RARE DISEASE
Cone rod dystrophy
Cone rod dystrophy
Cone rod dystrophy
Drug discovery
5
drugs
With orphan designations
Overview
Cone rod dystrophy (CRD) is a group of inherited retinal disorders characterized by progressive degeneration of cone photoreceptors (central vision, color perception) with subsequent rod involvement (peripheral/night vision). Caused by mutations in >30 genes, it presents with photophobia, central vision loss, and dyschromatopsia, progressing to peripheral vision loss and legal blindness by mid-adulthood. Diagnosis integrates clinical exam, electroretinography (cone dysfunction > rod), retinal imaging, and genetic testing. No approved therapies exist, though gene replacement trials (e.g., CDHR1-targeted AAV8) show preclinical promise [1][3][11][19].
Categories: rare genetic diseases, rare ophthalmic disorders
Research Papers
406 drug discovery papers about Cone rod dystrophy, with 2 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
406 drug discovery papers about Cone rod dystrophy, with 2 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
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.
2026-04-28 | 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.
2026-03-18 | Reviewer #2 (Public review): Cdhr1a and pcdh15b link photoreceptor outer segments with inner segment calyceal processes revealing a potential mechanism for cone-rod dystrophy
Cone rod dystrophy (CRD) is a macular degeneration disorder characterized by initial cone cell photoreceptor degeneration and subsequently of rod photoreceptors. Mutations in CDHR1, a photoreceptor specific cadherin have been found to be associated with the incidence of cone-rod dystrophy and recapitulated in mouse CDHR1 knockouts. However, the molecular function of CDHR1 remains unknown. CDHR1 has been shown to localize at the leading edge of murine rod nascent outer segment (OS) making junctions to an unknown partner in the inner segment. Using Structured Illumination Microscopy (SIM), we observed that the localization of zebrafish cdhr1a extends from basal nascent OS discs above the periciliary ridge of the inner segment to a considerable length along the OS, akin to calyceal process (CPs). When labeling the CPs using pcdh15b, a CP specific cadherin, we observed that cdhr1a at the leading edge of OS juxtaposes with pcdh15b in the CP. Similar localization patterns were detected in human, macaque, xenopus, ducks, and various rodent PRCs indicating conservation. Importantly, using immunoprecipitation and K652 cell aggregation assays we demonstrate that pcdh15b and cdhr1a can interact and potentially link the OS and CP. To analyze the consequences of OS-CP interactions in CRD, we established a zebrafish cdhr1a mutant line (cdhr1afs*146) and analyzed CRD progression at high temporal resolution. Homozygous cdhr1afs*146 mutants begin to exhibit minor cone OS morphology defects starting at 15 dpf (days post fertilization) and severe OS disruption and cell loss by 3 months. Rod OS defects were delayed until 3-6 months.Furthermore, we show that loss of cdhr1a function leads to disorganization and shortening of CPs coinciding with cone outer OS defects which is significantly exacerbated when combined with the loss of pcdh15b. In conclusion, we propose that cdhr1a and pcdh15b function to link cone OSs with CPs to maintain proper OS homeostasis thus revealing a potential novel mechanism for CRD.
2025-06-02 | Characterizing Inner Retinal Changes in End-Stage Inherited Retinal Diseases That Might be Suitable for Optogenetic Therapies.
The purpose of this study was to characterize retinal structure in patients with late-stage inherited retinal diseases (IRD) for their suitability for optogenetic gene therapy. This was a retrospective study using clinical data and spectral-domain optical coherence tomography (SD-OCT) images of patients with late-stage IRD (visual acuity ≤ 1.0), between December 2012 and 2023 from Oxford Eye Hospital, United Kingdom. Depending on the clinical phenotype and history, the patients were divided into three groups: rod-cone dystrophy (group 1), cone-rod/cone dystrophy (group 2), and macular dystrophy (group 3). SD-OCT structural parameters including total subfoveal thickness and, if possible, individual inner layers thickness were analyzed. 36 patients with late-stage IRD (11, 13, and 12 in groups 1, 2, and 3) and 54 eyes (18 per group) with mean age of 55.9 ± 9.8 years and mean visual acuity of 1.72 ± 0.66 were analyzed. Mean subfoveal thickness was reduced to 167.8 ± 54.3, 153.2 ± 65.3, and 138.1 ± 41.7 µm in groups 1, 2, and 3, respectively, with no significant difference among each group (P = 0.33). Twenty-five of 54 eyes had well-defined inner retinal layers with mean subfoveal thickness of nerve fiber, ganglion cell, inner plexiform, and inner nuclear layers were 12.6 ± 3.9, 17.3 ± 9.9, 18.6 ± 6.7, and 29.4 ± 11.3 µm, respectively. In our cohort, 46.3% of degenerate retinae had preservation of the inner retina, including nerve fiber, ganglion cell, and inner plexiform layers, and/or thickening of the inner nuclear layer and may benefit from targeted cell-specific optogenetic gene therapy. Patients with indiscernible or disrupted inner layers may be amenable to a non-cell-specific approach, to target all surviving neurons. SD-OCT structural characterization of different groups of late-stage IRD offers insight into vector selection and patient eligibility for optogenetic treatments.
2025-05-23 | Design, Expression, and Purification of a Soluble Form of the Retina-Specific Membrane Transporter, ABCA4
The ATP-binding cassette transporter A-subfamily member, ABCA4, is highly expressed in rod and cone photoreceptors in the retina, where it transports cis- and trans-retinal and is indispensable for vision. Genetic mutations in the ABCA4 gene lead to a wide range of inherited retinal degenerative diseases, including Stargardt disease (STGD1) and autosomal recessive cone-rod dystrophy. It is an integral membrane protein with twelve transmembrane α-helices that complicates studies with the full-length ABCA4 transporter. We have engineered the full-length ABCA4 by transforming its membrane helices, creating a soluble homolog (ABCA4s). Most hydrophobic residues in the membrane helices were substituted with structurally compatible but hydrophilic residues. The re-engineered ABCA4s was expressed in insect cells, and it was found in the cytosolic extract, which was purified by immunoaffinity chromatography. Purified ABCA4s was enzymatically active, all-trans-retinal stimulated its ATPase activity, and its activity remained stable.
small molecules
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.
2025-10-18 | Dysfunction of Unc119, a Transducin-Binding Protein, Leads to Cone-Rod Dystrophy through Activating JAK-Stat and NF-κB Inflammatory Pathways in the Mouse Retina.
Transducin is a heterotrimeric G-protein that is a component of the phototransduction cascade in rod and cone photoreceptor cells of the retina. Gnat1, a rod-specific transducin α-subunit, regulates light/dark adaptation by changing its subcellular localization depending on light. Our previous study revealed that Gnat1 translocation in rod photoreceptor cells under light/dark conditions requires E3 ligase Klhl18-mediated ubiquitination and degradation of Unc119, a Gnat1-binding protein. A mutation in the human UNC119 gene is associated with cone-rod dystrophy (CRD); however, the underlying pathological mechanism remains unclear. In this study, we generated and analyzed Unc119-deficient (Unc119-/- ) mice. We found that the retinas of Unc119-/- mice of both sexes exhibited progressive photoreceptor degeneration, resembling CRD in humans. We also found that Unc119 interacts with Gnat2 in cone photoreceptor cells and that Unc119 is essential for the translocation of Gnat2 to the outer segment in cone photoreceptor cells. RNA-seq and subsequent bioinformatics analysis revealed the predicted activation of the JAK-STAT and NF-κB pathways in the Unc119-/- retina. Treatment of Unc119-/- mice with curcumin, an inhibitor of the JAK-STAT and NF-κB pathways, suppressed inflammation and cone photoreceptor cell degeneration in Unc119-/- retinas. Furthermore, a human CRD-associated UNC119 mutant protein competitively inhibited the interaction between UNC119 and GNAT1 or GNAT2. Taken together, the current study suggests that UNC119 dysfunction leads to CRD by affecting the JAK-STAT and NF-κB pathways and may advance our understanding of the pathological mechanisms of CRD.
2025-05-26 | The pathogenicity of a novel frame-shift variant c.2321delC of PROM1 in an autosomal recessive cone-rod dystrophy pedigree may be associated with augment of autophagy.
PROM1 gene mutations are increasingly recognized as significant contributors to inherited retinal diseases, demonstrating considerable heterogeneity in mutation loci and types. In our investigation of a Chinese pedigree presenting with autosomal recessive cone-rod dystrophy, we identified two compound heterozygous frame-shift variants of the PROM1 gene: c.1645-1648del (p.K549Qfs∗3) and c.2321delC (p.A774Vfs∗2). We focused on elucidating the pathogenicity and underlying mechanisms of the novel c.2321delC variant. Following the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, this novel variant was assessed as likely pathogenic. Cellular assays demonstrated that the mutated protein exhibited aberrant subcellular localization and decreased stability compared to wild-type counterparts. Notably, cellular models revealed significant autophagic activation evidenced by elevated LC3II/I ratios, while apoptosis markers remained unaffected. Despite preserved apoptotic pathways, the variant induced marked cellular viability impairment.
2024-11-28 | CBL syndrome presenting with severe EBV infection and panuveitis masquerade.
To describe a case of CBL syndrome presenting with life-threatening pediatric Epstein-Barr virus (EBV) infection and sight-threatening rod-cone dystrophy (RCD) masquerading as severe panuveitis. Single case report with results of whole-exome sequencing (WES) analysis in the proband and his parents. Data were collected from July 2009 to December 2022. A 35-month-old boy presented with severe primary EBV infection complicated by encephalitis and hemophagocytic lymphohistiocytosis. The clinical picture abated with systemic corticosteroids. Genetic testing revealed a heterozygous germline pathogenic variant in the CBL gene c.1141T > G (p.Cys381Gly). At 6 years old, he developed a severe bilateral panuveitis requiring multiple lines of immunosuppressants, mostly to control refractory cystoid macular edema (CME). During follow-up, intraretinal pigment deposits and peripheral retinal atrophy started to appear. Full-field electroretinogram (ffERG) revealed a pattern consistent with RCD. Repeat WES targeting known inherited retinal disease (IRD) genes was negative. A diagnosis of CBL syndrome complicated by RCD masquerading as severe bilateral panuveitis was made, and CME treatment was switched to oral acetazolamide. CBL syndrome can present with severe EBV infection early in life. RCD masquerading as severe panuveitis is also a possible feature of CBL syndrome. RCD should be kept in mind in patients with this syndrome who present with idiopathic intraocular inflammation and are refractory to IMT. Carbonic anhydrase inhibitors (CAI) should be tried early to treat CME.
2024-05-24 | Retinoid Synthesis Regulation by Retinal Cells in Health and Disease.
Vision starts in retinal photoreceptors when specialized proteins (opsins) sense photons via their covalently bonded vitamin A derivative 11cis retinaldehyde (11cis-RAL). The reaction of non-enzymatic aldehydes with amino groups lacks specificity, and the reaction products may trigger cell damage. However, the reduced synthesis of 11cis-RAL results in photoreceptor demise and suggests the need for careful control over 11cis-RAL handling by retinal cells. This perspective focuses on retinoid(s) synthesis, their control in the adult retina, and their role during retina development. It also explores the potential importance of 9cis vitamin A derivatives in regulating retinoid synthesis and their impact on photoreceptor development and survival. Additionally, recent advancements suggesting the pivotal nature of retinoid synthesis regulation for cone cell viability are discussed.
gene therapies
2026-08-17 | StoneRounds Case: SR1780
StoneRounds Case SR1780 was diagnosed with AR Cone and Cone Rod Dystrophy likely caused by mutations in the gene: NMNAT1.
2026-08-10 | Defining a Novel RPGR Phenotype of Sector Retinitis Pigmentosa With Cone Dystrophy.
RPGRORF15-associated retinal degeneration is characterized by clinical and genetic heterogeneity: Proximal mutations typically result in rod-cone dystrophy, distal mutations in cone-dominated disease, and mutations within open-reading frame 15 (ORF15) in either phenotype. This study characterizes an intermediate phenotype in which patients exhibit a combination of cone dystrophy and incomplete (sectoral) rod-cone dystrophy associated with mutations in the ORF15 region and explores potential mechanistic explanations. A multinational, multicenter, observational, cross-sectional case series was conducted using databases from RPGR-related retinal dystrophy clinical trial referral centers. Patients with molecularly confirmed RPGR-related cone dystrophy or RPGR-related cone-rod dystrophy were studied. Individuals exhibiting a mixed phenotype of cone dystrophy and sectoral retinitis pigmentosa were identified. In silico analyses assessed the impact of identified mutations on RPGR transcript expression and protein structure. Fourteen patients exhibited a cone dystrophy phenotype with bilateral, symmetrical regions of outer retinal atrophy distributed along the inferior vascular arcades and extending nasally. All harbored ORF15 mutations within a defined transitional zone. All of the mutations were predicted to produce truncated proteins with partial or complete loss of function. Additionally, several were predicted to disrupt splicing regulatory elements. An intermediate phenotype consisting of a cone dystrophy with sectoral retinitis pigmentosa development was characterized. These patients may benefit from full-length RPGR gene therapy. Furthermore, we demonstrate that this rare presentation closely resembles the phenotype observed in some patients with loss-of-function TTLL5-associated cone dystrophy with sectoral involvement.
2026-08-07 | CDHR1-associated retinal degeneration: Clinical phenotypes and therapeutic approaches.
CDHR1 is a recently identified cause of autosomal recessive retinal degeneration manifesting as three distinct clinical phenotypes: macular dystrophy, cone-rod dystrophy or retinitis pigmentosa. In this review, we summarise the discovery and characterisation of CDHR1, clinical phenotypes, natural history and therapeutic approaches including gene supplementation and CRISPR gene editing. CDHR1 is a non-classical cadherin that is highly expressed in cone and rod photoreceptors and is essential for the higher-order organisation of the functionally critical outer segments. Promising pre-clinical data show that AAV gene supplementation therapy delivered by subretinal injection can lead to long-term morphological, structural, functional and behavioural improvements in the Cdhr1 knockout mouse model. Notably, CDHR1 supplementation restored full-length photoreceptor outer segments that are usually shortened and disorganised in disease models and prolonged photoreceptor survival - key mechanisms for the functional and behavioural rescue effects that were observed. The disease is likely to be underdiagnosed because CDHR1-associated macular dystrophy - likely to be the most common disease phenotype - is most often caused by a 'silent' nucleotide substitution that has previously been overlooked by genetic testing. Since the macular dystrophy phenotype has phenotypic similarities to advanced dry age-related macular degeneration (AMD), misdiagnoses are common. CDHR1-associated macular dystrophy also shares phenotypic features with a variety of monogenic masquerades such as ABCA4, PRPH2 and GUCY2D-associated macular dystrophies; we present a flowchart to guide the clinical distinction of these disorders which is now critical for patients as their treatments diverge. AAV gene therapy may be beneficial across the CDHR1 disease spectrum - including those with hypomorphic variants associated with macular dystrophy or retinitis pigmentosa. The coding sequence fits into AAV and with the macular dystrophy phenotype, there is a large time window for potential intervention and a large treatable population. Hence clinical trials are anticipated. It is therefore important that patients with CDHR1-associated retinal degeneration are accurately phenotyped and genetically confirmed to support the application of CDHR1 gene therapy.
2026-06-10 | Correcting photoreceptor diseases at their source: CRISPR strategies for cone-rod dystrophy and achromatopsia.
Cone-rod dystrophy (CORD) and achromatopsia (ACHM) are inherited retinal dystrophies for which conventional adeno-associated virus (AAV) gene augmentation has important limitations, particularly in autosomal-dominant gain-of-function CORD and recessive ACHM. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) offers the potential for one-time, mutation-specific gene correction or allele ablation. This systematic review summarizes preclinical evidence on CRISPR/Cas9-based approaches for CORD and ACHM, focusing on editing efficiency, phenotypic rescue, and safety. This review followed PRISMA guidelines. PubMed, Google Scholar, and ScienceDirect were searched through June 2025 for original experimental studies using CRISPR/Cas9 in CORD or ACHM animal models or human-derived cell lines. Dual independent screening and data extraction were performed. Outcomes related to editing efficiency, structural or functional rescue, and safety were synthesized narratively. Four studies were included: three targeting CORD and one targeting ACHM. In vivo studies used AAV-delivered SaCas9 to disrupt GUCY2D (or murine orthologs) in mouse and macaque photoreceptors, achieving approximately 8-45% on-target editing in mice and approximately 13% in macaques. Although ablation alone reduced retGC1 expression, it did not improve retinal function; however, a dual-AAV "ablate-and-replace" strategy preserved outer nuclear layer thickness for up to 24 weeks in CORD6 mice. In vitro, PROM1 correction in patient-derived iPSCs restored CD133 expression, and SpCas9-HiFi-mediated PDE6C correction in ACHM iPSCs achieved approximately 80% editing efficiency while preserving pluripotency and showing no detectable off-target effects. Safety data were limited, with immune responses assessed in only one primate study. CRISPR/Cas9 shows promising preclinical efficacy for CORD and ACHM, particularly allele-specific ablate-and-replace strategies for CORD and precise HDR-based correction for ACHM. However, the available evidence remains limited, underscoring the need for expanded safety assessment, non-human primate studies, and standardized functional outcomes measures before clinical translation.
2026-06-09 | Promfusion : a synthetic fusion promoter enabling enhanced and balanced photoreceptor transgene expression
Abstract Achieving efficient and balanced transgene expression in both rods and cones remains a major challenge in retinal gene therapy. Current promoters either lack specificity or fail to provide sufficient cellular coverage and expression level. To address this limitation, we developed and evaluated two fusion promoters, Pikali and Nocchu, by combining PR1.7, a cone-specific promoter and GRK1, a promoter most active in rods. Here, we show that Pikali and Nocchu outperform their parental promoters, driving broader and more balanced GFP expression in rods and cones of human iPSC-derived retinal organoids. These constructs achieved transduction in 30% to 45% of photoreceptors, with higher expression levels than GRK1 and broader cellular coverage than PR1.7. Our findings establish Pikali and Nocchu as excellent candidates for retinal gene therapy, overcoming the limitations of existing promoters. By combining specificity, efficiency, and extensive photoreceptor targeting, these fusion constructs represent a novel and promising strategy for next-generation gene therapy vectors, addressing inherited retinal dystrophies and advancing clinical translation.
oligonucleotides
2023-09-22 | Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in rodent and swine photoreceptors
Abstract Inherited retinal dystrophies caused by dominant mutations in photoreceptor-expressed genes, are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. In the early days, small interfering RNAs (siRNAs) were explored in clinical trials for retinal disorders with limited success due to a lack of stability and efficient cellular delivery. Thus, an unmet need exists to identify siRNA chemistry that targets photoreceptor-expressed genes. Here we evaluated 12 different fully chemically modified siRNA configurations, where the valency and conjugate structure were systematically altered. The impact on retinal distribution following intravitreal delivery was examined. We found that the increase in valency (tetravalent siRNA) supports the best photoreceptor accumulation. A single intravitreal administration induces multi-months efficacy in rodent and porcine retinas while showing a good safety profile. The data suggest that this configuration can treat retinal diseases caused by photoreceptor-expressed genes with 1-2 intravitreal injections per year.
2023-08-23 | Genetic treatment for autosomal dominant inherited retinal dystrophies: approaches, challenges and targeted genotypes.
Inherited retinal diseases (IRDs) have been in the front line of gene therapy development for the last decade, providing a useful platform to test novel therapeutic approaches. More than 40 clinical trials have been completed or are ongoing, tackling autosomal recessive and X-linked conditions, mostly through adeno-associated viral vector delivery of a normal copy of the disease-causing gene. However, only recently has autosomal dominant (ad) disease been targeted, with the commencement of a trial for rhodopsin (RHO)-associated retinitis pigmentosa (RP), implementing antisense oligonucleotide (AON) therapy, with promising preliminary results (NCT04123626).Autosomal dominant RP represents 15%-25% of all RP, with RHO accounting for 20%-30% of these cases. Autosomal dominant macular and cone-rod dystrophies (MD/CORD) correspond to approximately 7.5% of all IRDs, and approximately 35% of all MD/CORD cases, with the main causative gene being BEST1 Autosomal dominant IRDs are not only less frequent than recessive, but also tend to be less severe and have later onset; for example, an individual with RHO-adRP would typically become severely visually impaired at an age 2-3 times older than in X-linked RPGR-RP.Gain-of-function and dominant negative aetiologies are frequently seen in the prevalent adRP genes RHO, RP1 and PRPF31 among others, which would not be effectively addressed by gene supplementation alone and need creative, novel approaches. Zinc fingers, RNA interference, AON, translational read-through therapy, and gene editing by clustered regularly interspaced short palindromic repeats/Cas are some of the strategies that are currently under investigation and will be discussed here.
2023-06-23 | Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci.
Canine RPGRIP1-cone-rod dystrophy (CRD), a model for human inherited retinal diseases (IRDs), was originally identified as autosomal recessive early-onset blindness. However, later studies revealed extensive phenotypic variability among RPGRIP1 mutants. This led to the identification of a homozygous MAP9 variant as a modifier associated with early-onset disease. Based on further phenotypic variation affecting cone photoreceptor function, we report mapping of L3 as an additional modifier locus, within a 4.1-Mb locus on canine chromosome 30. We establish the natural disease history of RPGRIP1-CRD based on up to 9-year long-term functional and structural retinal data from 58 dogs including 44 RPGRIP1 mutants grouped according to the modifier status. RPGRIP1 mutants affected by both MAP9 and L3 modifiers exhibited the most severe phenotypes with rapid disease progression. MAP9 alone was found to act as an overall accelerator of rod and cone diseases, while L3 had a cone-specific effect. Ultrastructural analysis of photoreceptors revealed varying degrees of rod and cone damage, while the connecting cilia appeared structurally preserved in all groups. We conclude that RPGRIP1-CRD is an oligogenic disease with at least three loci contributing to the pathogenesis. While the RPGRIP1 variant is required for developing the disease, MAP9 and L3 modifiers exacerbate the phenotype, individually and cumulatively. Oligogenic canine RPGRIP1-CRD illustrates the impact of multiple genetic modifiers on disease phenotype and thus has the potential to reveal new targets for broad-spectrum therapies for oligogenic or polygenic forms of human IRDs.
2022-09-13 | Retinal cadherins and the retinal cadherinopathies: Current concepts and future directions.
Cadherins are a superfamily of calcium-dependent intercellular adhesion molecules that are widely expressed in living tissues. Within the retina and retinal pigment epithelium (RPE), cadherins contribute to tissue morphogenesis, neural circuit formation, adherens junctions of the outer blood-retinal barrier, photoreceptor disc morphogenesis, maintenance and survival. Four monogenic disorders involving genes which encode cadherins have been identified as causes of inherited retinal degeneration: the retinal cadherinopathies (CDHR1, CDH23, PCDH15, CDH3). Biallelic variants in CDHR1 result in cone-rod dystrophy, rod-cone dystrophy or late-onset macular dystrophy which may be misclassified as dry age-related macular degeneration. Biallelic variants in CDH23 and PCDH15 underlie Usher Syndrome type 1D and 1F. Hypotrichosis with juvenile macular dystrophy results from biallelic variants in CDH3, which contributes to adherens tight junctions between RPE cells. In this review, we summarise the classification of cadherins, and the role of cadherins in the physiology and morphogenesis of the inner and outer retina. Cadherins expressed in primate photoreceptors (CDHR1, CDH23 and PCDH15) have evolved complex roles in outer segment disc morphogenesis and maintenance involving intracellular heterophilic interactions which are as yet incompletely characterised. We highlight what is currently unknown about the molecular function of these cadherins, and review the pathogenesis, clinical phenotype and molecular genetics of each monogenic retinal cadherinopathy. Genes regulating the expression and post-translational modification of retinal cadherins, or those coding for as yet unidentified interacting partners, are candidates for unsolved cases of retinal degeneration. This group of disorders is potentially treatable; we summarise the likely molecular therapeutic approaches and future directions for each retinal cadherinopathy.
2022-07-12 | Retrospective Natural History Study of RPGR-Related Cone- and Cone-Rod Dystrophies While Expanding the Mutation Spectrum of the Disease.
Variants in the X-linked retinitis pigmentosa GTPase regulator gene (RPGR) and, specifically, in its retinal opening reading frame-15 isoform (RPGRORF15) may cause rod-cone (RCD), cone, and cone-rod dystrophies (CDs and CRDs). While RPGR-related RCDs have been frequently evaluated, the characteristics and progression of RPGR-related CD/CRDs are largely unknown. Therefore, the goal of our work was to perform genotype-phenotype correlations specifically in RPGRORF15-related CD/CRDs. This retrospective longitudinal study included 34 index patients and two affected relatives with a molecular diagnosis of RPGR-related CD/CRDs. Patients were recruited at the "Quinze-Vingts" Hospital, Paris, France and screened for mutations in RPGRORF15 at the Institut de la Vision, Paris, France. We identified 29 distinct variants, of which 27 were truncating. All were located in the 3' half of the RPGRORF15 transcript. Twenty of them were novel. Fifteen subjects were affected by CD, the remaining had CRD. When analyzing the longitudinal data, a progressive decline in visual acuity (VA) was noted, with more than 60% of the patients reaching VA ≥ 1 LogMar in the best eye after the fifth decade of life. To our knowledge, this is the largest described study of a cohort of CD/CRD patients affected by RPGRORF15 variants. Longitudinal data showed a rapidly progressive disease, possibly locating an optimal window of intervention for future therapies in younger ages.
other
2026-05-04 | Gene-Agnostic Therapeutic Strategies for Inherited Retinal Diseases: Neuroprotection and Immunomodulation.
Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors-including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin-have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable.
2025-12-01 | Two genes, one culprit - a functional candidate validation of a SPATA7 deletion in dogs with day blindness/retinal degeneration.
Inherited retinal diseases (IRDs) are a diverse group of disorders that share common vision deficits ranging from early onset blindness to severe and progressive later-onset disease. We report a form of early-onset day-vision loss, cone-rod dystrophy, in the Standard poodle. Through GWAS and homozygosity mapping, a large deletion on CFA8:NC_049229.1:g.60,022,583_60,040,453del was found which removes 3' portions of two different genes, PTPN21 and SPATA7, presenting a challenge for assessing the actual causative gene in a multi-gene large deletion. All affected dogs were homozygous for the mutant allele, which segregated perfectly with the phenotype within the breed. The variant was absent in 1879 dogs from the Dog10K database. While the role of SPATA7 for retinal disease has been established in human patients and genetically engineered mice, the role of PTPN21 in the retina is unclear even though it is expressed in rod and cone photoreceptors. Expression of whole and truncated transcripts for both genes was detected in skin fibroblasts from controls and cases. Retinal RNA analysis of PTPN21 splicing suggests that at least one unmodified transcript is still present in mutants. Ptpn21-/- knockout mice did not have an ocular phenotype, and IHC for rod- and cone-specific opsins detected no cone or rod abnormalities suggesting that PTPN21 loss has minimal to no contributory role towards the retinal phenotype in mutants. The variant leads to a deletion of the 3'-end of the SPATA7 transcript: XM_038545497.1:r.1,314_1,629delins[g.60,018,954-60,018,990], p.(XP_038401425.1: Asp361GlufsTer2), reducing the predicted protein from 595 to 361 AA. Ultrastructure expansion microscopy (U-ExM) enabled the detection of a distinct SPATA7 signal around the transition zone of the primary cilium in photoreceptors and fibroblasts of WT dogs, which was absent in affected dog. We posit that SPATA7 deficiency is the main cause of the condition, and propose this disease as a model for the SPATA7-related form of cone-rod dystrophy in humans. Our work shows an example of functional refinement of a multi-gene deletion variant using a multi-technique approach.
2025-11-24 | Data from: Two genes, one culprit - a functional candidate validation of a SPATA7 deletion in dogs with day blindness/retinal degeneration
Inherited retinal diseases (IRDs) are a diverse group of disorders that share common vision deficit ranging from early onset blindness to seInherited retinal diseases (IRDs) are a diverse group of disorders that share common vision deficit ranging from early onset blindness to severe and progressive blindness occurring in later years. We report a form of cone-rod dystrophy with early onset day vision loss in the Standard poodle. Through GWAS and homozygosity mapping, a large deletion on CFA8:g.(60,022,583_60,040,453del) was found, which removes 3’ portions of two different genes, PTPN21 and SPATA7, presenting a challenge for assessing the actual causative gene in a multi-gene large deletion. All affected dogs were homozygous for the mutant allele, which segregated perfectly with the phenotype within the breed. The variant was also absent fromand was also absent in more than control canine structural variants database(dog10k). While the role of SPATA7 for retinal disease has been established in human patients and genetically engineered mice, the role of PTPN21 in retina is unclear even though it is expressed in rod and cone photoreceptors. Expression of truncated transcripts for both genes was detected in skin fibroblasts from the cases. Retinal RNA analysis showed that PTPN21 splicing suggests that in mutant dogs at least one unmodified transcript is present. Ptpn21-/- knockout mice did not have an ocular phenotype, and opsin-specific IHC detected no cone or rod abnormalities in the mice suggesting that PTPN21 loss has none to minimal contributory role towards the retinal phenotype in the affected dogs. The SPATA7 deletion (XM_038674407.1:c.1,301-2,070del, p.Arg387_Asp595del) affects the coding region of the transcript, reducing the predicted protein from 595 to 386 AA . Ultrastructure expansion microscopy (U-ExM) enabled the detection of a distinct SPATA7 signal around the transition zone of the primary cilium in WT canine-skin fibroblasts, which was absent in that of affected dogs. We propose that SPATA7 deficiency is the main cause of the condition and propose this disease as a model for the SPATA7-related form of cone-rod dystrophy in human. Our work shows an example of functional refinement of a multi-gene deletion variant using a multi-technique approach.
2024-01-18 | Immunohistochemical characterization of pluripotency of an iPSC line derived from a patient with cone‐rod dystrophy related to a mutation in the PROM1 gene
Purpose: PROM1 gene encodes the protein Prominin‐1 which plays a critical role in the morphogenesis of photoreceptors outer segments. The c.1354dupT mutation in PROM1 causes a premature stop codon and it has been related with different inherited retinal diseases (IRD) phenotypes. The aim of this study was to demonstrate the expression of key pluripotency genes by studying protein transcription factors and surface markers on the iPSC line [DCB]‐FiPSC1‐Ep5F‐2. Methods: Our group generated the iPSC line [DCB]‐FiPSC1‐Ep5F‐2 from a patient with Cone‐rod dystrophy (CRD) related to the mutation c.1354dupT in the PROM1 gene. iPSC was grown on matrigel coated 15 μ‐slide 8‐well culture plates and fixed with 10% formalin solution. Plates were washed with Tris Buffered Saline and blocked (0.3%Triton X‐100 and 3%Donkey serum) for 60 min. Then, different combinations of primary antibodies related to pluripotency (OCT4, SSEA3, SOX2, SSEA4, TRA1‐60, NANOG and TRA1‐81) were incubated at 4°C overnight. Afterwards, species‐specific secondary antibodies were conjugated and immunostaining with DAPI was used. Finally, the samples were evaluated by confocal microscopy. Results: Immunofluorescence analysis of the iPSC line [DCB]‐FiPSC1‐Ep5F‐2 revealed the expression of the common embryonic stem cell markers such as the transcription factors OCT4, NANOG and SOX2, and the surface markers SSEA3, TRA‐1‐81, SSEA4 and TRA‐1‐60. Transcriptional markers stain cell nuclei, while surface markers stain cell membranes showing that iPSCs have the potential for pluripotency and multilineage differentiation. Conclusions: Although molecular characterization is necessary to completely elucidate iPSC pluripotency and bank this line in an international depository, the [DCB]‐FiPSC1‐Ep5F‐2 patient derived iPSC line could be useful as a disease model for the development of personalized therapies.
2024-01-17 | Sstr2 Defines the Cone Differentiation-Competent Late-Stage Retinal Progenitor Cells in the Developing Mouse Retina.
Cone cell death is a characteristic shared by various retinal degenerative disorders, such as cone-rod dystrophy, Stargardt disease, achromatopsia, and retinitis pigmentosa. This leads to conditions like color blindness and permanently impaired visual acuity. Stem cell therapy focused on photoreceptor replacement holds promise for addressing these conditions. However, identifying surface markers that aid in enriching retinal progenitor cells (RPCs) capable of differentiating into cones remains a complex task. In this study, we employed single-cell RNA sequencing to scrutinize the transcriptome of developing retinas in C57BL/6J mice. This revealed the distinctive expression of somatostatin receptor 2 (Sstr2), a surface protein, in late-stage RPCs exhibiting the potential for photoreceptor differentiation. In vivo lineage tracing experiments verified that Sstr2+ cells within the late embryonic retina gave rise to cones, amacrine and horizontal cells during the developmental process. Furthermore, Sstr2+ cells that were isolated from the late embryonic mouse retina displayed RPC markers and exhibited the capability to differentiate into cones in vitro. Upon subretinal transplantation into both wild-type and retinal degeneration 10 (rd10) mice, Sstr2+ cells survived and expressed cone-specific markers. This study underscores the ability of Sstr2 to enrich late-stage RPCs primed for cone differentiation to a large extent. It proposes the utility of Sstr2 as a biomarker for RPCs capable of generating cones for transplantation purposes.
proteins
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.
2026-04-28 | 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.
2026-03-18 | Reviewer #2 (Public review): Cdhr1a and pcdh15b link photoreceptor outer segments with inner segment calyceal processes revealing a potential mechanism for cone-rod dystrophy
Cone rod dystrophy (CRD) is a macular degeneration disorder characterized by initial cone cell photoreceptor degeneration and subsequently of rod photoreceptors. Mutations in CDHR1, a photoreceptor specific cadherin have been found to be associated with the incidence of cone-rod dystrophy and recapitulated in mouse CDHR1 knockouts. However, the molecular function of CDHR1 remains unknown. CDHR1 has been shown to localize at the leading edge of murine rod nascent outer segment (OS) making junctions to an unknown partner in the inner segment. Using Structured Illumination Microscopy (SIM), we observed that the localization of zebrafish cdhr1a extends from basal nascent OS discs above the periciliary ridge of the inner segment to a considerable length along the OS, akin to calyceal process (CPs). When labeling the CPs using pcdh15b, a CP specific cadherin, we observed that cdhr1a at the leading edge of OS juxtaposes with pcdh15b in the CP. Similar localization patterns were detected in human, macaque, xenopus, ducks, and various rodent PRCs indicating conservation. Importantly, using immunoprecipitation and K652 cell aggregation assays we demonstrate that pcdh15b and cdhr1a can interact and potentially link the OS and CP. To analyze the consequences of OS-CP interactions in CRD, we established a zebrafish cdhr1a mutant line (cdhr1afs*146) and analyzed CRD progression at high temporal resolution. Homozygous cdhr1afs*146 mutants begin to exhibit minor cone OS morphology defects starting at 15 dpf (days post fertilization) and severe OS disruption and cell loss by 3 months. Rod OS defects were delayed until 3-6 months.Furthermore, we show that loss of cdhr1a function leads to disorganization and shortening of CPs coinciding with cone outer OS defects which is significantly exacerbated when combined with the loss of pcdh15b. In conclusion, we propose that cdhr1a and pcdh15b function to link cone OSs with CPs to maintain proper OS homeostasis thus revealing a potential novel mechanism for CRD.
2025-06-02 | Characterizing Inner Retinal Changes in End-Stage Inherited Retinal Diseases That Might be Suitable for Optogenetic Therapies.
The purpose of this study was to characterize retinal structure in patients with late-stage inherited retinal diseases (IRD) for their suitability for optogenetic gene therapy. This was a retrospective study using clinical data and spectral-domain optical coherence tomography (SD-OCT) images of patients with late-stage IRD (visual acuity ≤ 1.0), between December 2012 and 2023 from Oxford Eye Hospital, United Kingdom. Depending on the clinical phenotype and history, the patients were divided into three groups: rod-cone dystrophy (group 1), cone-rod/cone dystrophy (group 2), and macular dystrophy (group 3). SD-OCT structural parameters including total subfoveal thickness and, if possible, individual inner layers thickness were analyzed. 36 patients with late-stage IRD (11, 13, and 12 in groups 1, 2, and 3) and 54 eyes (18 per group) with mean age of 55.9 ± 9.8 years and mean visual acuity of 1.72 ± 0.66 were analyzed. Mean subfoveal thickness was reduced to 167.8 ± 54.3, 153.2 ± 65.3, and 138.1 ± 41.7 µm in groups 1, 2, and 3, respectively, with no significant difference among each group (P = 0.33). Twenty-five of 54 eyes had well-defined inner retinal layers with mean subfoveal thickness of nerve fiber, ganglion cell, inner plexiform, and inner nuclear layers were 12.6 ± 3.9, 17.3 ± 9.9, 18.6 ± 6.7, and 29.4 ± 11.3 µm, respectively. In our cohort, 46.3% of degenerate retinae had preservation of the inner retina, including nerve fiber, ganglion cell, and inner plexiform layers, and/or thickening of the inner nuclear layer and may benefit from targeted cell-specific optogenetic gene therapy. Patients with indiscernible or disrupted inner layers may be amenable to a non-cell-specific approach, to target all surviving neurons. SD-OCT structural characterization of different groups of late-stage IRD offers insight into vector selection and patient eligibility for optogenetic treatments.
2025-05-23 | Design, Expression, and Purification of a Soluble Form of the Retina-Specific Membrane Transporter, ABCA4
The ATP-binding cassette transporter A-subfamily member, ABCA4, is highly expressed in rod and cone photoreceptors in the retina, where it transports cis- and trans-retinal and is indispensable for vision. Genetic mutations in the ABCA4 gene lead to a wide range of inherited retinal degenerative diseases, including Stargardt disease (STGD1) and autosomal recessive cone-rod dystrophy. It is an integral membrane protein with twelve transmembrane α-helices that complicates studies with the full-length ABCA4 transporter. We have engineered the full-length ABCA4 by transforming its membrane helices, creating a soluble homolog (ABCA4s). Most hydrophobic residues in the membrane helices were substituted with structurally compatible but hydrophilic residues. The re-engineered ABCA4s was expressed in insect cells, and it was found in the cytosolic extract, which was purified by immunoaffinity chromatography. Purified ABCA4s was enzymatically active, all-trans-retinal stimulated its ATPase activity, and its activity remained stable.
small molecules
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.
2025-10-18 | Dysfunction of Unc119, a Transducin-Binding Protein, Leads to Cone-Rod Dystrophy through Activating JAK-Stat and NF-κB Inflammatory Pathways in the Mouse Retina.
Transducin is a heterotrimeric G-protein that is a component of the phototransduction cascade in rod and cone photoreceptor cells of the retina. Gnat1, a rod-specific transducin α-subunit, regulates light/dark adaptation by changing its subcellular localization depending on light. Our previous study revealed that Gnat1 translocation in rod photoreceptor cells under light/dark conditions requires E3 ligase Klhl18-mediated ubiquitination and degradation of Unc119, a Gnat1-binding protein. A mutation in the human UNC119 gene is associated with cone-rod dystrophy (CRD); however, the underlying pathological mechanism remains unclear. In this study, we generated and analyzed Unc119-deficient (Unc119-/- ) mice. We found that the retinas of Unc119-/- mice of both sexes exhibited progressive photoreceptor degeneration, resembling CRD in humans. We also found that Unc119 interacts with Gnat2 in cone photoreceptor cells and that Unc119 is essential for the translocation of Gnat2 to the outer segment in cone photoreceptor cells. RNA-seq and subsequent bioinformatics analysis revealed the predicted activation of the JAK-STAT and NF-κB pathways in the Unc119-/- retina. Treatment of Unc119-/- mice with curcumin, an inhibitor of the JAK-STAT and NF-κB pathways, suppressed inflammation and cone photoreceptor cell degeneration in Unc119-/- retinas. Furthermore, a human CRD-associated UNC119 mutant protein competitively inhibited the interaction between UNC119 and GNAT1 or GNAT2. Taken together, the current study suggests that UNC119 dysfunction leads to CRD by affecting the JAK-STAT and NF-κB pathways and may advance our understanding of the pathological mechanisms of CRD.
2025-05-26 | The pathogenicity of a novel frame-shift variant c.2321delC of PROM1 in an autosomal recessive cone-rod dystrophy pedigree may be associated with augment of autophagy.
PROM1 gene mutations are increasingly recognized as significant contributors to inherited retinal diseases, demonstrating considerable heterogeneity in mutation loci and types. In our investigation of a Chinese pedigree presenting with autosomal recessive cone-rod dystrophy, we identified two compound heterozygous frame-shift variants of the PROM1 gene: c.1645-1648del (p.K549Qfs∗3) and c.2321delC (p.A774Vfs∗2). We focused on elucidating the pathogenicity and underlying mechanisms of the novel c.2321delC variant. Following the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, this novel variant was assessed as likely pathogenic. Cellular assays demonstrated that the mutated protein exhibited aberrant subcellular localization and decreased stability compared to wild-type counterparts. Notably, cellular models revealed significant autophagic activation evidenced by elevated LC3II/I ratios, while apoptosis markers remained unaffected. Despite preserved apoptotic pathways, the variant induced marked cellular viability impairment.
2024-11-28 | CBL syndrome presenting with severe EBV infection and panuveitis masquerade.
To describe a case of CBL syndrome presenting with life-threatening pediatric Epstein-Barr virus (EBV) infection and sight-threatening rod-cone dystrophy (RCD) masquerading as severe panuveitis. Single case report with results of whole-exome sequencing (WES) analysis in the proband and his parents. Data were collected from July 2009 to December 2022. A 35-month-old boy presented with severe primary EBV infection complicated by encephalitis and hemophagocytic lymphohistiocytosis. The clinical picture abated with systemic corticosteroids. Genetic testing revealed a heterozygous germline pathogenic variant in the CBL gene c.1141T > G (p.Cys381Gly). At 6 years old, he developed a severe bilateral panuveitis requiring multiple lines of immunosuppressants, mostly to control refractory cystoid macular edema (CME). During follow-up, intraretinal pigment deposits and peripheral retinal atrophy started to appear. Full-field electroretinogram (ffERG) revealed a pattern consistent with RCD. Repeat WES targeting known inherited retinal disease (IRD) genes was negative. A diagnosis of CBL syndrome complicated by RCD masquerading as severe bilateral panuveitis was made, and CME treatment was switched to oral acetazolamide. CBL syndrome can present with severe EBV infection early in life. RCD masquerading as severe panuveitis is also a possible feature of CBL syndrome. RCD should be kept in mind in patients with this syndrome who present with idiopathic intraocular inflammation and are refractory to IMT. Carbonic anhydrase inhibitors (CAI) should be tried early to treat CME.
2024-05-24 | Retinoid Synthesis Regulation by Retinal Cells in Health and Disease.
Vision starts in retinal photoreceptors when specialized proteins (opsins) sense photons via their covalently bonded vitamin A derivative 11cis retinaldehyde (11cis-RAL). The reaction of non-enzymatic aldehydes with amino groups lacks specificity, and the reaction products may trigger cell damage. However, the reduced synthesis of 11cis-RAL results in photoreceptor demise and suggests the need for careful control over 11cis-RAL handling by retinal cells. This perspective focuses on retinoid(s) synthesis, their control in the adult retina, and their role during retina development. It also explores the potential importance of 9cis vitamin A derivatives in regulating retinoid synthesis and their impact on photoreceptor development and survival. Additionally, recent advancements suggesting the pivotal nature of retinoid synthesis regulation for cone cell viability are discussed.
gene therapies
2026-08-17 | StoneRounds Case: SR1780
StoneRounds Case SR1780 was diagnosed with AR Cone and Cone Rod Dystrophy likely caused by mutations in the gene: NMNAT1.
2026-08-10 | Defining a Novel RPGR Phenotype of Sector Retinitis Pigmentosa With Cone Dystrophy.
RPGRORF15-associated retinal degeneration is characterized by clinical and genetic heterogeneity: Proximal mutations typically result in rod-cone dystrophy, distal mutations in cone-dominated disease, and mutations within open-reading frame 15 (ORF15) in either phenotype. This study characterizes an intermediate phenotype in which patients exhibit a combination of cone dystrophy and incomplete (sectoral) rod-cone dystrophy associated with mutations in the ORF15 region and explores potential mechanistic explanations. A multinational, multicenter, observational, cross-sectional case series was conducted using databases from RPGR-related retinal dystrophy clinical trial referral centers. Patients with molecularly confirmed RPGR-related cone dystrophy or RPGR-related cone-rod dystrophy were studied. Individuals exhibiting a mixed phenotype of cone dystrophy and sectoral retinitis pigmentosa were identified. In silico analyses assessed the impact of identified mutations on RPGR transcript expression and protein structure. Fourteen patients exhibited a cone dystrophy phenotype with bilateral, symmetrical regions of outer retinal atrophy distributed along the inferior vascular arcades and extending nasally. All harbored ORF15 mutations within a defined transitional zone. All of the mutations were predicted to produce truncated proteins with partial or complete loss of function. Additionally, several were predicted to disrupt splicing regulatory elements. An intermediate phenotype consisting of a cone dystrophy with sectoral retinitis pigmentosa development was characterized. These patients may benefit from full-length RPGR gene therapy. Furthermore, we demonstrate that this rare presentation closely resembles the phenotype observed in some patients with loss-of-function TTLL5-associated cone dystrophy with sectoral involvement.
2026-08-07 | CDHR1-associated retinal degeneration: Clinical phenotypes and therapeutic approaches.
CDHR1 is a recently identified cause of autosomal recessive retinal degeneration manifesting as three distinct clinical phenotypes: macular dystrophy, cone-rod dystrophy or retinitis pigmentosa. In this review, we summarise the discovery and characterisation of CDHR1, clinical phenotypes, natural history and therapeutic approaches including gene supplementation and CRISPR gene editing. CDHR1 is a non-classical cadherin that is highly expressed in cone and rod photoreceptors and is essential for the higher-order organisation of the functionally critical outer segments. Promising pre-clinical data show that AAV gene supplementation therapy delivered by subretinal injection can lead to long-term morphological, structural, functional and behavioural improvements in the Cdhr1 knockout mouse model. Notably, CDHR1 supplementation restored full-length photoreceptor outer segments that are usually shortened and disorganised in disease models and prolonged photoreceptor survival - key mechanisms for the functional and behavioural rescue effects that were observed. The disease is likely to be underdiagnosed because CDHR1-associated macular dystrophy - likely to be the most common disease phenotype - is most often caused by a 'silent' nucleotide substitution that has previously been overlooked by genetic testing. Since the macular dystrophy phenotype has phenotypic similarities to advanced dry age-related macular degeneration (AMD), misdiagnoses are common. CDHR1-associated macular dystrophy also shares phenotypic features with a variety of monogenic masquerades such as ABCA4, PRPH2 and GUCY2D-associated macular dystrophies; we present a flowchart to guide the clinical distinction of these disorders which is now critical for patients as their treatments diverge. AAV gene therapy may be beneficial across the CDHR1 disease spectrum - including those with hypomorphic variants associated with macular dystrophy or retinitis pigmentosa. The coding sequence fits into AAV and with the macular dystrophy phenotype, there is a large time window for potential intervention and a large treatable population. Hence clinical trials are anticipated. It is therefore important that patients with CDHR1-associated retinal degeneration are accurately phenotyped and genetically confirmed to support the application of CDHR1 gene therapy.
2026-06-10 | Correcting photoreceptor diseases at their source: CRISPR strategies for cone-rod dystrophy and achromatopsia.
Cone-rod dystrophy (CORD) and achromatopsia (ACHM) are inherited retinal dystrophies for which conventional adeno-associated virus (AAV) gene augmentation has important limitations, particularly in autosomal-dominant gain-of-function CORD and recessive ACHM. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) offers the potential for one-time, mutation-specific gene correction or allele ablation. This systematic review summarizes preclinical evidence on CRISPR/Cas9-based approaches for CORD and ACHM, focusing on editing efficiency, phenotypic rescue, and safety. This review followed PRISMA guidelines. PubMed, Google Scholar, and ScienceDirect were searched through June 2025 for original experimental studies using CRISPR/Cas9 in CORD or ACHM animal models or human-derived cell lines. Dual independent screening and data extraction were performed. Outcomes related to editing efficiency, structural or functional rescue, and safety were synthesized narratively. Four studies were included: three targeting CORD and one targeting ACHM. In vivo studies used AAV-delivered SaCas9 to disrupt GUCY2D (or murine orthologs) in mouse and macaque photoreceptors, achieving approximately 8-45% on-target editing in mice and approximately 13% in macaques. Although ablation alone reduced retGC1 expression, it did not improve retinal function; however, a dual-AAV "ablate-and-replace" strategy preserved outer nuclear layer thickness for up to 24 weeks in CORD6 mice. In vitro, PROM1 correction in patient-derived iPSCs restored CD133 expression, and SpCas9-HiFi-mediated PDE6C correction in ACHM iPSCs achieved approximately 80% editing efficiency while preserving pluripotency and showing no detectable off-target effects. Safety data were limited, with immune responses assessed in only one primate study. CRISPR/Cas9 shows promising preclinical efficacy for CORD and ACHM, particularly allele-specific ablate-and-replace strategies for CORD and precise HDR-based correction for ACHM. However, the available evidence remains limited, underscoring the need for expanded safety assessment, non-human primate studies, and standardized functional outcomes measures before clinical translation.
2026-06-09 | Promfusion : a synthetic fusion promoter enabling enhanced and balanced photoreceptor transgene expression
Abstract Achieving efficient and balanced transgene expression in both rods and cones remains a major challenge in retinal gene therapy. Current promoters either lack specificity or fail to provide sufficient cellular coverage and expression level. To address this limitation, we developed and evaluated two fusion promoters, Pikali and Nocchu, by combining PR1.7, a cone-specific promoter and GRK1, a promoter most active in rods. Here, we show that Pikali and Nocchu outperform their parental promoters, driving broader and more balanced GFP expression in rods and cones of human iPSC-derived retinal organoids. These constructs achieved transduction in 30% to 45% of photoreceptors, with higher expression levels than GRK1 and broader cellular coverage than PR1.7. Our findings establish Pikali and Nocchu as excellent candidates for retinal gene therapy, overcoming the limitations of existing promoters. By combining specificity, efficiency, and extensive photoreceptor targeting, these fusion constructs represent a novel and promising strategy for next-generation gene therapy vectors, addressing inherited retinal dystrophies and advancing clinical translation.
oligonucleotides
2023-09-22 | Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in rodent and swine photoreceptors
Abstract Inherited retinal dystrophies caused by dominant mutations in photoreceptor-expressed genes, are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. In the early days, small interfering RNAs (siRNAs) were explored in clinical trials for retinal disorders with limited success due to a lack of stability and efficient cellular delivery. Thus, an unmet need exists to identify siRNA chemistry that targets photoreceptor-expressed genes. Here we evaluated 12 different fully chemically modified siRNA configurations, where the valency and conjugate structure were systematically altered. The impact on retinal distribution following intravitreal delivery was examined. We found that the increase in valency (tetravalent siRNA) supports the best photoreceptor accumulation. A single intravitreal administration induces multi-months efficacy in rodent and porcine retinas while showing a good safety profile. The data suggest that this configuration can treat retinal diseases caused by photoreceptor-expressed genes with 1-2 intravitreal injections per year.
2023-08-23 | Genetic treatment for autosomal dominant inherited retinal dystrophies: approaches, challenges and targeted genotypes.
Inherited retinal diseases (IRDs) have been in the front line of gene therapy development for the last decade, providing a useful platform to test novel therapeutic approaches. More than 40 clinical trials have been completed or are ongoing, tackling autosomal recessive and X-linked conditions, mostly through adeno-associated viral vector delivery of a normal copy of the disease-causing gene. However, only recently has autosomal dominant (ad) disease been targeted, with the commencement of a trial for rhodopsin (RHO)-associated retinitis pigmentosa (RP), implementing antisense oligonucleotide (AON) therapy, with promising preliminary results (NCT04123626).Autosomal dominant RP represents 15%-25% of all RP, with RHO accounting for 20%-30% of these cases. Autosomal dominant macular and cone-rod dystrophies (MD/CORD) correspond to approximately 7.5% of all IRDs, and approximately 35% of all MD/CORD cases, with the main causative gene being BEST1 Autosomal dominant IRDs are not only less frequent than recessive, but also tend to be less severe and have later onset; for example, an individual with RHO-adRP would typically become severely visually impaired at an age 2-3 times older than in X-linked RPGR-RP.Gain-of-function and dominant negative aetiologies are frequently seen in the prevalent adRP genes RHO, RP1 and PRPF31 among others, which would not be effectively addressed by gene supplementation alone and need creative, novel approaches. Zinc fingers, RNA interference, AON, translational read-through therapy, and gene editing by clustered regularly interspaced short palindromic repeats/Cas are some of the strategies that are currently under investigation and will be discussed here.
2023-06-23 | Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci.
Canine RPGRIP1-cone-rod dystrophy (CRD), a model for human inherited retinal diseases (IRDs), was originally identified as autosomal recessive early-onset blindness. However, later studies revealed extensive phenotypic variability among RPGRIP1 mutants. This led to the identification of a homozygous MAP9 variant as a modifier associated with early-onset disease. Based on further phenotypic variation affecting cone photoreceptor function, we report mapping of L3 as an additional modifier locus, within a 4.1-Mb locus on canine chromosome 30. We establish the natural disease history of RPGRIP1-CRD based on up to 9-year long-term functional and structural retinal data from 58 dogs including 44 RPGRIP1 mutants grouped according to the modifier status. RPGRIP1 mutants affected by both MAP9 and L3 modifiers exhibited the most severe phenotypes with rapid disease progression. MAP9 alone was found to act as an overall accelerator of rod and cone diseases, while L3 had a cone-specific effect. Ultrastructural analysis of photoreceptors revealed varying degrees of rod and cone damage, while the connecting cilia appeared structurally preserved in all groups. We conclude that RPGRIP1-CRD is an oligogenic disease with at least three loci contributing to the pathogenesis. While the RPGRIP1 variant is required for developing the disease, MAP9 and L3 modifiers exacerbate the phenotype, individually and cumulatively. Oligogenic canine RPGRIP1-CRD illustrates the impact of multiple genetic modifiers on disease phenotype and thus has the potential to reveal new targets for broad-spectrum therapies for oligogenic or polygenic forms of human IRDs.
2022-09-13 | Retinal cadherins and the retinal cadherinopathies: Current concepts and future directions.
Cadherins are a superfamily of calcium-dependent intercellular adhesion molecules that are widely expressed in living tissues. Within the retina and retinal pigment epithelium (RPE), cadherins contribute to tissue morphogenesis, neural circuit formation, adherens junctions of the outer blood-retinal barrier, photoreceptor disc morphogenesis, maintenance and survival. Four monogenic disorders involving genes which encode cadherins have been identified as causes of inherited retinal degeneration: the retinal cadherinopathies (CDHR1, CDH23, PCDH15, CDH3). Biallelic variants in CDHR1 result in cone-rod dystrophy, rod-cone dystrophy or late-onset macular dystrophy which may be misclassified as dry age-related macular degeneration. Biallelic variants in CDH23 and PCDH15 underlie Usher Syndrome type 1D and 1F. Hypotrichosis with juvenile macular dystrophy results from biallelic variants in CDH3, which contributes to adherens tight junctions between RPE cells. In this review, we summarise the classification of cadherins, and the role of cadherins in the physiology and morphogenesis of the inner and outer retina. Cadherins expressed in primate photoreceptors (CDHR1, CDH23 and PCDH15) have evolved complex roles in outer segment disc morphogenesis and maintenance involving intracellular heterophilic interactions which are as yet incompletely characterised. We highlight what is currently unknown about the molecular function of these cadherins, and review the pathogenesis, clinical phenotype and molecular genetics of each monogenic retinal cadherinopathy. Genes regulating the expression and post-translational modification of retinal cadherins, or those coding for as yet unidentified interacting partners, are candidates for unsolved cases of retinal degeneration. This group of disorders is potentially treatable; we summarise the likely molecular therapeutic approaches and future directions for each retinal cadherinopathy.
2022-07-12 | Retrospective Natural History Study of RPGR-Related Cone- and Cone-Rod Dystrophies While Expanding the Mutation Spectrum of the Disease.
Variants in the X-linked retinitis pigmentosa GTPase regulator gene (RPGR) and, specifically, in its retinal opening reading frame-15 isoform (RPGRORF15) may cause rod-cone (RCD), cone, and cone-rod dystrophies (CDs and CRDs). While RPGR-related RCDs have been frequently evaluated, the characteristics and progression of RPGR-related CD/CRDs are largely unknown. Therefore, the goal of our work was to perform genotype-phenotype correlations specifically in RPGRORF15-related CD/CRDs. This retrospective longitudinal study included 34 index patients and two affected relatives with a molecular diagnosis of RPGR-related CD/CRDs. Patients were recruited at the "Quinze-Vingts" Hospital, Paris, France and screened for mutations in RPGRORF15 at the Institut de la Vision, Paris, France. We identified 29 distinct variants, of which 27 were truncating. All were located in the 3' half of the RPGRORF15 transcript. Twenty of them were novel. Fifteen subjects were affected by CD, the remaining had CRD. When analyzing the longitudinal data, a progressive decline in visual acuity (VA) was noted, with more than 60% of the patients reaching VA ≥ 1 LogMar in the best eye after the fifth decade of life. To our knowledge, this is the largest described study of a cohort of CD/CRD patients affected by RPGRORF15 variants. Longitudinal data showed a rapidly progressive disease, possibly locating an optimal window of intervention for future therapies in younger ages.
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2026-05-04 | Gene-Agnostic Therapeutic Strategies for Inherited Retinal Diseases: Neuroprotection and Immunomodulation.
Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors-including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin-have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable.
2025-12-01 | Two genes, one culprit - a functional candidate validation of a SPATA7 deletion in dogs with day blindness/retinal degeneration.
Inherited retinal diseases (IRDs) are a diverse group of disorders that share common vision deficits ranging from early onset blindness to severe and progressive later-onset disease. We report a form of early-onset day-vision loss, cone-rod dystrophy, in the Standard poodle. Through GWAS and homozygosity mapping, a large deletion on CFA8:NC_049229.1:g.60,022,583_60,040,453del was found which removes 3' portions of two different genes, PTPN21 and SPATA7, presenting a challenge for assessing the actual causative gene in a multi-gene large deletion. All affected dogs were homozygous for the mutant allele, which segregated perfectly with the phenotype within the breed. The variant was absent in 1879 dogs from the Dog10K database. While the role of SPATA7 for retinal disease has been established in human patients and genetically engineered mice, the role of PTPN21 in the retina is unclear even though it is expressed in rod and cone photoreceptors. Expression of whole and truncated transcripts for both genes was detected in skin fibroblasts from controls and cases. Retinal RNA analysis of PTPN21 splicing suggests that at least one unmodified transcript is still present in mutants. Ptpn21-/- knockout mice did not have an ocular phenotype, and IHC for rod- and cone-specific opsins detected no cone or rod abnormalities suggesting that PTPN21 loss has minimal to no contributory role towards the retinal phenotype in mutants. The variant leads to a deletion of the 3'-end of the SPATA7 transcript: XM_038545497.1:r.1,314_1,629delins[g.60,018,954-60,018,990], p.(XP_038401425.1: Asp361GlufsTer2), reducing the predicted protein from 595 to 361 AA. Ultrastructure expansion microscopy (U-ExM) enabled the detection of a distinct SPATA7 signal around the transition zone of the primary cilium in photoreceptors and fibroblasts of WT dogs, which was absent in affected dog. We posit that SPATA7 deficiency is the main cause of the condition, and propose this disease as a model for the SPATA7-related form of cone-rod dystrophy in humans. Our work shows an example of functional refinement of a multi-gene deletion variant using a multi-technique approach.
2025-11-24 | Data from: Two genes, one culprit - a functional candidate validation of a SPATA7 deletion in dogs with day blindness/retinal degeneration
Inherited retinal diseases (IRDs) are a diverse group of disorders that share common vision deficit ranging from early onset blindness to seInherited retinal diseases (IRDs) are a diverse group of disorders that share common vision deficit ranging from early onset blindness to severe and progressive blindness occurring in later years. We report a form of cone-rod dystrophy with early onset day vision loss in the Standard poodle. Through GWAS and homozygosity mapping, a large deletion on CFA8:g.(60,022,583_60,040,453del) was found, which removes 3’ portions of two different genes, PTPN21 and SPATA7, presenting a challenge for assessing the actual causative gene in a multi-gene large deletion. All affected dogs were homozygous for the mutant allele, which segregated perfectly with the phenotype within the breed. The variant was also absent fromand was also absent in more than control canine structural variants database(dog10k). While the role of SPATA7 for retinal disease has been established in human patients and genetically engineered mice, the role of PTPN21 in retina is unclear even though it is expressed in rod and cone photoreceptors. Expression of truncated transcripts for both genes was detected in skin fibroblasts from the cases. Retinal RNA analysis showed that PTPN21 splicing suggests that in mutant dogs at least one unmodified transcript is present. Ptpn21-/- knockout mice did not have an ocular phenotype, and opsin-specific IHC detected no cone or rod abnormalities in the mice suggesting that PTPN21 loss has none to minimal contributory role towards the retinal phenotype in the affected dogs. The SPATA7 deletion (XM_038674407.1:c.1,301-2,070del, p.Arg387_Asp595del) affects the coding region of the transcript, reducing the predicted protein from 595 to 386 AA . Ultrastructure expansion microscopy (U-ExM) enabled the detection of a distinct SPATA7 signal around the transition zone of the primary cilium in WT canine-skin fibroblasts, which was absent in that of affected dogs. We propose that SPATA7 deficiency is the main cause of the condition and propose this disease as a model for the SPATA7-related form of cone-rod dystrophy in human. Our work shows an example of functional refinement of a multi-gene deletion variant using a multi-technique approach.
2024-01-18 | Immunohistochemical characterization of pluripotency of an iPSC line derived from a patient with cone‐rod dystrophy related to a mutation in the PROM1 gene
Purpose: PROM1 gene encodes the protein Prominin‐1 which plays a critical role in the morphogenesis of photoreceptors outer segments. The c.1354dupT mutation in PROM1 causes a premature stop codon and it has been related with different inherited retinal diseases (IRD) phenotypes. The aim of this study was to demonstrate the expression of key pluripotency genes by studying protein transcription factors and surface markers on the iPSC line [DCB]‐FiPSC1‐Ep5F‐2. Methods: Our group generated the iPSC line [DCB]‐FiPSC1‐Ep5F‐2 from a patient with Cone‐rod dystrophy (CRD) related to the mutation c.1354dupT in the PROM1 gene. iPSC was grown on matrigel coated 15 μ‐slide 8‐well culture plates and fixed with 10% formalin solution. Plates were washed with Tris Buffered Saline and blocked (0.3%Triton X‐100 and 3%Donkey serum) for 60 min. Then, different combinations of primary antibodies related to pluripotency (OCT4, SSEA3, SOX2, SSEA4, TRA1‐60, NANOG and TRA1‐81) were incubated at 4°C overnight. Afterwards, species‐specific secondary antibodies were conjugated and immunostaining with DAPI was used. Finally, the samples were evaluated by confocal microscopy. Results: Immunofluorescence analysis of the iPSC line [DCB]‐FiPSC1‐Ep5F‐2 revealed the expression of the common embryonic stem cell markers such as the transcription factors OCT4, NANOG and SOX2, and the surface markers SSEA3, TRA‐1‐81, SSEA4 and TRA‐1‐60. Transcriptional markers stain cell nuclei, while surface markers stain cell membranes showing that iPSCs have the potential for pluripotency and multilineage differentiation. Conclusions: Although molecular characterization is necessary to completely elucidate iPSC pluripotency and bank this line in an international depository, the [DCB]‐FiPSC1‐Ep5F‐2 patient derived iPSC line could be useful as a disease model for the development of personalized therapies.
2024-01-17 | Sstr2 Defines the Cone Differentiation-Competent Late-Stage Retinal Progenitor Cells in the Developing Mouse Retina.
Cone cell death is a characteristic shared by various retinal degenerative disorders, such as cone-rod dystrophy, Stargardt disease, achromatopsia, and retinitis pigmentosa. This leads to conditions like color blindness and permanently impaired visual acuity. Stem cell therapy focused on photoreceptor replacement holds promise for addressing these conditions. However, identifying surface markers that aid in enriching retinal progenitor cells (RPCs) capable of differentiating into cones remains a complex task. In this study, we employed single-cell RNA sequencing to scrutinize the transcriptome of developing retinas in C57BL/6J mice. This revealed the distinctive expression of somatostatin receptor 2 (Sstr2), a surface protein, in late-stage RPCs exhibiting the potential for photoreceptor differentiation. In vivo lineage tracing experiments verified that Sstr2+ cells within the late embryonic retina gave rise to cones, amacrine and horizontal cells during the developmental process. Furthermore, Sstr2+ cells that were isolated from the late embryonic mouse retina displayed RPC markers and exhibited the capability to differentiate into cones in vitro. Upon subretinal transplantation into both wild-type and retinal degeneration 10 (rd10) mice, Sstr2+ cells survived and expressed cone-specific markers. This study underscores the ability of Sstr2 to enrich late-stage RPCs primed for cone differentiation to a large extent. It proposes the utility of Sstr2 as a biomarker for RPCs capable of generating cones for transplantation purposes.
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Drug Discovery Landscape
5 orphan drug designations for Cone rod dystrophy.
5 orphan drug designations for Cone rod dystrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Allogeneic human induced pluripotent stem cell-derived photoreceptor precursor cells | cell therapies | EMA | BlueRock Therapeutics Germany GmbH | |
allogeneic human induced pluripotent stem cell-derived photoreceptor precursor cells | cell therapies | FDA | BlueRock Therapeutics LP | |
Sonpiretigene isteparvovec | gene therapies | EMA | — | Granzer Regulatory Consulting & Services GmbH |
Adeno-associated viral vector serotype 5 expressing the human cone-rod homeobox gene | gene therapies | EMA | — | Variant |
adeno-Associated Virus containing human Nuclear Hormone Receptor NR2E3 (AAV-hNR2E3) gene therapy | gene therapies | FDA | Ocugen Inc. |
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