RARE DISEASE
Stargardt disease
Stargardt disease
Stargardt disease
Synonyms: Fundus flavimaculatus, Stargardt 1
Synonyms: Fundus flavimaculatus, Stargardt 1
Synonyms: Fundus flavimaculatus, Stargardt 1
Drug discovery
32
drugs
With orphan designations
Overview
Stargardt disease is an inherited macular dystrophy caused primarily by biallelic ABCA4 mutations, leading to toxic lipofuscin accumulation in retinal pigment epithelium and photoreceptor degeneration. It manifests as progressive central vision loss, typically emerging in childhood/adolescence, with characteristic yellow retinal flecks. Visual acuity often stabilizes at 20/200–20/400, sparing peripheral vision. Inheritance is usually autosomal recessive, though dominant forms exist (e.g., ELOVL4 mutations). Diagnosis combines fundus imaging, autofluorescence, and genetic testing [1][5][6].
Burden
Visual impairment: 48.7% of eyes develop moderate impairment (>20/70–20/200); 16.5% progress to severe impairment (>20/400) [2][5]
Functional impact: Central vision loss disrupts education/employment, with 47.5% of patients being students [2][13]
Socioeconomic costs: High disability burden due to early-onset, progressive decline, and limited treatments [4][16]
Therapies
Investigational: Visual cycle modulators (emixustat), RBP4 antagonists (tinlarebant), deuterated vitamin A (ALK-001), and optogenetic therapies (MCO-010) [3][7][11]
Gene therapies: RNA exon editors (ACDN-01) and ABCA4 replacement trials underway [11][18]
Supportive care: Low-vision aids, vitamin A restriction, UV-protective lenses [9][17]
Categories: rare genetic diseases, rare ophthalmic disorders
Research Papers
585 drug discovery papers about Stargardt disease, with 4 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
585 drug discovery papers about Stargardt disease, with 4 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-06-04 | Update on the Management of ABCA4 Retinopathy (Stargardt Disease).
ABCA4-associated retinopathies (Stargardt disease) are the most common inherited macular dystrophy and a leading cause of early onset central vision loss. Biallelic pathogenic variants in the ABCA4 gene cause impaired clearance of retinoid byproducts, leading to toxic bisretinoid accumulation, retinal pigment epithelium dysfunction, and progressive photoreceptor degeneration. Clinical presentation and disease progression are highly heterogeneous, largely influenced by genotype, age at onset, and environmental modifiers. Current management remains supportive and includes low-vision rehabilitation and counseling. Recent advances in molecular genetics, retinal imaging, and translational science have substantially expanded the therapeutic pipeline for ABCA4 retinopathy. Disease-modifying strategies under active investigation include visual-cycle modulation, deuterated vitamin A analogs, retinol-binding protein antagonists, gene augmentation and editing approaches, antisense oligonucleotides, and cell-based regenerative therapies. Several pharmacologic agents have demonstrated promising structural outcomes in clinical trials, while gene-based and regenerative approaches continue to evolve amid challenges related to gene size, delivery efficiency, and long-term safety. Optogenetic therapy has emerged as a gene-agnostic option for functional vision restoration in advanced disease stages. This review provides an integrated overview of ABCA4 retinopathy, summarizing disease mechanisms, current management strategies, emerging therapies, and the evolving clinical trial landscape. Emphasis is placed on stage-adapted treatment paradigms, appropriate monitoring endpoints, and the potential role of combination therapies. Ongoing innovation and precision-based approaches offer cautious optimism for durable disease modification and functional preservation in this currently untreatable condition.
2026-06-02 | Exendin-4 averts all-trans-retinal-driven damage to photoreceptors and the retina via the GLP-1R/PKA/CREB1 signaling axis.
Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL. Cell and animal paradigms of STGD1 and dry AMD were generated by atRAL-loaded 661W cells and light-exposed Abca4-/-Rdh8-/- mice, respectively. RNA-sequencing, cell viability assays, morphometric analysis, annexin V/propidium-iodide staining using flow cytometry, quantitative polymerase chain reaction (qPCR), western blotting, immunofluorescence, electroretinography (ERG), fundus photography, hematoxylin and eosin (H&E) histology, and TUNEL staining were integrated to delineate the anti-apoptotic actions of EX-4 and to uncover its underlying protective mechanism. GLP-1R/cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP response element-binding protein 1 (CREB1) signaling was markedly downregulated in atRAL-challenged 661W cells and in neural retina of light-exposed Abca4-/-Rdh8-/- mice. EX-4 reinstated this pathway, suppressed caspase-3 activation and DNA damage, and curtailed apoptosis in both cell and tissue contexts. Silencing of Glp1r or the PKA catalytic subunits by small interfering RNA (siRNA) abrogated EX-4-induced activation of the PKA/CREB1 axis in atRAL-loaded 661W cells. Pharmacologic blockade of CREB1 phosphorylation with the PKA inhibitor H-89 or the CREB1 inhibitor 666-15 largely nullified the DNA-protective and anti-apoptotic benefits conferred by EX-4 in 661W cells following atRAL exposure, suggesting that the GLP-1R/PKA/CREB1 signaling axis contributes to its cytoprotection action. More importantly, intraperitoneal injection of EX-4 significantly preserved retinal structure and function in Abca4-/-Rdh8-/- mice after exposure to light, and mitigated punctate lesions in the fundus. EX-4 exerted anti-apoptotic and DNA-protective effects against atRAL-induced photoreceptor loss and retinal degeneration at least partially through activating the GLP-1R/PKA/CREB1 pathway. These findings suggest that GLP-1R agonists could serve as potential preventive therapeutics for atrophic macular degeneration associated with atRAL toxicity, including dry AMD and STGD1.
2025-08-21 | Safety and efficacy of MCO-010 optogenetic therapy in patients with Stargardt disease in USA (STARLIGHT): an open-label multi-center Ph2 trial.
Stargardt disease (SD) is an inherited degenerative retinal disease affecting rod and cone photoreceptors and retinal pigment epithelial (RPE) cells, leading to severe and irreversible vision loss. Optogenetics is a promising approach to restoring vision by photosensitizing spared healthy retinal neurons. The STARLIGHT phase 2 open-label study (NCT05417126) was conducted over 48-weeks at two US sites to assess the safety and efficacy of MCO-010 administered via a single intravitreal injection in the worse-seeing eye of SD patients. The study began on July 5, 2022, and was completed on September 28, 2023. MCO-010 targets bipolar cells rather than retinal ganglion cells (RGCs) to utilize more abundant cells that respond to ambient light while preserving natural visual processing pathways after treatment. Six adults (mean age 50 years, range 32-71 years, four males and two females) received 1.2E11 genome copies (gc)/eye of MCO-010. The primary outcome was the incidence, nature, severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), intraocular inflammation, retinal thickness, best-corrected visual acuity (BCVA), and lesion size. Secondary endpoints included change in BCVA, vision-guided mobility, and shape determination accuracy. Visual field perimetry and Michigan Retinal Degeneration Questionnaire (MRDQ) were exploratory endpoints. All six participants had at least one ocular TEAE; non-ocular TEAEs occurred in three participants. The most common TEAEs were conjunctival hemorrhage, ocular hypertension, and vitreous cells (two subjects). There were no deaths, hospitalization, loss of eye, retinal detachment, endophthalmitis, or TEAEs leading to study discontinuation. The BCVA (mean ± SD) of the six treated eyes at baseline and 48-week follow-up was 22.8 ± 9.87 (range 9-35), and 28.3 ± 13.28 (range 4-42) ETDRS letters, respectively. The BCVA change from baseline was 7.2 ± 11.74, 4.2 ± 14.81, and 5.5 ± 12.29 at 12, 24, and 48 weeks, respectively. With a wearable magnifier (low-vision glasses), the BCVA change was 17.8 ± 13.35, 15.7 ± 17.37, 13.3 ± 21.37 at 12, 24, and 48 weeks, respectively. The improvement in mean defect in visual field perimetry was 1.02 ± 3.54, 2.47 ± 5.00, and 2.63 ± 5.26 dB at 12, 24, and 48 weeks, respectively. Specific improvements were noted in reading, and color, and contrast domains of the MRDQ. MCO-010 optogenetic phase 2 results support further investigation for treatment SD. To our knowledge, this is the first report of improving on(eye)-chart vision of SD participants utilizing optogenetics. Nanoscope Therapeutics Inc.
2023-11-12 | A Vicious NGF-p75NTR Positive Feedback Loop Exacerbates the Toxic Effects of Oxidative Damage in the Human Retinal Epithelial Cell Line ARPE-19
In spite of its variety of biological activities, the clinical exploitation of human NGF (hNGF) is currently limited to ocular pathologies. It is therefore interesting to test the effects of hNGF in preclinical models that may predict their efficacy and safety in the clinical setting of ocular disorders and compare the effects of hNGF with those of its analogs. We used a human retinal pigment cell line, ARPE-19 cells, to investigate the effects of hNGF and its analogs, mouse NGF (mNGF) and painless NGF (pNGF), on cell viability under basal conditions and after exposure to oxidative stimuli, i.e., hydrogen peroxide (H2O2) and ultraviolet (UV)-A rays. The effects of hNGF and pNGF were also tested on the gene expression and protein synthesis of the two NGF receptor subtypes, p75 neurotrophic receptors (p75NTR) and tyrosine kinase A (TrkA) receptors. We drew the following conclusions: (i) the exposure of ARPE-19 cells to H2O2 or UV-A causes a dose-dependent decrease in the number of viable cells; (ii) under baseline conditions, hNGF, but not pNGF, causes a concentration-dependent decrease in cell viability in the range of doses 1-100 ng/mL; (iii) hNGF, but not pNGF, significantly potentiates the toxic effects of H2O2 or of UV-A on ARPE-19 cells in the range of doses 1-100 ng/mL, while mNGF at the same doses presents an intermediate behavior; (iv) 100 ng/mL of hNGF triggers an increase in p75NTR expression in H2O2-treated ARPE-19 cells, while pNGF at the same dose does not; (v) pNGF, but not hNGF (both given at 100 ng/mL), increases the total cell fluorescence intensity for TrkA receptors in H2O2-treated ARPE-19 cells. The present findings suggest a vicious positive feedback loop through which NGF-mediated upregulation of p75NTR contributes to worsening the toxic effects of oxidative damage in the human retinal epithelial cell line ARPE-19. Looking at the possible clinical relevance of these findings, one can postulate that pNGF might show a better benefit/risk ratio than hNGF in the treatment of ocular disorders.
2023-02-08 | Protein-Mediated Carotenoid Delivery Suppresses the Photoinducible Oxidation of Lipofuscin in Retinal Pigment Epithelial Cells
Lipofuscin of retinal pigment epithelium (RPE) cells is a complex heterogeneous system of chromophores which accumulates as granules during the cell’s lifespan. Lipofuscin serves as a source of various cytotoxic effects linked with oxidative stress. Several age-related eye diseases such as macular degeneration of the retina, as well as some severe inherited eye pathologies, are accompanied by a significant increase in lipofuscin granule concentration. The accumulation of carotenoids in the RPE could provide an effective antioxidant protection against lipofuscin cytotoxic manifestations. Given the highly lipophilic nature of carotenoids, their targeted delivery to the vulnerable tissues can potentially be assisted by special proteins. In this study, we demonstrate how protein-mediated delivery of zeaxanthin using water-soluble Bombyx mori carotenoid-binding protein (BmCBP-ZEA) suppresses the photoinducible oxidative stress in RPE cells caused by irradiation of lipofuscin with intense white light. We implemented fluorescence lifetime imaging of the RPE cell culture ARPE-19 fed with lipofuscin granules and then irradiated by white light with and without the addition of BmCBP-ZEA. We demonstrate that after irradiation the mean fluorescence lifetime of lipofuscin significantly increases, while the presence of BmCBP-ZEA at 200 nM concentration suppresses the increase in the average lifetime of lipofuscin fluorescence, indicating an approx. 35% inhibition of the oxidative stress. This phenomenon serves as indirect yet important evidence of the efficiency of the protein-mediated carotenoid delivery into pigment epithelium cells.
small molecules
2026-09-24 | [Stargardt disease: genetics, molecular mechanisms, potential lifestyle interventions and pharmacotherapy].
Stargardt disease (STGD1) is the most common inherited macular dystrophy. It is caused by biallelic variants in the ABCA4 gene and leads to impaired retinoid transport within photoreceptors. Disruption of retinoid clearance results in the accumulation of lipofuscin in the retinal pigment epithelium (RPE), which in turn induces oxidative stress, complement activation and progressive degeneration of the RPE and photoreceptors. Despite substantial advances in the understanding of the underlying pathophysiological mechanisms, no approved causal therapy is currently available; however, several promising pharmacological approaches are under preclinical and clinical investigation, targeting different metabolic steps within and around the visual cycle. This review article summarizes the genetic and pathophysiological basis of Stargardt disease and provides an overview of potential lifestyle interventions and emerging pharmacological treatment strategies. These advances could soon translate into disease-modifying therapies, highlighting the importance of early diagnosis and patient referral to specialized centers.
2026-09-03 | Safety and Effects of Gildeuretinol Acetate on Retinal Atrophic Lesions in Stargardt Disease: The TEASE-1 Randomized Clinical Trial.
Stargardt disease (STGD) is the most common macular dystrophy, resulting in profound loss of vision. There is no approved treatment. To evaluate the safety and effects of oral gildeuretinol acetate on the growth of retinal atrophic lesions in individuals with STGD. TEASE-1 was a 2-year, multicenter, double-masked, placebo-controlled randomized clinical trial incorporating a crossover group and additional natural history (NH) cases selected prior to drafting the statistical analysis plan. The trial was conducted at 7 outpatient clinics in the US. Participants were aged 12 years or older, clinically diagnosed with STGD, with well-demarcated area(s) of significantly reduced autofluorescence, and supported with at least 1 ABCA4 disease-causing or likely disease-causing variant. The study was conducted between August 2015 and October 2019; data were analyzed between July and December 2020. Participants were randomized 1.5:1.5:1:1 to daily oral gildeuretinol acetate, 14 mg; gildeuretinol acetate, 24 mg; or placebo for 24 months; or placebo for 12 months followed by gildeuretinol for 12 months. The primary efficacy end point was the growth rate of well-delineated and homogeneous areas of retinal atrophic lesions over 24 months of treatment on fundus autofluorescence imaging. Safety end points included treatment-emergent adverse events (AEs), serious AEs, and clinical laboratory assessments. A total of 50 participants were randomized, and 54 NH cases included. The mean (range) age of randomized participants was 44.3 (18-60) years. Overall, 58 of 104 participants or cases (55.8%) were female. The growth rate of retinal atrophic lesions was 0.182 mm/y with gildeuretinol and 0.232 mm/y in the untreated group (placebo and NH), representing a mean difference of -0.050 mm/y (95% CI, -0.072 to -0.027; P < .001) and a 21.6% relative reduction. In a prespecified sensitivity analysis restricted to randomized participants, the growth rate was 0.206 mm/y with gildeuretinol and 0.242 mm/y with placebo, representing a mean difference of -0.036 mm/y (95% CI, -0.062 to -0.009; P = .008) and a 14.9% relative reduction. The majority of AEs were mild or moderate and equally distributed between groups. No treatment-related serious AEs, clinically significant liver function abnormalities, or participant-reported night blindness or dark adaption difficulties occurred. In the TEASE-1 randomized clinical trial, the primary efficacy end point of retinal atrophic lesion growth from 6 to 24 months was 0.05 mm/y greater on average in the untreated group (placebo and NH) than the gildeuretinol acetate group. Further research is needed to determine the clinical relevance of this end point. ClinicalTrials.gov Identifier: NCT02402660.
2026-08-13 | Does Crocus sativus (Saffron) Have an Influence or Effect on Ocular Health: A Systematic Literature Review.
BackgroundCrocus sativus (Saffron) and its bioactive constituents, crocin and crocetin have gained attention for their neuroprotective and antioxidant properties in ocular health. This review synthesises clinical evidence from extracted studies evaluating their efficacy, safety and dosing across Age-related Macular Degeneration (AMD), Primary Open-Angle Glaucoma (POAG), Diabetic Macular Edema (DME), Central Serous Retinopathy (CSR), Stargardt Disease (STGD1) and Paediatric Myopia (PM).MethodologyA systematic literature review was undertaken assessing randomized trials, observational or cohort studies, case studies or series written in English between January 2015 to January 2025. Studies were identified using PubMed, AMED, CINHAL, ScienceDirect and Scopus as well as the grey literature.ResultsTen clinical trials were identified from 529 citations. Interventions involved oral supplementation of saffron (20-50mg/day), crocin (5-15mg/day) and crocetin (7.5mg/day) over durations ranging from 6 weeks to 12 months. Primary outcomes included visual acuity, retinal electrophysiology, intra-ocular pressure, macular thickness, and safety profiles.ConclusionSaffron, crocin and crocetin, demonstrate consistent efficacy and exceptional safety profiles across a range of ocular conditions. Saffron's dose-dependent therapeutic effects are a promising adjunctive therapy in ophthalmology. Further large-scale trials are warranted to confirm these findings and refine condition specific dosing.
2026-07-29 | V3-RGN-09 Molecular Simulator: A Formally Verified Ada/SPARK In Silico Engine for Dual-Target Retinal Regeneration and Biophysical Blind-Test Validation
BACKGROUND & PURPOSE: Retinal degenerative disorders—such as age-related macular degeneration (AMD), diabetic macular edema (DME), and glaucoma—represent complex multi-layered neuropathologies that remain challenging to model in silico without computational instability or artificial bias. Traditional computational biology frameworks (primarily C/C++ or Python) lack formal safety guarantees and deterministic physical boundaries. This work introduces the "V3-RGN-09 Molecular Simulator", an in silico biophysical platform developed entirely in Ada/SPARK 2022 to simulate the complete mechanics of multi-layered retinal regeneration and drug-target interactions with 100% formal mathematical proof (zero runtime exceptions, zero memory bugs). METHODOLOGY & ARCHITECTURE: The simulator relies on four locked V3 Invariants: 1. Physical Mass/Pressure Invariant (Ψ_V3 = 48,016.8 kg·m⁻²), 2. Critical Biophysical Phase Lock Attractor (Φ_critical = -51.10 mV vs. Φ_basal = -70.00 mV), 3. Heptadic Layer Closure (k = 7, modeling all 7 distinct anatomical retinal layers), 4. Modulo-9 Checksum Predicates guaranteeing structural integrity across all execution threads. The core module evaluates the novel synthetic hybrid molecule V3-RGN-09 (Molecular Weight: 842.6 Da, ΔG = -11.8 kcal/mol, Kd = 0.042 nM), engineered from 3D atomic coordinates of PDB 6M76 (TGFBR1 / Anti-TGF-β Domain A) and PDB 1BND (TrkB/PEDF Neurotrophic Domain B). EXPERIMENTAL VALIDATION & BLIND TESTS: The architecture underwent extensive stress-testing and empirical validation: 1. Blind Diagnostic Simulations (16/16 Successful): Without diagnostic tags or clinical labels, the engine evaluated raw physical parameters (fluid pressure, ion gradients, mechanical stress, enzymatic clearance). Through differential integration across the 7 layers (k=7), the engine autonomously rediscovered exact real-world pathological footprints, including Wet/Dry AMD, Glaucoma, Stargardt Disease, Central Retinal Artery Occlusion (CRAO), Macular Holes, and CAR Retinopathy with 100% concordance to clinical benchmarks. 2. Reverse Engineering / Back-Propagation Test: By setting an optimal clinical recovery target (Phase Lock at -51.10 mV in 18 days with >75% fibrosis reduction), back-propagation equations independently generated the precise structural and affinity constraints of the V3-RGN-09 hybrid pharmacophore. 3. Extreme Stress Testing & Fuzzing: Monte-Carlo simulations (100,000 runs under ±15% parameter noise) demonstrated a 99.98% convergence rate to the Φ_critical attractor. Simulated memory corruption and bit-flips triggered instantaneous execution isolation (0.00 ms crash rate) via SPARK pre/post-conditions. 4. Clinical Benchmark Cross-Validation: Predicted clinical outcomes (+16.4 ETDRS letters gain, 78% fibrosis reduction, 92% RPE preservation) were cross-validated against real-world trial datasets from ANCHOR (n=423) and MARINA (n=716). CONCLUSION: The V3-RGN-09 Molecular Simulator bridges high-integrity critical software engineering (DO-178C standards) with computational biophysics. It provides a proven, deterministic, and formally verified foundation for in silico drug discovery, ready for TRL 4 in vitro and in vivo translational research.
2026-04-29 | RIPK3 suppresses photoreceptor degeneration in a Stargardt disease mouse model
Abstract Autosomal recessive Stargardt disease type 1 (STGD1) is the most prevalent inherited juvenile macular degeneration, ultimately leading to irreversible blindness through photoreceptor cell loss, yet the underlying cell death mechanisms remain poorly defined. Receptor-interacting protein kinase 3 (RIPK3) is a well-established mediator of necroptosis and, under certain circumstances, apoptosis downstream of TNF family ligands, and it was found to be progressively upregulated in the retina of a STGD1 abca4 −/− rdh8 −/− (DKO) mouse model coinciding with the onset and progression of photoreceptor degeneration. Despite elevated RIPK3 expression, necroptosis was not detectable in this model, as evidenced by the absence of phosphorylated MLKL and unaltered photoreceptor degeneration in abca4 -/- rdh8 -/- mlkl -/- mice. Intriguingly, genetic ablation of Ripk3 exacerbated photoreceptor loss in DKO mice in both chronic (age-dependent) and acute (light-induced) retinal degeneration paradigms. This detrimental effect was partially ameliorated by pan-caspase inhibition in the acute degeneration model, indicating caspase-dependent apoptosis as the primary executioner. Mechanistically, we demonstrated that RIPK3 suppressed extrinsic apoptosis by attenuating caspase-8 activation downstream of TNF family ligands. Collectively, our findings reveal a non-canonical, protective role of RIPK3 in photoreceptors, as a brake on apoptotic signaling rather than a necroptotic executor, in the context of STGD1. These findings redefine the role of RIPK3 in retinal degeneration and emphasize the contextual plasticity of cell death regulators in neurodegenerative diseases.
gene therapies
2026-09-23 | Stargardt disease: clinical studies over the past 5 years—a systematic review
Summary Background Stargardt disease type 1 (STGD1) is the most common juvenile macular degeneration and one of the leading causes of visual impairment and blindness among children and working adults across Europe. There are currently no approved therapies for STGD1, but several therapeutic approaches including pharmacotherapy, gene therapy, neuroprotection, and stem cell therapy are under investigation in clinical studies and trials. Here, we review the current status of evolving therapies for STDG1. Methods This systematic review is based on the PRISMA‑P checklist using various scientific databases. Only case series and (non-)randomized clinical studies were included, with preclinical and basic science studies excluded. All included studies were individually assessed using the ROBINS‑I Tool of the Cochrane Collaboration and the TREND-Checklist for BIAS assessment. Results From the initial search, 314 records were identified, including 72 from PubMed, 96 from Embase, 41 from the Cochrane Library, 68 from Google Scholar, and 37 from Epistemonikos. After removing duplicates, the titles, abstracts, and full texts were screened according to predefined PICO criteria: population with genetically and clinically confirmed STDG1, interventions such as gene therapy, pharmacological approaches, stem cell therapy, and neuroprotection; comparison groups appropriate to the study design, such as placebo, the fellow eye, natural progression, or historical cohorts; and outcomes , including structural progression (assessed by fundus autofluorescence and optical coherence tomography), functional outcomes, and safety. Six studies met these criteria and were included. Of these, one investigated the gene therapy SAR422459, one evaluated the pharmacological agent emixustat, three assessed stem cell-based retinal pigment epithelium transplantation, and one examined neuroprotection through saffron supplementation. Conclusion Although STGD1 remains a challenging condition, new therapies in this review have shown potential in clinical trials. Ongoing methods aim to optimize the use of stem cell-based retinal pigment epithelium cells, refine delivery methods for the large ABCA4 gene, and explore genome editing techniques, such as CRISPR, to correct ABCA4 mutations, even though challenges such as off-target effects and DNA repair errors remain. Pharmacological approaches are focused on optimizing dosing for safety and efficacy. With further research on larger cohorts and long-term evaluation, there is hope for effective therapies.
2026-06-26 | Therapeutic Efficacy of Multi-Characteristic Opsin Gene Therapy in a Mouse Model of Stargardt Disease.
Optogenetic gene therapy-based treatment offers a unique approach to bypass dysfunctional or degenerated photoreceptors in retinal degenerative disorders. Ambient light-activatable multi-characteristic opsin (MCO) targeted to bipolar cells of the retina has demonstrated partial vision restoration in animal models of retinitis pigmentosa (RP). Here, we describe the potential therapeutic efficacy of intravitreally delivered AAV-carried MCO-010 in a mouse model of Stargardt disease. MCO-010 treatment led to significantly improved behavioral outcomes in the visually guided radial arm water maze. Furthermore, longitudinal optical coherence tomographic imaging showed that the MCO-010 treatment led to no notable change in the retina thickness. Furthermore, the MCO-010-treated mice exhibited higher electrophysiological responses compared to the control group. Together, these findings demonstrate potential vision-restoring and disease-modifying aspects of ambient light-activatable intravitreal MCO-010 therapy.
2026-03-23 | Retinal gene therapies for inherited ocular diseases: Translational delivery strategies from bench to bedside.
Inherited retinal diseases (IRDs), including retinitis pigmentosa, Leber congenital amaurosis, and Stargardt disease, represent a major cause of inherited visual impairment and blindness, particularly in working-age populations. These disorders are genetically heterogeneous and result in progressive degeneration of photoreceptors and the retinal pigment epithelium. The eye offers a uniquely favorable environment for gene therapy due to its anatomical compartmentalization, accessibility, and relative immune privilege; however, successful clinical translation remains constrained by multiple biological and technological barriers. In this review, we adopt a comparative, delivery-centric framework to analyze how different gene delivery strategies navigate key translational challenges, including the blood-retinal barrier, vector tropism, immune responses, payload size limitations, re-dosing feasibility, and manufacturing cost. We systematically contrast viral and non-viral platforms, highlighting their respective strengths, limitations, and suitability across administration routes and target cell populations. While adeno-associated viral vectors currently dominate clinical development, emerging non-viral systems, such as lipid-based formulations, polyplexes, exosomes, and peptide-based carriers, offer complementary advantages in safety, payload flexibility, and repeat dosing. By integrating insights from retinal biology, biomaterials engineering, and clinical trial experience, this review offers decision-oriented guidance for selecting appropriate delivery strategies based on disease context, target cells, and translational constraints. We further discuss how advances in genome editing, administration routes, and carrier design may shape the next generation of economically viable and clinically scalable gene therapies for IRDs.
2026-03-14 | Precise CRISPR/Cas9 and Cas12 Correction Using Lipoplexes in Retinal Models Derived from Patients with Inherited Retinal Dystrophies.
Gene editing, particularly CRISPR/Cas technology, represents a promising approach for the treatment of rare genetic diseases, including inherited retinal dystrophies, for which effective therapies are largely unavailable. Despite extensive research investigating gene editing across a wide range of cell types, transient delivery of CRISPR/Cas components and efficient homology-directed repair (HDR) in differentiated cells remain challenging. In this study, we employed hiPSCs derived from patients with Stargardt disease or Best disease, carrying pathogenic variants in ABCA4 or BEST1, respectively, to explore gene editing in human models. CRISPR/Cas9 and Cas12 nucleases were delivered into hiPS-derived retinal pigment epithelium (RPE) and retinal organoids using lipoplexes and compared with electroporation. We evaluated transfection efficiency, sgRNA-mediated DNA cleavage, and HDR-based correction. Precise repair of the pathogenic BEST1 variant was successfully achieved in hiPS-derived RPE cells using both nucleases, with Cas12 yielding the highest efficiency, exceeding 10% of HDR correction. Edited RPE cells preserved normal morphology and expressed specific maturity markers. In contrast, retinal organoids exhibited moderate transfection efficiency but showed no detectable CRISPR/Cas-induced DNA cleavage, highlighting the need for further optimization of gene editing in more complex cellular tissues. This study demonstrates, for the first time, precise correction of a single-nucleotide mutation in patient-derived RPE using CRISPR/Cas9 and Cas12 delivered using lipoplexes. These findings underscore the therapeutic potential of CRISPR/Cas-based strategies for inherited retinal dystrophies and provide a proof of concept for future clinical approximations.
2026-03-05 | Advances in vision restoration using multi-characteristic opsin
This presentation reviews the preclinical foundation, clinical trial program—including efficacy results—and the recent expansion of the MCO optogenetic program into geographic atrophy. MCO represents a paradigm-shifting, mutation-agnostic optogenetic approach for vision restoration. From robust preclinical evidence to multiple clinical trials demonstrating efficacy and durability, this therapy has shown the potential to restore meaningful vision in previously untreatable conditions such as RP and Stargardt disease. The expansion to geographic atrophy further highlights its versatility and transformative potential. Collectively, these advances position MCO as a leading candidate in the emerging field of vision restoration, offering hope to millions of patients affected by retinal degenerative diseases.
cell therapies
2025-12-01 | Postmortem Retinal Structural and Metabolic Analysis After Human Embryonic Stem Cell-derived Retinal Pigment Epithelium Transplantation in a Patient With Stargardt Disease.
Purpose: Stargardt disease is an inherited form of retinal degeneration characterized by early-onset central vision loss. This report describes the long-term retinal histologic characteristics of a patient with Stargardt disease after human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) transplantation. Methods: Eyes were obtained postmortem from an 80-year-old legally blind male patient with Stargardt disease. The patient had previously undergone hESC-RPE transplantation of his left eye, and the right eye (untransplanted) served as a control. Fluorescence lifetime imaging microscopy was used to study retinal structure and metabolic activity. Staining of the retina for lipofuscin was performed using the Armed Forces Institute of Pathology method. Results: Metabolic analysis showed that the macular area had more oxidative phosphorylation relative to the mid-peripheral retina, in both the transplanted and untransplanted eye. Melanin-laden RPE cells were detected in the transplanted eye, which correlated with a pigment band present on fundus images post-hESC-RPE transplantation. Conclusions: This case description illustrates the long-term survival of subretinal hESC-RPE cells post-transplantation in a patient with Stargardt disease.
2025-08-30 | Retinal Pigment Epithelium Transplantation in Retinal Disease: Clinical Trial Development, Challenges, and Future Directions.
Replacement of the retinal pigment epithelium (RPE) is emerging as a promising approach to treat degenerative retinal diseases, including age-related macular degeneration and Stargardt disease, in which RPE function cannot otherwise be restored. Despite the limitations of existing treatments, advances in cell sourcing and surgical methods have enabled initial human trials of RPE transplantation, with early results indicating potential efficacy. This review comprehensively examines the evolution of RPE transplantation in recent decades, highlighting the advantages and limitations of different cell sources and delivery methods. Current clinical trial data are analyzed with a particular focus on immune rejection risks, surgical complications, and long-term safety. Despite encouraging safety profiles, achieving consistent and sustained visual improvement remains a challenge, as vision outcomes might be influenced by factors such as disease stage at intervention, transplantation site, number of cells transplanted, and duration of follow-up. Key challenges, such as cell or graft survival and integration with the host retina, are discussed in depth, as overcoming these obstacles is essential for achieving stable and effective RPE replacement. Future research directions, including innovations in biomaterials, molecular modification strategies, and personalized approaches, hold promise for enhancing the efficacy and durability of RPE transplantation for retinal disease.
2024-12-01 | Maculopathies: A Systematic Literature Review on Pathophysiology, Public Health, and Treatment.
Macular degeneration (MD) is a pathological condition affecting the macula, an area located near the center of the retina. This disease affects individuals of all ages, both children and adults, causing severe visual impairment. Age-related macular degeneration (AMD) is the leading cause of visual loss in the older population while Stargardt disease (SD) is the most common hereditary maculopathy with an autosomal dominant pattern of inheritance. Current management involves anti-vascular endothelial growth factor intravitreal injections, visual aids, and other conservative prevention mechanisms that can only delay the inevitable progress of the disease. Macular dystrophies have an impact on both individuals and societies with psychological and financial implications, respectively. It is evident that vision impairment has a significant impact on patients' physical and mental well-being, and therefore it is important to improve current treatment modalities, develop stem cell therapies, and further novel treatments in order to provide a better prognosis and overall quality of life.
2024-11-04 | Lipopeptide-mediated Cas9 RNP delivery: A promising broad therapeutic strategy for safely removing deep-intronic variants in ABCA4.
Deep-intronic (DI) variants represent approximately 10%-12% of disease-causing genetic defects in ABCA4-associated Stargardt disease (STGD1). Although many of these DI variants are amenable to antisense oligonucleotide-based splicing-modulation therapy, no treatment is currently available. These molecules are mostly variant specific, limiting their applicability to a broader patient population. In this study, we investigated the therapeutic potential of the CRISPR-Cas9 system combined with the amphipathic lipopeptide C18:1-LAH5 for intracellular delivery to correct splicing defects caused by different DI variants within the same intron. The combination of these components facilitated efficient editing of two target introns (introns 30 and 36) of ABCA4 in which several recurrent DI variants are found. The partial removal of these introns did not affect ABCA4 splicing or its expression levels when assessed in two different human cellular models: fibroblasts and induced pluripotent stem cell-derived photoreceptor precursor cells (PPCs). Furthermore, the DNA editing in STGD1 patient-derived PPCs led to a ∼50% reduction of the pseudoexon-containing transcripts resulting from the c.4539+2001G>A variant in intron 30. Overall, we provide proof-of-concept evidence of the use of C18:1-LAH5 as a delivery system for therapeutic genome editing for ABCA4-associated DI variants, offering new opportunities for clinical translation.
2023-02-03 | Upregulation of rhodopsin gene in regenerated retina followed by adipose-derived stem cell therapy in a rat model
Abstract Background : Retinal degenerative diseases, including age-related macular degeneration, Stargardt disease, and retinitis pigmentosa are phenotypically diverse and lead to photoreceptor cell death and downregulation of rhodopsin gene expression. Retinal degeneration is difficult to treat; therefore, artificial devices, autologous grafts, and the retinal donation should be used to replace damaged tissues or organs. Methods : In this study, the photoreceptor layer of the retinal tissue of rats was damaged by intravitreal sodium iodate (NaIO 3 ) administration. Following the confirmation of retinal damage, intravitreal injections of adipose stem cells with a hydrogel scaffold were implanted into the intravitreal space’s retinas of rats. The process of retinal regeneration was assessed by histopathology, and RT-PCR analyzed the expression of the rhodopsin gene. Results : Histopathological examination demonstrated that injecting a suitable biomaterial hydrogel and mesenchymal stem cells improved tissue regeneration. In addition, the data showed that the expression of the rhodopsin gene was upregulated in repaired retinal tissue compared to damaged tissue. Conclusion: NaIO 3 injection into the intravitreal space of rats’ results in severe retina injury. The application of mesenchymal stem cells is suggested as competent cells to cure degenerative retinal defects. This model could be a valuable tool for seeking and evaluating novel therapeutic modalities for the treatment of retinal degeneration.
other
2024-12-10 | Transferrin ameliorates retinal degeneration by mediating the dimerization of all-trans-retinal.
High levels of all-trans-retinal (atRAL) in the retina is considered to be responsible for the development of autosomal recessive Stargardt's disease (STGD1) and dry age-related macular degeneration (dAMD). Two bisretinoids, all-trans-retinal dimer (atRAL-dimer) and N-retinyl-N-retinylidene ethanolamine (A2E), form from the dimerization of atRAL in the retina but they possess much lower toxicity and phototoxicity toward retinal pigment epithelium (RPE) cells than atRAL. Here, we introduced a novel function of transferrin (TRF) in mediating the conversion of atRAL into atRAL-dimer and A2E, which effectively protected the retina from damage by atRAL and prevented retinal function decline in mice, and rescued atRAL-loaded RPE cells. Moreover, TRF-mediated conversion of atRAL to atRAL-dimer and A2E required the help of bicarbonate ions (HCO3-). atRAL had the capacity to stimulate the expression of TRF in RPE and photoreceptor cells as well as RPE/choroid and neural retina of mice, reflecting that the elevation of TRF levels by atRAL is most likely to help defy level increase and cytotoxicity of atRAL through facilitating its dimerization and thereby serves as a mechanism of retinal self-protection. Our findings offer a promising avenue for the treatment of retinopathies characterized by disrupted clearance of atRAL.
2021-12-03 | Stargardt disease: A clinical case report of two sisters with different clinical development.
The purpose of this article is to describe the clinical manifestations and complementary diagnostic tests of two sisters aged 26 and 31 with a diagnosis of Stargardt's disease. One of them presented with an initial visual acuity of 0.7 and showed a progressive central visual loss due to the atrophy of the external layers of the retina in the subfoveal region. She was recruited to participate in a clinical trial of Avancincaptad Pegol (Zimura®), an inhibitor of C5 of the complement's system. The other sister remained asymptomatic with a visual acuity of 1 in both eyes. In both cases white-yellow pisciform lesions were observed on the posterior pole. Although there is no curative treatment for this disease, there are many lines of investigation on this topic. The clinical and diagnostic tests can confirm the disease, and provide patients with an accurate prognosis.
2021-06-18 | Evidence of complement dysregulation in outer retina of Stargardt disease donor eyes.
Stargardt macular degeneration (STGD) is a central blinding disease caused by loss of or dysfunctional ABCA4 transporter in both photoreceptors and retinal pigment epithelial (RPE) cells. Toxic bisretinoid-lipofuscin buildup in the RPE cells is a pathological hallmark of STGD patients and its mouse model, the Abca4-/-. These vitamin A-derived fluorophores have been shown to induce oxidative stress, stimulate complement activity, and cause chronic inflammation of the RPE. In vivo modulation of complement regulatory pathway in the STGD mouse model has partially rescued the STGD phenotype suggesting that complement attack on the RPE is an important etiologic factor in disease pathogenesis. While bisretinoid-dependent complement activation was further evidenced in cultured RPE cells, this pathway has never been investigated directly in the context of RPE from STGD donor eyes. In the current study, we evaluate the complement reactivity in postmortem donor eyes of clinically diagnosed STGD patients. All three STGD donor eyes RPE displayed strong immunoreactivity for an antibody specific to 4-Hydroxynonenal, a lipid peroxidation byproduct. Also, unlike the control eyes, all three STGD donor eyes showed significantly increased membrane attack complex deposition on the RPE cells. In STGD eyes, increased MAC accumulation was mirrored by elevated C3 fragments internalized by the RPE and inversely correlated with the levels of complement factor H, a major complement regulatory protein. Here, we report the first direct evidence of RPE complement dysregulation as a causative factor in developing Stargardt phenotype.
2019-08-01 | Oxidative stress in retinal pigment epithelial cells increased endogenous complement-dependent inflammatory and angiogenic responses - independent from exogenous complement sources
ABSTRACT Oxidative stress-induced damage of the retinal pigment epithelium (RPE) together with chronic inflammation has been suggested as major contributors to retinal diseases. Here, we examine the effects of oxidative stress and endogenous complement components on the RPE and its pro-inflammatory and –angiogenic responses. The RPE cell line, ARPE-19, treated with H 2 O 2 reduced cell-cell contacts, increased marker for epithelial–mesenchymal transition but showed less cell death. Stressed ARPE-19 cells increased the expression of complement receptors CR3 and C5aR1. CR3 was co-localized with cell-derived complement protein C3, which was observed in its activated form in ARPE-19 cells. C3 as well as its regulators CFH and properdin accumulated in ARPE-19 cells after oxidative stress independent from external complement sources. This cell-associated complement accumulation promoted nlrp3 and foxp3 expression and subsequent increased secretion of pro-inflammatory and pro-angiogenic factors. The complement-associated ARPE-19 reaction to oxidative stress, independent from external complement source, was increased by the PARP-inhibitor olaparib. Our results indicated that RPE cell-derived complement proteins and receptors are involved in RPE cell homeostasis following oxidative stress and should be considered as targets for treatment developments for retinal degeneration. GRAPHICAL ABSTRACT We show a functional link between oxidative stress, complement receptors, endogenous complement proteins, pro-angiogenic and -inflammatory responses in ARPE-19 cells. These effects are independent from extracellularly added complement proteins or receptor ligands. We suggest an oxidative stress-associated autocrine mechanism of complement receptor regulation in ARPE-19 cells in connection with upregulated intracellular proteases. HIGHLIGHTS Oxidative stress accumulates complement proteins and receptors in RPE cells Oxidative stress activates the RPE inflammasome without external complement proteins Oxidative stress increases foxp3 expression and IL-8/VEGF secretion in RPE cells Olaparib enhances pro-inflammatory response of RPE
2018-08-07 | ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease.
Stargardt disease is caused by variants in the ABCA4 gene, a significant part of which are noncanonical splice site (NCSS) variants. In case a gene of interest is not expressed in available somatic cells, small genomic fragments carrying potential disease-associated variants are tested for splice abnormalities using in vitro splice assays. We recently discovered that when using small minigenes lacking the proper genomic context, in vitro results do not correlate with splice defects observed in patient cells. We therefore devised a novel strategy in which a bacterial artificial chromosome was employed to generate midigenes, splice vectors of varying lengths (up to 11.7 kb) covering almost the entire ABCA4 gene. These midigenes were used to analyze the effect of all 44 reported and three novel NCSS variants on ABCA4 pre-mRNA splicing. Intriguingly, multi-exon skipping events were observed, as well as exon elongation and intron retention. The analysis of all reported NCSS variants in ABCA4 allowed us to reveal the nature of aberrant splicing events and to classify the severity of these mutations based on the residual fraction of wild-type mRNA. Our strategy to generate large overlapping splice vectors carrying multiple exons, creating a toolbox for robust and high-throughput analysis of splice variants, can be applied to all human genes.
proteins
2026-06-04 | Update on the Management of ABCA4 Retinopathy (Stargardt Disease).
ABCA4-associated retinopathies (Stargardt disease) are the most common inherited macular dystrophy and a leading cause of early onset central vision loss. Biallelic pathogenic variants in the ABCA4 gene cause impaired clearance of retinoid byproducts, leading to toxic bisretinoid accumulation, retinal pigment epithelium dysfunction, and progressive photoreceptor degeneration. Clinical presentation and disease progression are highly heterogeneous, largely influenced by genotype, age at onset, and environmental modifiers. Current management remains supportive and includes low-vision rehabilitation and counseling. Recent advances in molecular genetics, retinal imaging, and translational science have substantially expanded the therapeutic pipeline for ABCA4 retinopathy. Disease-modifying strategies under active investigation include visual-cycle modulation, deuterated vitamin A analogs, retinol-binding protein antagonists, gene augmentation and editing approaches, antisense oligonucleotides, and cell-based regenerative therapies. Several pharmacologic agents have demonstrated promising structural outcomes in clinical trials, while gene-based and regenerative approaches continue to evolve amid challenges related to gene size, delivery efficiency, and long-term safety. Optogenetic therapy has emerged as a gene-agnostic option for functional vision restoration in advanced disease stages. This review provides an integrated overview of ABCA4 retinopathy, summarizing disease mechanisms, current management strategies, emerging therapies, and the evolving clinical trial landscape. Emphasis is placed on stage-adapted treatment paradigms, appropriate monitoring endpoints, and the potential role of combination therapies. Ongoing innovation and precision-based approaches offer cautious optimism for durable disease modification and functional preservation in this currently untreatable condition.
2026-06-02 | Exendin-4 averts all-trans-retinal-driven damage to photoreceptors and the retina via the GLP-1R/PKA/CREB1 signaling axis.
Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL. Cell and animal paradigms of STGD1 and dry AMD were generated by atRAL-loaded 661W cells and light-exposed Abca4-/-Rdh8-/- mice, respectively. RNA-sequencing, cell viability assays, morphometric analysis, annexin V/propidium-iodide staining using flow cytometry, quantitative polymerase chain reaction (qPCR), western blotting, immunofluorescence, electroretinography (ERG), fundus photography, hematoxylin and eosin (H&E) histology, and TUNEL staining were integrated to delineate the anti-apoptotic actions of EX-4 and to uncover its underlying protective mechanism. GLP-1R/cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP response element-binding protein 1 (CREB1) signaling was markedly downregulated in atRAL-challenged 661W cells and in neural retina of light-exposed Abca4-/-Rdh8-/- mice. EX-4 reinstated this pathway, suppressed caspase-3 activation and DNA damage, and curtailed apoptosis in both cell and tissue contexts. Silencing of Glp1r or the PKA catalytic subunits by small interfering RNA (siRNA) abrogated EX-4-induced activation of the PKA/CREB1 axis in atRAL-loaded 661W cells. Pharmacologic blockade of CREB1 phosphorylation with the PKA inhibitor H-89 or the CREB1 inhibitor 666-15 largely nullified the DNA-protective and anti-apoptotic benefits conferred by EX-4 in 661W cells following atRAL exposure, suggesting that the GLP-1R/PKA/CREB1 signaling axis contributes to its cytoprotection action. More importantly, intraperitoneal injection of EX-4 significantly preserved retinal structure and function in Abca4-/-Rdh8-/- mice after exposure to light, and mitigated punctate lesions in the fundus. EX-4 exerted anti-apoptotic and DNA-protective effects against atRAL-induced photoreceptor loss and retinal degeneration at least partially through activating the GLP-1R/PKA/CREB1 pathway. These findings suggest that GLP-1R agonists could serve as potential preventive therapeutics for atrophic macular degeneration associated with atRAL toxicity, including dry AMD and STGD1.
2025-08-21 | Safety and efficacy of MCO-010 optogenetic therapy in patients with Stargardt disease in USA (STARLIGHT): an open-label multi-center Ph2 trial.
Stargardt disease (SD) is an inherited degenerative retinal disease affecting rod and cone photoreceptors and retinal pigment epithelial (RPE) cells, leading to severe and irreversible vision loss. Optogenetics is a promising approach to restoring vision by photosensitizing spared healthy retinal neurons. The STARLIGHT phase 2 open-label study (NCT05417126) was conducted over 48-weeks at two US sites to assess the safety and efficacy of MCO-010 administered via a single intravitreal injection in the worse-seeing eye of SD patients. The study began on July 5, 2022, and was completed on September 28, 2023. MCO-010 targets bipolar cells rather than retinal ganglion cells (RGCs) to utilize more abundant cells that respond to ambient light while preserving natural visual processing pathways after treatment. Six adults (mean age 50 years, range 32-71 years, four males and two females) received 1.2E11 genome copies (gc)/eye of MCO-010. The primary outcome was the incidence, nature, severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), intraocular inflammation, retinal thickness, best-corrected visual acuity (BCVA), and lesion size. Secondary endpoints included change in BCVA, vision-guided mobility, and shape determination accuracy. Visual field perimetry and Michigan Retinal Degeneration Questionnaire (MRDQ) were exploratory endpoints. All six participants had at least one ocular TEAE; non-ocular TEAEs occurred in three participants. The most common TEAEs were conjunctival hemorrhage, ocular hypertension, and vitreous cells (two subjects). There were no deaths, hospitalization, loss of eye, retinal detachment, endophthalmitis, or TEAEs leading to study discontinuation. The BCVA (mean ± SD) of the six treated eyes at baseline and 48-week follow-up was 22.8 ± 9.87 (range 9-35), and 28.3 ± 13.28 (range 4-42) ETDRS letters, respectively. The BCVA change from baseline was 7.2 ± 11.74, 4.2 ± 14.81, and 5.5 ± 12.29 at 12, 24, and 48 weeks, respectively. With a wearable magnifier (low-vision glasses), the BCVA change was 17.8 ± 13.35, 15.7 ± 17.37, 13.3 ± 21.37 at 12, 24, and 48 weeks, respectively. The improvement in mean defect in visual field perimetry was 1.02 ± 3.54, 2.47 ± 5.00, and 2.63 ± 5.26 dB at 12, 24, and 48 weeks, respectively. Specific improvements were noted in reading, and color, and contrast domains of the MRDQ. MCO-010 optogenetic phase 2 results support further investigation for treatment SD. To our knowledge, this is the first report of improving on(eye)-chart vision of SD participants utilizing optogenetics. Nanoscope Therapeutics Inc.
2023-11-12 | A Vicious NGF-p75NTR Positive Feedback Loop Exacerbates the Toxic Effects of Oxidative Damage in the Human Retinal Epithelial Cell Line ARPE-19
In spite of its variety of biological activities, the clinical exploitation of human NGF (hNGF) is currently limited to ocular pathologies. It is therefore interesting to test the effects of hNGF in preclinical models that may predict their efficacy and safety in the clinical setting of ocular disorders and compare the effects of hNGF with those of its analogs. We used a human retinal pigment cell line, ARPE-19 cells, to investigate the effects of hNGF and its analogs, mouse NGF (mNGF) and painless NGF (pNGF), on cell viability under basal conditions and after exposure to oxidative stimuli, i.e., hydrogen peroxide (H2O2) and ultraviolet (UV)-A rays. The effects of hNGF and pNGF were also tested on the gene expression and protein synthesis of the two NGF receptor subtypes, p75 neurotrophic receptors (p75NTR) and tyrosine kinase A (TrkA) receptors. We drew the following conclusions: (i) the exposure of ARPE-19 cells to H2O2 or UV-A causes a dose-dependent decrease in the number of viable cells; (ii) under baseline conditions, hNGF, but not pNGF, causes a concentration-dependent decrease in cell viability in the range of doses 1-100 ng/mL; (iii) hNGF, but not pNGF, significantly potentiates the toxic effects of H2O2 or of UV-A on ARPE-19 cells in the range of doses 1-100 ng/mL, while mNGF at the same doses presents an intermediate behavior; (iv) 100 ng/mL of hNGF triggers an increase in p75NTR expression in H2O2-treated ARPE-19 cells, while pNGF at the same dose does not; (v) pNGF, but not hNGF (both given at 100 ng/mL), increases the total cell fluorescence intensity for TrkA receptors in H2O2-treated ARPE-19 cells. The present findings suggest a vicious positive feedback loop through which NGF-mediated upregulation of p75NTR contributes to worsening the toxic effects of oxidative damage in the human retinal epithelial cell line ARPE-19. Looking at the possible clinical relevance of these findings, one can postulate that pNGF might show a better benefit/risk ratio than hNGF in the treatment of ocular disorders.
2023-02-08 | Protein-Mediated Carotenoid Delivery Suppresses the Photoinducible Oxidation of Lipofuscin in Retinal Pigment Epithelial Cells
Lipofuscin of retinal pigment epithelium (RPE) cells is a complex heterogeneous system of chromophores which accumulates as granules during the cell’s lifespan. Lipofuscin serves as a source of various cytotoxic effects linked with oxidative stress. Several age-related eye diseases such as macular degeneration of the retina, as well as some severe inherited eye pathologies, are accompanied by a significant increase in lipofuscin granule concentration. The accumulation of carotenoids in the RPE could provide an effective antioxidant protection against lipofuscin cytotoxic manifestations. Given the highly lipophilic nature of carotenoids, their targeted delivery to the vulnerable tissues can potentially be assisted by special proteins. In this study, we demonstrate how protein-mediated delivery of zeaxanthin using water-soluble Bombyx mori carotenoid-binding protein (BmCBP-ZEA) suppresses the photoinducible oxidative stress in RPE cells caused by irradiation of lipofuscin with intense white light. We implemented fluorescence lifetime imaging of the RPE cell culture ARPE-19 fed with lipofuscin granules and then irradiated by white light with and without the addition of BmCBP-ZEA. We demonstrate that after irradiation the mean fluorescence lifetime of lipofuscin significantly increases, while the presence of BmCBP-ZEA at 200 nM concentration suppresses the increase in the average lifetime of lipofuscin fluorescence, indicating an approx. 35% inhibition of the oxidative stress. This phenomenon serves as indirect yet important evidence of the efficiency of the protein-mediated carotenoid delivery into pigment epithelium cells.
small molecules
2026-09-24 | [Stargardt disease: genetics, molecular mechanisms, potential lifestyle interventions and pharmacotherapy].
Stargardt disease (STGD1) is the most common inherited macular dystrophy. It is caused by biallelic variants in the ABCA4 gene and leads to impaired retinoid transport within photoreceptors. Disruption of retinoid clearance results in the accumulation of lipofuscin in the retinal pigment epithelium (RPE), which in turn induces oxidative stress, complement activation and progressive degeneration of the RPE and photoreceptors. Despite substantial advances in the understanding of the underlying pathophysiological mechanisms, no approved causal therapy is currently available; however, several promising pharmacological approaches are under preclinical and clinical investigation, targeting different metabolic steps within and around the visual cycle. This review article summarizes the genetic and pathophysiological basis of Stargardt disease and provides an overview of potential lifestyle interventions and emerging pharmacological treatment strategies. These advances could soon translate into disease-modifying therapies, highlighting the importance of early diagnosis and patient referral to specialized centers.
2026-09-03 | Safety and Effects of Gildeuretinol Acetate on Retinal Atrophic Lesions in Stargardt Disease: The TEASE-1 Randomized Clinical Trial.
Stargardt disease (STGD) is the most common macular dystrophy, resulting in profound loss of vision. There is no approved treatment. To evaluate the safety and effects of oral gildeuretinol acetate on the growth of retinal atrophic lesions in individuals with STGD. TEASE-1 was a 2-year, multicenter, double-masked, placebo-controlled randomized clinical trial incorporating a crossover group and additional natural history (NH) cases selected prior to drafting the statistical analysis plan. The trial was conducted at 7 outpatient clinics in the US. Participants were aged 12 years or older, clinically diagnosed with STGD, with well-demarcated area(s) of significantly reduced autofluorescence, and supported with at least 1 ABCA4 disease-causing or likely disease-causing variant. The study was conducted between August 2015 and October 2019; data were analyzed between July and December 2020. Participants were randomized 1.5:1.5:1:1 to daily oral gildeuretinol acetate, 14 mg; gildeuretinol acetate, 24 mg; or placebo for 24 months; or placebo for 12 months followed by gildeuretinol for 12 months. The primary efficacy end point was the growth rate of well-delineated and homogeneous areas of retinal atrophic lesions over 24 months of treatment on fundus autofluorescence imaging. Safety end points included treatment-emergent adverse events (AEs), serious AEs, and clinical laboratory assessments. A total of 50 participants were randomized, and 54 NH cases included. The mean (range) age of randomized participants was 44.3 (18-60) years. Overall, 58 of 104 participants or cases (55.8%) were female. The growth rate of retinal atrophic lesions was 0.182 mm/y with gildeuretinol and 0.232 mm/y in the untreated group (placebo and NH), representing a mean difference of -0.050 mm/y (95% CI, -0.072 to -0.027; P < .001) and a 21.6% relative reduction. In a prespecified sensitivity analysis restricted to randomized participants, the growth rate was 0.206 mm/y with gildeuretinol and 0.242 mm/y with placebo, representing a mean difference of -0.036 mm/y (95% CI, -0.062 to -0.009; P = .008) and a 14.9% relative reduction. The majority of AEs were mild or moderate and equally distributed between groups. No treatment-related serious AEs, clinically significant liver function abnormalities, or participant-reported night blindness or dark adaption difficulties occurred. In the TEASE-1 randomized clinical trial, the primary efficacy end point of retinal atrophic lesion growth from 6 to 24 months was 0.05 mm/y greater on average in the untreated group (placebo and NH) than the gildeuretinol acetate group. Further research is needed to determine the clinical relevance of this end point. ClinicalTrials.gov Identifier: NCT02402660.
2026-08-13 | Does Crocus sativus (Saffron) Have an Influence or Effect on Ocular Health: A Systematic Literature Review.
BackgroundCrocus sativus (Saffron) and its bioactive constituents, crocin and crocetin have gained attention for their neuroprotective and antioxidant properties in ocular health. This review synthesises clinical evidence from extracted studies evaluating their efficacy, safety and dosing across Age-related Macular Degeneration (AMD), Primary Open-Angle Glaucoma (POAG), Diabetic Macular Edema (DME), Central Serous Retinopathy (CSR), Stargardt Disease (STGD1) and Paediatric Myopia (PM).MethodologyA systematic literature review was undertaken assessing randomized trials, observational or cohort studies, case studies or series written in English between January 2015 to January 2025. Studies were identified using PubMed, AMED, CINHAL, ScienceDirect and Scopus as well as the grey literature.ResultsTen clinical trials were identified from 529 citations. Interventions involved oral supplementation of saffron (20-50mg/day), crocin (5-15mg/day) and crocetin (7.5mg/day) over durations ranging from 6 weeks to 12 months. Primary outcomes included visual acuity, retinal electrophysiology, intra-ocular pressure, macular thickness, and safety profiles.ConclusionSaffron, crocin and crocetin, demonstrate consistent efficacy and exceptional safety profiles across a range of ocular conditions. Saffron's dose-dependent therapeutic effects are a promising adjunctive therapy in ophthalmology. Further large-scale trials are warranted to confirm these findings and refine condition specific dosing.
2026-07-29 | V3-RGN-09 Molecular Simulator: A Formally Verified Ada/SPARK In Silico Engine for Dual-Target Retinal Regeneration and Biophysical Blind-Test Validation
BACKGROUND & PURPOSE: Retinal degenerative disorders—such as age-related macular degeneration (AMD), diabetic macular edema (DME), and glaucoma—represent complex multi-layered neuropathologies that remain challenging to model in silico without computational instability or artificial bias. Traditional computational biology frameworks (primarily C/C++ or Python) lack formal safety guarantees and deterministic physical boundaries. This work introduces the "V3-RGN-09 Molecular Simulator", an in silico biophysical platform developed entirely in Ada/SPARK 2022 to simulate the complete mechanics of multi-layered retinal regeneration and drug-target interactions with 100% formal mathematical proof (zero runtime exceptions, zero memory bugs). METHODOLOGY & ARCHITECTURE: The simulator relies on four locked V3 Invariants: 1. Physical Mass/Pressure Invariant (Ψ_V3 = 48,016.8 kg·m⁻²), 2. Critical Biophysical Phase Lock Attractor (Φ_critical = -51.10 mV vs. Φ_basal = -70.00 mV), 3. Heptadic Layer Closure (k = 7, modeling all 7 distinct anatomical retinal layers), 4. Modulo-9 Checksum Predicates guaranteeing structural integrity across all execution threads. The core module evaluates the novel synthetic hybrid molecule V3-RGN-09 (Molecular Weight: 842.6 Da, ΔG = -11.8 kcal/mol, Kd = 0.042 nM), engineered from 3D atomic coordinates of PDB 6M76 (TGFBR1 / Anti-TGF-β Domain A) and PDB 1BND (TrkB/PEDF Neurotrophic Domain B). EXPERIMENTAL VALIDATION & BLIND TESTS: The architecture underwent extensive stress-testing and empirical validation: 1. Blind Diagnostic Simulations (16/16 Successful): Without diagnostic tags or clinical labels, the engine evaluated raw physical parameters (fluid pressure, ion gradients, mechanical stress, enzymatic clearance). Through differential integration across the 7 layers (k=7), the engine autonomously rediscovered exact real-world pathological footprints, including Wet/Dry AMD, Glaucoma, Stargardt Disease, Central Retinal Artery Occlusion (CRAO), Macular Holes, and CAR Retinopathy with 100% concordance to clinical benchmarks. 2. Reverse Engineering / Back-Propagation Test: By setting an optimal clinical recovery target (Phase Lock at -51.10 mV in 18 days with >75% fibrosis reduction), back-propagation equations independently generated the precise structural and affinity constraints of the V3-RGN-09 hybrid pharmacophore. 3. Extreme Stress Testing & Fuzzing: Monte-Carlo simulations (100,000 runs under ±15% parameter noise) demonstrated a 99.98% convergence rate to the Φ_critical attractor. Simulated memory corruption and bit-flips triggered instantaneous execution isolation (0.00 ms crash rate) via SPARK pre/post-conditions. 4. Clinical Benchmark Cross-Validation: Predicted clinical outcomes (+16.4 ETDRS letters gain, 78% fibrosis reduction, 92% RPE preservation) were cross-validated against real-world trial datasets from ANCHOR (n=423) and MARINA (n=716). CONCLUSION: The V3-RGN-09 Molecular Simulator bridges high-integrity critical software engineering (DO-178C standards) with computational biophysics. It provides a proven, deterministic, and formally verified foundation for in silico drug discovery, ready for TRL 4 in vitro and in vivo translational research.
2026-04-29 | RIPK3 suppresses photoreceptor degeneration in a Stargardt disease mouse model
Abstract Autosomal recessive Stargardt disease type 1 (STGD1) is the most prevalent inherited juvenile macular degeneration, ultimately leading to irreversible blindness through photoreceptor cell loss, yet the underlying cell death mechanisms remain poorly defined. Receptor-interacting protein kinase 3 (RIPK3) is a well-established mediator of necroptosis and, under certain circumstances, apoptosis downstream of TNF family ligands, and it was found to be progressively upregulated in the retina of a STGD1 abca4 −/− rdh8 −/− (DKO) mouse model coinciding with the onset and progression of photoreceptor degeneration. Despite elevated RIPK3 expression, necroptosis was not detectable in this model, as evidenced by the absence of phosphorylated MLKL and unaltered photoreceptor degeneration in abca4 -/- rdh8 -/- mlkl -/- mice. Intriguingly, genetic ablation of Ripk3 exacerbated photoreceptor loss in DKO mice in both chronic (age-dependent) and acute (light-induced) retinal degeneration paradigms. This detrimental effect was partially ameliorated by pan-caspase inhibition in the acute degeneration model, indicating caspase-dependent apoptosis as the primary executioner. Mechanistically, we demonstrated that RIPK3 suppressed extrinsic apoptosis by attenuating caspase-8 activation downstream of TNF family ligands. Collectively, our findings reveal a non-canonical, protective role of RIPK3 in photoreceptors, as a brake on apoptotic signaling rather than a necroptotic executor, in the context of STGD1. These findings redefine the role of RIPK3 in retinal degeneration and emphasize the contextual plasticity of cell death regulators in neurodegenerative diseases.
gene therapies
2026-09-23 | Stargardt disease: clinical studies over the past 5 years—a systematic review
Summary Background Stargardt disease type 1 (STGD1) is the most common juvenile macular degeneration and one of the leading causes of visual impairment and blindness among children and working adults across Europe. There are currently no approved therapies for STGD1, but several therapeutic approaches including pharmacotherapy, gene therapy, neuroprotection, and stem cell therapy are under investigation in clinical studies and trials. Here, we review the current status of evolving therapies for STDG1. Methods This systematic review is based on the PRISMA‑P checklist using various scientific databases. Only case series and (non-)randomized clinical studies were included, with preclinical and basic science studies excluded. All included studies were individually assessed using the ROBINS‑I Tool of the Cochrane Collaboration and the TREND-Checklist for BIAS assessment. Results From the initial search, 314 records were identified, including 72 from PubMed, 96 from Embase, 41 from the Cochrane Library, 68 from Google Scholar, and 37 from Epistemonikos. After removing duplicates, the titles, abstracts, and full texts were screened according to predefined PICO criteria: population with genetically and clinically confirmed STDG1, interventions such as gene therapy, pharmacological approaches, stem cell therapy, and neuroprotection; comparison groups appropriate to the study design, such as placebo, the fellow eye, natural progression, or historical cohorts; and outcomes , including structural progression (assessed by fundus autofluorescence and optical coherence tomography), functional outcomes, and safety. Six studies met these criteria and were included. Of these, one investigated the gene therapy SAR422459, one evaluated the pharmacological agent emixustat, three assessed stem cell-based retinal pigment epithelium transplantation, and one examined neuroprotection through saffron supplementation. Conclusion Although STGD1 remains a challenging condition, new therapies in this review have shown potential in clinical trials. Ongoing methods aim to optimize the use of stem cell-based retinal pigment epithelium cells, refine delivery methods for the large ABCA4 gene, and explore genome editing techniques, such as CRISPR, to correct ABCA4 mutations, even though challenges such as off-target effects and DNA repair errors remain. Pharmacological approaches are focused on optimizing dosing for safety and efficacy. With further research on larger cohorts and long-term evaluation, there is hope for effective therapies.
2026-06-26 | Therapeutic Efficacy of Multi-Characteristic Opsin Gene Therapy in a Mouse Model of Stargardt Disease.
Optogenetic gene therapy-based treatment offers a unique approach to bypass dysfunctional or degenerated photoreceptors in retinal degenerative disorders. Ambient light-activatable multi-characteristic opsin (MCO) targeted to bipolar cells of the retina has demonstrated partial vision restoration in animal models of retinitis pigmentosa (RP). Here, we describe the potential therapeutic efficacy of intravitreally delivered AAV-carried MCO-010 in a mouse model of Stargardt disease. MCO-010 treatment led to significantly improved behavioral outcomes in the visually guided radial arm water maze. Furthermore, longitudinal optical coherence tomographic imaging showed that the MCO-010 treatment led to no notable change in the retina thickness. Furthermore, the MCO-010-treated mice exhibited higher electrophysiological responses compared to the control group. Together, these findings demonstrate potential vision-restoring and disease-modifying aspects of ambient light-activatable intravitreal MCO-010 therapy.
2026-03-23 | Retinal gene therapies for inherited ocular diseases: Translational delivery strategies from bench to bedside.
Inherited retinal diseases (IRDs), including retinitis pigmentosa, Leber congenital amaurosis, and Stargardt disease, represent a major cause of inherited visual impairment and blindness, particularly in working-age populations. These disorders are genetically heterogeneous and result in progressive degeneration of photoreceptors and the retinal pigment epithelium. The eye offers a uniquely favorable environment for gene therapy due to its anatomical compartmentalization, accessibility, and relative immune privilege; however, successful clinical translation remains constrained by multiple biological and technological barriers. In this review, we adopt a comparative, delivery-centric framework to analyze how different gene delivery strategies navigate key translational challenges, including the blood-retinal barrier, vector tropism, immune responses, payload size limitations, re-dosing feasibility, and manufacturing cost. We systematically contrast viral and non-viral platforms, highlighting their respective strengths, limitations, and suitability across administration routes and target cell populations. While adeno-associated viral vectors currently dominate clinical development, emerging non-viral systems, such as lipid-based formulations, polyplexes, exosomes, and peptide-based carriers, offer complementary advantages in safety, payload flexibility, and repeat dosing. By integrating insights from retinal biology, biomaterials engineering, and clinical trial experience, this review offers decision-oriented guidance for selecting appropriate delivery strategies based on disease context, target cells, and translational constraints. We further discuss how advances in genome editing, administration routes, and carrier design may shape the next generation of economically viable and clinically scalable gene therapies for IRDs.
2026-03-14 | Precise CRISPR/Cas9 and Cas12 Correction Using Lipoplexes in Retinal Models Derived from Patients with Inherited Retinal Dystrophies.
Gene editing, particularly CRISPR/Cas technology, represents a promising approach for the treatment of rare genetic diseases, including inherited retinal dystrophies, for which effective therapies are largely unavailable. Despite extensive research investigating gene editing across a wide range of cell types, transient delivery of CRISPR/Cas components and efficient homology-directed repair (HDR) in differentiated cells remain challenging. In this study, we employed hiPSCs derived from patients with Stargardt disease or Best disease, carrying pathogenic variants in ABCA4 or BEST1, respectively, to explore gene editing in human models. CRISPR/Cas9 and Cas12 nucleases were delivered into hiPS-derived retinal pigment epithelium (RPE) and retinal organoids using lipoplexes and compared with electroporation. We evaluated transfection efficiency, sgRNA-mediated DNA cleavage, and HDR-based correction. Precise repair of the pathogenic BEST1 variant was successfully achieved in hiPS-derived RPE cells using both nucleases, with Cas12 yielding the highest efficiency, exceeding 10% of HDR correction. Edited RPE cells preserved normal morphology and expressed specific maturity markers. In contrast, retinal organoids exhibited moderate transfection efficiency but showed no detectable CRISPR/Cas-induced DNA cleavage, highlighting the need for further optimization of gene editing in more complex cellular tissues. This study demonstrates, for the first time, precise correction of a single-nucleotide mutation in patient-derived RPE using CRISPR/Cas9 and Cas12 delivered using lipoplexes. These findings underscore the therapeutic potential of CRISPR/Cas-based strategies for inherited retinal dystrophies and provide a proof of concept for future clinical approximations.
2026-03-05 | Advances in vision restoration using multi-characteristic opsin
This presentation reviews the preclinical foundation, clinical trial program—including efficacy results—and the recent expansion of the MCO optogenetic program into geographic atrophy. MCO represents a paradigm-shifting, mutation-agnostic optogenetic approach for vision restoration. From robust preclinical evidence to multiple clinical trials demonstrating efficacy and durability, this therapy has shown the potential to restore meaningful vision in previously untreatable conditions such as RP and Stargardt disease. The expansion to geographic atrophy further highlights its versatility and transformative potential. Collectively, these advances position MCO as a leading candidate in the emerging field of vision restoration, offering hope to millions of patients affected by retinal degenerative diseases.
cell therapies
2025-12-01 | Postmortem Retinal Structural and Metabolic Analysis After Human Embryonic Stem Cell-derived Retinal Pigment Epithelium Transplantation in a Patient With Stargardt Disease.
Purpose: Stargardt disease is an inherited form of retinal degeneration characterized by early-onset central vision loss. This report describes the long-term retinal histologic characteristics of a patient with Stargardt disease after human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) transplantation. Methods: Eyes were obtained postmortem from an 80-year-old legally blind male patient with Stargardt disease. The patient had previously undergone hESC-RPE transplantation of his left eye, and the right eye (untransplanted) served as a control. Fluorescence lifetime imaging microscopy was used to study retinal structure and metabolic activity. Staining of the retina for lipofuscin was performed using the Armed Forces Institute of Pathology method. Results: Metabolic analysis showed that the macular area had more oxidative phosphorylation relative to the mid-peripheral retina, in both the transplanted and untransplanted eye. Melanin-laden RPE cells were detected in the transplanted eye, which correlated with a pigment band present on fundus images post-hESC-RPE transplantation. Conclusions: This case description illustrates the long-term survival of subretinal hESC-RPE cells post-transplantation in a patient with Stargardt disease.
2025-08-30 | Retinal Pigment Epithelium Transplantation in Retinal Disease: Clinical Trial Development, Challenges, and Future Directions.
Replacement of the retinal pigment epithelium (RPE) is emerging as a promising approach to treat degenerative retinal diseases, including age-related macular degeneration and Stargardt disease, in which RPE function cannot otherwise be restored. Despite the limitations of existing treatments, advances in cell sourcing and surgical methods have enabled initial human trials of RPE transplantation, with early results indicating potential efficacy. This review comprehensively examines the evolution of RPE transplantation in recent decades, highlighting the advantages and limitations of different cell sources and delivery methods. Current clinical trial data are analyzed with a particular focus on immune rejection risks, surgical complications, and long-term safety. Despite encouraging safety profiles, achieving consistent and sustained visual improvement remains a challenge, as vision outcomes might be influenced by factors such as disease stage at intervention, transplantation site, number of cells transplanted, and duration of follow-up. Key challenges, such as cell or graft survival and integration with the host retina, are discussed in depth, as overcoming these obstacles is essential for achieving stable and effective RPE replacement. Future research directions, including innovations in biomaterials, molecular modification strategies, and personalized approaches, hold promise for enhancing the efficacy and durability of RPE transplantation for retinal disease.
2024-12-01 | Maculopathies: A Systematic Literature Review on Pathophysiology, Public Health, and Treatment.
Macular degeneration (MD) is a pathological condition affecting the macula, an area located near the center of the retina. This disease affects individuals of all ages, both children and adults, causing severe visual impairment. Age-related macular degeneration (AMD) is the leading cause of visual loss in the older population while Stargardt disease (SD) is the most common hereditary maculopathy with an autosomal dominant pattern of inheritance. Current management involves anti-vascular endothelial growth factor intravitreal injections, visual aids, and other conservative prevention mechanisms that can only delay the inevitable progress of the disease. Macular dystrophies have an impact on both individuals and societies with psychological and financial implications, respectively. It is evident that vision impairment has a significant impact on patients' physical and mental well-being, and therefore it is important to improve current treatment modalities, develop stem cell therapies, and further novel treatments in order to provide a better prognosis and overall quality of life.
2024-11-04 | Lipopeptide-mediated Cas9 RNP delivery: A promising broad therapeutic strategy for safely removing deep-intronic variants in ABCA4.
Deep-intronic (DI) variants represent approximately 10%-12% of disease-causing genetic defects in ABCA4-associated Stargardt disease (STGD1). Although many of these DI variants are amenable to antisense oligonucleotide-based splicing-modulation therapy, no treatment is currently available. These molecules are mostly variant specific, limiting their applicability to a broader patient population. In this study, we investigated the therapeutic potential of the CRISPR-Cas9 system combined with the amphipathic lipopeptide C18:1-LAH5 for intracellular delivery to correct splicing defects caused by different DI variants within the same intron. The combination of these components facilitated efficient editing of two target introns (introns 30 and 36) of ABCA4 in which several recurrent DI variants are found. The partial removal of these introns did not affect ABCA4 splicing or its expression levels when assessed in two different human cellular models: fibroblasts and induced pluripotent stem cell-derived photoreceptor precursor cells (PPCs). Furthermore, the DNA editing in STGD1 patient-derived PPCs led to a ∼50% reduction of the pseudoexon-containing transcripts resulting from the c.4539+2001G>A variant in intron 30. Overall, we provide proof-of-concept evidence of the use of C18:1-LAH5 as a delivery system for therapeutic genome editing for ABCA4-associated DI variants, offering new opportunities for clinical translation.
2023-02-03 | Upregulation of rhodopsin gene in regenerated retina followed by adipose-derived stem cell therapy in a rat model
Abstract Background : Retinal degenerative diseases, including age-related macular degeneration, Stargardt disease, and retinitis pigmentosa are phenotypically diverse and lead to photoreceptor cell death and downregulation of rhodopsin gene expression. Retinal degeneration is difficult to treat; therefore, artificial devices, autologous grafts, and the retinal donation should be used to replace damaged tissues or organs. Methods : In this study, the photoreceptor layer of the retinal tissue of rats was damaged by intravitreal sodium iodate (NaIO 3 ) administration. Following the confirmation of retinal damage, intravitreal injections of adipose stem cells with a hydrogel scaffold were implanted into the intravitreal space’s retinas of rats. The process of retinal regeneration was assessed by histopathology, and RT-PCR analyzed the expression of the rhodopsin gene. Results : Histopathological examination demonstrated that injecting a suitable biomaterial hydrogel and mesenchymal stem cells improved tissue regeneration. In addition, the data showed that the expression of the rhodopsin gene was upregulated in repaired retinal tissue compared to damaged tissue. Conclusion: NaIO 3 injection into the intravitreal space of rats’ results in severe retina injury. The application of mesenchymal stem cells is suggested as competent cells to cure degenerative retinal defects. This model could be a valuable tool for seeking and evaluating novel therapeutic modalities for the treatment of retinal degeneration.
other
2024-12-10 | Transferrin ameliorates retinal degeneration by mediating the dimerization of all-trans-retinal.
High levels of all-trans-retinal (atRAL) in the retina is considered to be responsible for the development of autosomal recessive Stargardt's disease (STGD1) and dry age-related macular degeneration (dAMD). Two bisretinoids, all-trans-retinal dimer (atRAL-dimer) and N-retinyl-N-retinylidene ethanolamine (A2E), form from the dimerization of atRAL in the retina but they possess much lower toxicity and phototoxicity toward retinal pigment epithelium (RPE) cells than atRAL. Here, we introduced a novel function of transferrin (TRF) in mediating the conversion of atRAL into atRAL-dimer and A2E, which effectively protected the retina from damage by atRAL and prevented retinal function decline in mice, and rescued atRAL-loaded RPE cells. Moreover, TRF-mediated conversion of atRAL to atRAL-dimer and A2E required the help of bicarbonate ions (HCO3-). atRAL had the capacity to stimulate the expression of TRF in RPE and photoreceptor cells as well as RPE/choroid and neural retina of mice, reflecting that the elevation of TRF levels by atRAL is most likely to help defy level increase and cytotoxicity of atRAL through facilitating its dimerization and thereby serves as a mechanism of retinal self-protection. Our findings offer a promising avenue for the treatment of retinopathies characterized by disrupted clearance of atRAL.
2021-12-03 | Stargardt disease: A clinical case report of two sisters with different clinical development.
The purpose of this article is to describe the clinical manifestations and complementary diagnostic tests of two sisters aged 26 and 31 with a diagnosis of Stargardt's disease. One of them presented with an initial visual acuity of 0.7 and showed a progressive central visual loss due to the atrophy of the external layers of the retina in the subfoveal region. She was recruited to participate in a clinical trial of Avancincaptad Pegol (Zimura®), an inhibitor of C5 of the complement's system. The other sister remained asymptomatic with a visual acuity of 1 in both eyes. In both cases white-yellow pisciform lesions were observed on the posterior pole. Although there is no curative treatment for this disease, there are many lines of investigation on this topic. The clinical and diagnostic tests can confirm the disease, and provide patients with an accurate prognosis.
2021-06-18 | Evidence of complement dysregulation in outer retina of Stargardt disease donor eyes.
Stargardt macular degeneration (STGD) is a central blinding disease caused by loss of or dysfunctional ABCA4 transporter in both photoreceptors and retinal pigment epithelial (RPE) cells. Toxic bisretinoid-lipofuscin buildup in the RPE cells is a pathological hallmark of STGD patients and its mouse model, the Abca4-/-. These vitamin A-derived fluorophores have been shown to induce oxidative stress, stimulate complement activity, and cause chronic inflammation of the RPE. In vivo modulation of complement regulatory pathway in the STGD mouse model has partially rescued the STGD phenotype suggesting that complement attack on the RPE is an important etiologic factor in disease pathogenesis. While bisretinoid-dependent complement activation was further evidenced in cultured RPE cells, this pathway has never been investigated directly in the context of RPE from STGD donor eyes. In the current study, we evaluate the complement reactivity in postmortem donor eyes of clinically diagnosed STGD patients. All three STGD donor eyes RPE displayed strong immunoreactivity for an antibody specific to 4-Hydroxynonenal, a lipid peroxidation byproduct. Also, unlike the control eyes, all three STGD donor eyes showed significantly increased membrane attack complex deposition on the RPE cells. In STGD eyes, increased MAC accumulation was mirrored by elevated C3 fragments internalized by the RPE and inversely correlated with the levels of complement factor H, a major complement regulatory protein. Here, we report the first direct evidence of RPE complement dysregulation as a causative factor in developing Stargardt phenotype.
2019-08-01 | Oxidative stress in retinal pigment epithelial cells increased endogenous complement-dependent inflammatory and angiogenic responses - independent from exogenous complement sources
ABSTRACT Oxidative stress-induced damage of the retinal pigment epithelium (RPE) together with chronic inflammation has been suggested as major contributors to retinal diseases. Here, we examine the effects of oxidative stress and endogenous complement components on the RPE and its pro-inflammatory and –angiogenic responses. The RPE cell line, ARPE-19, treated with H 2 O 2 reduced cell-cell contacts, increased marker for epithelial–mesenchymal transition but showed less cell death. Stressed ARPE-19 cells increased the expression of complement receptors CR3 and C5aR1. CR3 was co-localized with cell-derived complement protein C3, which was observed in its activated form in ARPE-19 cells. C3 as well as its regulators CFH and properdin accumulated in ARPE-19 cells after oxidative stress independent from external complement sources. This cell-associated complement accumulation promoted nlrp3 and foxp3 expression and subsequent increased secretion of pro-inflammatory and pro-angiogenic factors. The complement-associated ARPE-19 reaction to oxidative stress, independent from external complement source, was increased by the PARP-inhibitor olaparib. Our results indicated that RPE cell-derived complement proteins and receptors are involved in RPE cell homeostasis following oxidative stress and should be considered as targets for treatment developments for retinal degeneration. GRAPHICAL ABSTRACT We show a functional link between oxidative stress, complement receptors, endogenous complement proteins, pro-angiogenic and -inflammatory responses in ARPE-19 cells. These effects are independent from extracellularly added complement proteins or receptor ligands. We suggest an oxidative stress-associated autocrine mechanism of complement receptor regulation in ARPE-19 cells in connection with upregulated intracellular proteases. HIGHLIGHTS Oxidative stress accumulates complement proteins and receptors in RPE cells Oxidative stress activates the RPE inflammasome without external complement proteins Oxidative stress increases foxp3 expression and IL-8/VEGF secretion in RPE cells Olaparib enhances pro-inflammatory response of RPE
2018-08-07 | ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease.
Stargardt disease is caused by variants in the ABCA4 gene, a significant part of which are noncanonical splice site (NCSS) variants. In case a gene of interest is not expressed in available somatic cells, small genomic fragments carrying potential disease-associated variants are tested for splice abnormalities using in vitro splice assays. We recently discovered that when using small minigenes lacking the proper genomic context, in vitro results do not correlate with splice defects observed in patient cells. We therefore devised a novel strategy in which a bacterial artificial chromosome was employed to generate midigenes, splice vectors of varying lengths (up to 11.7 kb) covering almost the entire ABCA4 gene. These midigenes were used to analyze the effect of all 44 reported and three novel NCSS variants on ABCA4 pre-mRNA splicing. Intriguingly, multi-exon skipping events were observed, as well as exon elongation and intron retention. The analysis of all reported NCSS variants in ABCA4 allowed us to reveal the nature of aberrant splicing events and to classify the severity of these mutations based on the residual fraction of wild-type mRNA. Our strategy to generate large overlapping splice vectors carrying multiple exons, creating a toolbox for robust and high-throughput analysis of splice variants, can be applied to all human genes.
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Drug Discovery Landscape
32 orphan drug designations for Stargardt disease.
32 orphan drug designations for Stargardt disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
retinol binding protein 4 (RBP4) inhibitor | small molecules | FDA | Heronova Pharmaceuticals, LLC | |
Antisense oligonucleotide against ABCA4 pre-mRNA | oligonucleotides | EMA | — | Astherna B.V. |
Gildeuretinol, gildeuretinol acetate | small molecules | EMA | Voisin Consulting | |
AAV2.GL-3¿ABCA4 + AAV2.GL-5¿ABCA4 | gene therapies | FDA | VeonGen Therapeutics GmbH | |
Two AAV vectors, the first expressing the N- and the second expressing the C-region of the ATP-binding cassette subfamily A member 4 (ABCA4) protein fused to N- or C-terminal split-intein sequences | gene therapies | FDA | SpliceBio S.L. | |
AAV8_ABCA4 RNA Exon Editor | gene therapies | FDA | Ascidian Therapeutics, Inc. | |
Adeno-Associated Virus Serotype 5 capsid protein containing gene construct encoding human Retinoic Acid Receptor-Related Orphan Receptor Alpha | gene therapies | FDA | Ocugen, Inc. | |
Vutrisiran [Amvuttra] | RNAs | EMA | — | Alnylam Netherlands B.V. |
Echothiophate iodide | small molecules | FDA | — | Fera Pharmaceuticals, LLC |
Adeno Associate Virus carried Multi Characteristic Opsin | gene therapies | FDA | Nanoscope Therapeutics Inc. | |
sulfo butyl ether beta-cyclodextrin | small molecules | FDA | — | reVision Therapeutics, Inc. |
Combination of two adeno-associated viral vectors of serotype 8 containing the 5'- and the 3'- half coding sequences of human ABCA4 fused to inteins | gene therapies | EMA | Aavantgarde Bio S.r.l. | |
Emixustat hydrochloride | small molecules | EMA | Pharma Gateway AB | |
3-(3-(3,5-bis(trifluoromethyl)phenyl)-1h-pyrazol-1-yl)propanoic acid | small molecules | EMA | [INACTIVE] TMC Pharma (EU) Limited | |
3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl) propanoic acid | small molecules | FDA | Stargazer Pharmaceuticals, Inc. | |
1-(3-{4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl}-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one | small molecules | EMA | Voisin Consulting Life Sciences | |
soraprazan | small molecules | FDA | Katairo GmbH | |
tinlarebant | small molecules | FDA | Belite Bio, LLC | |
emixustat | small molecules | FDA | Acucela Inc. | |
ABCA4 DNA nanoparticles | oligonucleotides | FDA | — | Copernicus Therapeutics, Inc. |
Ecothiopate iodide | small molecules | EMA | — | Dorian Regulatory Affairs B.V. |
Mixture of two adeno-associated viral vectors of serotype 8 containing the 5'-half sequence of human ABCA4 gene and the 3'-half sequence of human ABCA4 gene | gene therapies | EMA | Fondazione Telethon Ets | |
echothiophate iodide | small molecules | FDA | — | Makindus, Inc. |
Soraprazan | small molecules | EMA | Katairo GmbH | |
Ramiprilat | small molecules | EMA | — | Yes Pharmaceutical Development Services GmbH |
Envuretcel | cell therapies | EMA | Astellas Pharma Europe B.V. | |
C20-D3-retinyl acetate | small molecules | FDA | Alkeus pharmaceuticals, Inc. | |
lentiviral vector containing the human ABCA4 gene | gene therapies | FDA | Sanofi US Services Inc. | |
Lentiviral vector containing the human ABCA4 gene | gene therapies | EMA | Sanofi Winthrop Industrie | |
MA09-hRPE cells | cell therapies | FDA | Astellas Pharma Global Development Inc. | |
Adeno-associated viral vector serotype 5 containing the human ABCA4 gene | gene therapies | EMA | — | Fondazione Telethon Ets |
Adeno-associated viral vector serotype 5 containing human ABCA4 gene | gene therapies | FDA | — | Fondazione Telethon |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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