyze the genotype-phenotype of CERKL -related inherited retinal dystrophy in an outpatient clinic. For the study, 2841 medical records of Brazilian patients with a diagnosis of an inherited retinal dystrophy (IRD) registered at Instituto de Genética Ocular, Brazil, between January 2006 and July 2025 were retrospectively reviewed and 52 patients from 50 unrelated families with a molecular diagnosis of an IRD related to the CERKL gene were selected. Clinical data and molecular tests results were analyzed for genotype-phenotype correlation. Most patients (50/52) presented with the cone rod dystrophy (CORD) and two patients presented with the macular dystrophy (MD) phenotype. Age of presenting symptoms ranged from early childhood (7 years old) to adulthood (40 years old). BCVA Snellen measured at the first visit ranged from 20/25 to light perception, corresponding to 0.1 to 2.7 in log MAR visual acuity. Visual acuity data according to disease duration at the first visit of 37 double null (DN) alleles patients disclosed a Pearson coefficient R 2 of 0.315 for the right eye and 0.405 for the left eye, respectively. A highly significant association between disease duration and visual acuity loss was found suggesting consistent and predictable visual deterioration in patients with complete CERKL loss-of-function over time. Twenty-four different variants described in the CERKL gene were identified. The c.847C>T (p.Arg283) nonsense variant in exon 6 was the most common variant in this cohort, identified in 24 homozygous out of 52 individuals and in 12 compound heterozygous. The phenotype of CERKL -related IRD is CORD with an early age of presentation and fast decrease in visual acuity. In addition to OMIM classifying this gene as an retinitis pigmentosa IRD, we believe CERKL has CORD phenotype, in concordance with evidence described in the literature.
2026-09-23 | Nationwide epidemiology of retinitis pigmentosa in Japan, 2011-2020: a population-based cohort study.
Retinitis pigmentosa (RP) is an inherited retinal disorder with limited contemporary national epidemiological data. This study aimed to describe the nationwide epidemiology of RP in Japan using a comprehensive national health insurance claims database. This population-based longitudinal cohort study included approximately 126 million individuals covered by Japan's universal health coverage system. Data from the National Database of Health Insurance Claims from 2011 to 2020 were analysed. Patients with RP were identified as those who either had a confirmed RP diagnosis on electroretinography or had a confirmed RP diagnosis and received RP-specific treatment (e.g., helenien or vitamin A). Prevalence and incidence rates were calculated, and age-standardised rates were derived using the World Health Organization standard world population. Regional differences, mortality, and age at cataract surgery were also assessed. As of October 1, 2020, 52,964 RP cases were identified, corresponding to a prevalence of 42.0 per 100,000 persons (approximately 1:2,400). The incidence rate was 2.52 per 100,000 person-years. Incidence was higher in southwestern Japan, particularly Kyushu and Shikoku, and lower in northern regions. The mean age at death was 81.7 ± 10.9 years. The mean age at cataract surgery was 68.6 ± 11.6 years. This nationwide population-based study provides updated epidemiological data on RP in Japan, revealing higher prevalence than previously reported, geographic variation, and earlier age at the time of cataract surgery. These findings may inform clinical management, healthcare planning, and future research and clinical trials in inherited retinal diseases.
2026-09-14 | Progress in gene therapy for RPGR-associated X-linked retinitis pigmentosa.
X-linked retinitis pigmentosa (XLRP) caused by pathogenic variants in RPGR is among the most severe inherited retinal dystrophies, with childhood-onset nyctalopia followed by progressive visual-field constriction and central visual loss. The purine-rich ORF15 terminal exon has driven sustained development of adeno-associated virus-mediated gene supplementation. This review summarizes the molecular biology of RPGR, the challenge of stabilizing the ORF15 transgene, the principal clinical programs, and endpoint selection in pivotal trials. Clinical development has followed two transgene strategies: codon optimization preserving full-length RPGRORF15, or a construct containing a 126-amino-acid deletion removing approximately 36% of the Glu-Gly-rich region and 6 of 11 identified glutamylation consensus motifs. Beyond transgene design, appropriate endpoint selection is critical to demonstrating therapeutic efficacy in RPGR-XLRP. The multi-luminance mobility test was developed for RPE65-associated retinal dystrophy, where visual-cycle restoration can rapidly improve night vision, and may be less suited to slowly progressive RPGR-XLRP. Microperimetry can detect localized changes in retinal sensitivity but requires careful standardization and repeated baseline testing to minimize learning effects. Low-luminance visual acuity (LLVA) represents an attractive primary functional endpoint for: it is simple, standardized and clinically meaningful, while challenging central visual function under conditions in which RPGR-XLRP patients may be impaired despite preserved conventional acuity. Importantly, XIRIUS demonstrated treatment-related improvements in LLVA and mean microperimetry sensitivity, supporting the responsiveness of both measures to therapeutic intervention in RPGR-XLRP. LLVA and microperimetry are well suited to primary efficacy assessment in RPGR-XLRP, with endpoint selection guided by disease stage and the anticipated treatment effect and supported by complementary structural biomarkers.
2026-09-01 | Kcnv2 E151X Mouse Captures Hallmarks of KCNV2-Associated Retinal Dystrophy.
KCNV2-associated retinopathy is a rare inherited retinal dystrophy caused by variants in the KCNV2 gene, leading to disrupted photoreceptor behaviour and progressive deterioration of vision. Patients have characteristic electroretinography abnormalities, including reduced cone response, delayed and reduced rod response to low light flashes and paradoxically large rod-driven response to bright flashes of light. To model this condition, we have generated a Kcnv2 E151X mouse line and assessed its structural and functional retinal features. We have employed CRISPR/Cas 9 gene editing technology to generate a mouse line with an early stop mutation in position E151-orthologous to the commonly encountered E143X mutation in humans-and performed a combination of immunohistochemistry and Western blot to confirm the absence of the full-length KCNV2-encoded protein, Kv8.2. Next, to assess how closely it models the human disease, we have characterised the KCNV2 mutant mouse line at histological and functional levels, via immunohistochemistry and electroretinography experiments, respectively. Kcnv2 mutant mice showed markedly reduced photopic responses and reproduced the supernormal rod phenotype described in affected individuals. In the morphological context, mutant retinas demonstrated strong glial fibrillary acidic protein upregulation together with reduced cone arrestin positive cell counts and photoreceptor layers, indicating photoreceptor loss. The Kcnv2 mutant mouse line replicates key functional and structural hallmarks of KCNV2-associated retinopathy. This model provides a relevant platform for mechanistic studies and preclinical evaluation of gene-based or pharmacological therapies targeting cone and rod photoreceptor dysfunction.
2026-08-26 | The First Case Series of Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy in Türkiye Identified with EFEMP1 Gene Mutation.
This report aims to describe the clinical characteristics of the first Turkish family diagnosed with Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) associated with an EFEMP1 mutation. Four affected individuals from the same family (one male and three females; aged 25, 51, 53, and 73 years) underwent comprehensive ophthalmological evaluation. The assessment included best-corrected visual acuity, spectral-domain optical coherence tomography (OCT), color fundus photography, and OCT angiography. In addition, genetic analysis for EFEMP1 mutations was performed. The EFEMP1 variant was identified in all four patients. Clinical examination revealed numerous drusen-like deposits with a radial distribution in the posterior pole, consistent with the ML/DHRD phenotype. OCT imaging demonstrated subretinal and retinal pigment epithelium alterations, which were more advanced in the 73-year-old female patient. Visual acuity was largely preserved in the youngest patient but markedly reduced in older individuals. This case series describes the first Turkish family with genetically confirmed ML/DHRD. Structural imaging demonstrated progressive macular changes associated with aging, highlighting the value of multimodal imaging in assessing disease course.
cell therapies
2026-09-25 | Stem Cell-Based Strategies for Retinal Cell Restoration.
Retinal degenerative diseases, including age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and inherited retinal dystrophies, are among the leading causes of irreversible vision loss and blindness worldwide. Current treatments primarily slow disease progression and are unable to restore lost retinal cells or visual function, highlighting the need for regenerative therapeutic strategies. Stem cell-based therapies have emerged as a promising approach for retinal repair through multiple mechanisms, including retinal cell replacement, stimulation of endogenous regeneration, cellular reprogramming, immunomodulation, and paracrine signaling. This narrative review provides a comprehensive overview of the major stem cell sources investigated for retinal regeneration. In addition, the roles of extracellular vesicles and retinal organoids as emerging therapeutic platforms are discussed. Particular emphasis is placed on comparing the biological rationale, therapeutic potential, current preclinical and clinical evidence, and translational readiness of each approach. Despite encouraging progress, several challenges continue to limit routine clinical application, including poor survival and integration of transplanted cells, immune rejection, tumorigenicity, genomic instability, variability in differentiation efficiency, manufacturing standardization, and long-term safety. Continued advances in stem cell biology, tissue engineering, gene editing, and clinical trial design are expected to accelerate the development of safe and effective regenerative therapies for retinal diseases.
2026-09-24 | Modeling Rod and Cone Pathway Defects Of Visual Pigment Recycling in Zebrafish to Gain Insights Into the Genetics of Retinal Dystrophies
Photoreceptors are the primary light-sensitive neurons for visual perception. They are categorized into two main subgroups; the rod photoreceptors that respond to dim-light/dark and the cone photoreceptors that are responsive to bright-light. All photoreceptors require the 11-cis retinal (RAL) attached to their opsin for photon absorption and initiation of the phototransduction. The photoconverted all-trans RAL is recycled through two biochemical pathways, the RPE-mediated canonical visual cycle accessible to both photoreceptors and the MG-mediated cone-private pathway. Mutations in single components of the canonical visual cycle are known to cause severe retinopathies that ultimately lead to blindness. In contrast, components of the cone-specific visual cycle have not yet been directly associated with inherited retinal diseases, despite the fact that human vision, which largely operates under photopic conditions, relies on the sustained supply of 11-cis retinal to cone photoreceptors. Given the fact that cones comprise 3-5% of the human retina and more than 90% of our vision is generated by the cone-dominant macula. We hypothesized that cone-private pathway defects do not cause immediate vision loss and probably remain clinically undiagnosed due to the under-representation of cones. Thus, we used the cone-dominant retina of the zebrafish (Danio rerio) and the two distinct retinal mosaics in combination with light- and dark-adaptation paradigms, to investigate the dynamics of 11-cis RAL recycling and gain insights into cone pigment regeneration. In this dissertation I will introduce the photoreceptors and inherited retinal diseases (IRDs), with an emphasis on monogenic IRDs caused by components of the visual pigment recycling pathway associated with photoreceptor cell death. Chapter 2 describes the two distinct pathways responsible for the recycling of 11-cis RAL and discusses the advantages of using the cone-dominant zebrafish retina as a model system. In Chapters 3 and 4, I investigated the role of two visual cycle components, RGR and CRALBP1b, respectively, which are shared between both recycling pathways in larval and juvenile zebrafish retina, revealing novel physiological and morphological defects not previously observed in the rod-dominant models. Finally, Chapter 5 integrates the findings from these studies, discusses their limitations, and explores potential therapeutic approaches, highlighting the contribution of zebrafish models to advancing our understanding of visual cycle biology and retinal disease.
2026-07-30 | Macular holes in inherited retinal dystrophies and vitreoretinopathies.
A full-thickness macular hole is conventionally regarded as a vitreoretinal-interface disorder of later life caused by anomalous perifoveal posterior vitreous detachment, tangential traction, and failure of foveal tissue compliance. This model explains idiopathic macular holes. Secondary macular holes could occur secondary to trauma, retinal detachment and high myopia, but less is known about the nature of macular holes associated with inherited retinal dystrophies and vitreoretinopathies, in which the fovea, retinal pigment epithelium, basement membranes, or vitreous cortex may be genetically abnormal before traction is applied. We examine evidence on macular holes in inherited retinal disease, with emphasis on genotype, molecular pathology, optical coherence tomography phenotype and surgical strategy. Three mechanistic groups are clinically useful: (i) disorders of basement membrane and vitreoretinal-interface; (ii) disorders characterized by intrinsic neurosensory retinal weakness; and (iii) retinal pigment epithelium-driven outer-retinal disruption. Surgical closure is often possible, particularly when a tractional component is present and outer-retinal structure is preserved. Visual recovery, however, is limited by photoreceptor integrity, retinal pigment epithelium survival, chronicity and the extent of pre-existing degeneration. In select disorders, especially Alport syndrome, standard internal limiting membrane peeling may be impossible or inappropriate, and alternative scaffold techniques such as amniotic membrane graft may be beneficial. Genetic diagnosis helps to inform mechanism, prognosis, operative planning, counselling and eligibility for emerging gene-directed therapies. This framework may help clinicians interpret optical coherence tomography findings and consider disease-specific surgical risks;. however, the evidence base is dominated by case reports and small case series and varies substantially across diagnoses. Accordingly, the proposed classification and management considerations should be viewed as hypothesis-generating and clinically-pragmatic rather than guideline-level recommendations.
2026-07-27 | Stem cell-based therapies for neuroretinal degeneration: current landscape and future perspectives.
Retinal degenerations, comprising a heterogeneous group of disorders culminating in neuroretinal dysfunction, such as inherited retinal dystrophies (IRDs) and age-related retinal degeneration, are among the leading causes of irreversible vision loss worldwide. Restoring visual function through cell replacement therapy represents an attractive, yet challenging, strategy. Candidate retinal cell sources include retinal progenitor cells (RPCs), Müller glia, human neuroretinal stem-like cells (hNRSCs), and pluripotent stem cells (PSCs). In this review, we discuss their translational advantages and limitations, which in turn influence clinical implementation. We analyze critical manufacturing challenges, including GMP scalability, quality assurance, and ethical considerations in donor material sourcing. Experimental criteria for assessing cellular products' integration into host circuitry and their capacity to restore visual function in preclinical retinal degeneration models must account for donor maturity, host retina architecture, and immune modulation, which determine survival, synapse connectivity, and delivery requirements. Ongoing clinical trials highlight the diversity of cell replacement strategies-from fetal-derived and allogenic progenitor suspensions to laminated PSC-derived retinal sheets-with each approach presenting distinct implications for survival, true integration, and logistical complexity.
2026-07-26 | Photoreceptor replacement: a disease-agnostic approach for the treatment of advanced retinal degeneration.
Retinal dystrophies such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) affect millions of individuals worldwide and remain leading causes of irreversible blindness. Photoreceptor transplantation has emerged as a promising and disease-agnostic therapeutic approach for restoring vision in advanced degenerative retinal diseases characterised by the loss of rods and/or cones. This brief review summarises some key areas of progress and future directions for photoreceptor replacement therapy, with consideration given to translating pre-clinical findings to the clinic.
other
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.
2026-06-18 | Enhanced S-cone syndrome in a family: first long-term (12-year) follow-up and literature review.
To describe the long-term clinical course of Enhanced S-cone Syndrome (ESCS) in three siblings carrying the same NR2E3 variant, and to report therapeutic outcomes of choroidal neovascularization (CNV) and cystic macular changes during a 12-year follow-up from early childhood. This is a retrospective observational family case with literature review. Three siblings were examined periodically over 12 years beginning in early childhood. Clinical evaluation included best corrected visual acuity (BCVA), cycloplegic refraction, multimodal imaging. CNV was treated with intravitreal ranibizumab, while cystic macular changes were managed with topical carbonic anhydrase inhibitors (CAIs). The three siblings shared a homozygous splice site variant (c.119-2 A > C) in the NR2E3 gene and ERG showed ESCS pathognomonic features. In the eldest brother, acute onset esotropia secondary to visual impairment caused by CNV represented the first clinical manifestation. Following the onset of night blindness between ages 11 and 14, the older brother and sister developed macular cystic changes; however, topical CAIs were ineffective. Notably, they maintained stable visual acuity over a 12-year observation period. This family report underscores the clinical variability in ESCS and suggests that the visual acuity of young patients with ESCS remains stable, even in the presence of macular schisis. CNV was successfully treated with two intravitreal injections of ranibizumab, whilst topical CAIs proved ineffective for treating cystic patterns. Additional long-term studies are required to better understand the natural history of ESCS and improve therapeutic strategies.
2026-05-04 | Secondary punctate inner choroidopathy in an RP2 associated retinopathy female carrier.
To describe a case of punctate inner choroidopathy (PIC) occurring in a RP2 associated Retinopathy female carrier, highlighting the diagnostic contribution of multimodal imaging and the therapeutic course. Observational case report with multimodal retinal imaging, electrophysiology, and genetic testing. A 46-year-old woman with high myopia (- 8 diopters in both eyes) and a right Adie's pupil presented with a shadow-like visual disturbance in the right eye (RE). Family history was notable for X-linked retinitis pigmentosa: her brother was hemizygous for the pathogenic RP2 variant c.1 A > G (p.Met1?), and her mother was a heterozygous carrier with light perception vision in both eyes. At presentation, best-corrected visual acuity (BCVA) was 20/32 in the RE and 20/20 in the left eye (LE). Fundus examination revealed diffuse chorioretinal atrophy and multiple punched-out lesions, predominantly nasal, with some macular involvement suggestive of inactive PIC. Subtle peripheral bone spicules were also observed. Fundus autofluorescence (FAF) demonstrated hypoautofluorescent lesions corresponding to the punched-out scars and radial hyperautofluorescent streaks around the posterior pole, a characteristic pattern of X-linked RP carriers. Flash electroretinography revealed bilateral rod and cone dysfunction, more pronounced in the LE. Genetic testing confirmed the heterozygous RP2 c.1 A > G variant, establishing the patient as an X-linked RP carrier. Two years later, the patient developed a new greyish inflammatory lesion in the papillomacular bundle of the RE. OCT demonstrated hyperreflective subretinal material disrupting the RPE with posterior hypertransmission, consistent with an acute PIC lesion. She was treated with systemic corticosteroids and methotrexate. Subsequent flares required treatment escalation, including mycophenolate mofetil and later a combination of methotrexate and adalimumab due to intolerance. One year after initiating biologic therapy, the patient remains in remission with stable visual acuity (20/32 RE, 20/25 LE). Secondary PIC may occur in carriers of X-linked RP. Multimodal imaging and genetic testing are essential for accurate characterization, and immunosuppressive therapy can achieve sustained disease control.
2026-03-25 | Irreversible Ocular and Systemic Damage in ROSAH Syndrome.
This study aimed to describe the clinical, genetic, and pathophysiologic features of four Italian patients from two unrelated families with retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) syndrome, highlighting novel ocular and systemic manifestations and therapeutic considerations. We report detailed phenotypic, ophthalmologic, and systemic findings in four genetically confirmed cases (eight eyes). Special attention was given to ocular and systemic manifestations and complications, inflammatory markers, systemic complications, and treatment responses. All eyes exhibited bilateral optic disc and peripapillary involvement, cone-rod retinal dystrophy confirmed by full-field electroretinography and multimodal retinal imaging, low-grade uveitis and retinal vasculitis. Novel findings included keratoconus in one patient and dry eye in all patients. Acute angle-closure glaucoma was also observed in four eyes (two patients) with short axial lengths. Systemically, in addition to the previously described features of fever, splenomegaly, headache, dental anomalies, and anhidrosis, we report the first case of reactive amyloidosis in ROSAH syndrome, leading to severe renal failure and dialysis dependence. Splenectomy resolved recurrent fever in two patients. Conventional immunosuppressants were largely ineffective, whereas interleukin-6 inhibition provided systemic benefit but limited ocular improvement. ROSAH syndrome presents with distinctive ocular features, and recognition of ocular surface, corneal and anterior segment anomalies further broadens its phenotypic spectrum. Reactive amyloidosis is a possible complication of ROSAH syndrome, as in other autoinflammatory disorders. Early diagnosis is critical to prevent irreversible ocular and extraocular organ damage, and to guide timely, targeted therapeutic interventions.
2026-01-28 | RNA Sequencing and Targeted Knockdown Reveal miR-142a-5p as a Driver of Retinal Degeneration in rd1 Mice.
Retinitis pigmentosa (RP), an inherited retinal disorder, leads to progressive photoreceptor degeneration and irreversible blindness, with limited treatment options available. Emerging evidence implicates microRNAs (miRNAs) in the pathogenesis of retinal disease, yet understanding of their specific roles in RP remains incomplete. In this study, we employed high-throughput RNA sequencing to profile miRNA expression in a rd1 RP mouse model at postnatal day 14. Our analysis revealed 40 upregulated and 27 downregulated miRNAs in rd1 retinas compared to controls. Notably, miR-142a-5p, miR-223-3p, and miR-653-5p were significantly elevated, while miR-25-3p was downregulated. Given miR-142a-5p's established roles in apoptosis and inflammation, we investigated its contribution to retinal degeneration. Knockdown of miR-142a-5p in rd1 mice improved retinal function and preserved outer nuclear layer thickness, suggesting a protective effect against photoreceptor loss. These findings highlight miR-142a-5p as a key regulator of RP progression and a promising therapeutic target for mitigating vision loss in retinal degenerative diseases.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
20 orphan drug designations for Inherited retinal disorder.
20 orphan drug designations for Inherited retinal disorder.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
a replication-incompetent recombinant adeno-associated virus (rAAV) vector carrying a gene cassette that can express human Prominin1 | gene therapies | FDA | — | Langxin Qisheng (Suzhou) Biopharmaceutical Co., Ltd. |
Antisense oligonucleotide against USH2A pre-mRNA | oligonucleotides | EMA | Astherna B.V. | |
Allogeneic human induced pluripotent stem cell-derived photoreceptor precursor cells | cell therapies | EMA | — | BlueRock Therapeutics Germany GmbH |
Peptide-oligonucleotide conjugate against CNOT3 mRNA | oligonucleotides | EMA | Dokumeds SIA | |
(S)-N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl) thiazol-2-yl)-2,6-difluoro-4-(piperazin-1-yl) benzamide | — | FDA | Drug Farm | |
Non-replicating adeno-associated virus serotype 5 containing the human retinal guanylate cyclase 1 gene | gene therapies | EMA | — | Asphalion S.L. |
Adeno-associated virus vector serotype 8 containing the human CYP4V2 gene | gene therapies | EMA | Laura Nae | |
dual AAV8.ABCA4 gene replacement therapy for the production of human ABCA4 protein | gene therapies | FDA | AAVantgarde Bio SRL | |
Sonpiretigene isteparvovec | gene therapies | EMA | — | Granzer Regulatory Consulting & Services GmbH |
Sonpiretigene isteparvovec | gene therapies | EMA | — | Granzer Regulatory Consulting & Services GmbH |
Methotrexate | small molecules | EMA | Helio Vision Germany GmbH | |
Adeno-associated virus serotype 9 containing the human RPE65 gene | gene therapies | EMA | — | Granzer Regulatory Consulting & Services GmbH |
Dual, recombinant adeno-associated viral vector-based Prime Editing product targeting USH2A gene mutations | gene editing enzymes | FDA | — | Prime Medicine |
peptide-oligonucleotide conjugate that targets CNOT3 mRNA | other | FDA | PYC Therapeutics, LLC | |
Adeno-associated virus pseudotype 2/5 human Nephrocystin-5 (AAV2/5-NPHP5) | gene therapies | FDA | — | National Institutes of Health (NIH), National Center for Advancing Translational Sciences (NCATS) |
Adeno-associated virus vector serotype 8 encoding the ABCA4 protein, C-region, adeno-associated virus vector serotype 8 encoding the ABCA4 protein, N-region | gene therapies | EMA | — | Splicebio S.L. |
Adeno-associated viral 2/5 (AAV2/5) vector expressing the human KCNJ13 gene | gene therapies | FDA | — | Hubble Therapeutics |
Adeno-associated virus serotype 8 containing the human RdCVF sequence and the human RdCVFL sequence | gene therapies | EMA | SparingVision | |
Combination of three adeno-associated viral vectors of serotype 8 containing the 5'-, the body- and the 3'- coding sequences of human CEP290 fused to inteins | gene therapies | EMA | — | Fondazione Telethon Ets |
Adeno-associated viral vector serotype 8 containing the human RPGR gene | gene therapies | FDA | Biogen |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.