RARE DISEASE
Best vitelliform macular dystrophy
Best vitelliform macular dystrophy
Best vitelliform macular dystrophy
Synonyms: BMD, BVMD, Best disease, Best macular dystrophy, Early-onset vitelliform macular dystrophy, Juvenile-onset vitelliform macular dystrophy, Polymorphic vitelline macular degeneration, Vitelliform macular dystrophy type 2
Synonyms: BMD, BVMD, Best disease, Best macular dystrophy, Early-onset vitelliform macular dystrophy, Juvenile-onset vitelliform macular dystrophy, Polymorphic vitelline macular degeneration, Vitelliform macular dystrophy type 2
Synonyms: BMD, BVMD, Best disease, Best macular dystrophy, Early-onset vitelliform macular dystrophy, Juvenile-onset vitelliform macular dystrophy, Polymorphic vitelline macular degeneration, Vitelliform macular dystrophy type 2
Drug discovery
114
papers
On emerging therapies
Overview
Best vitelliform macular dystrophy (BVMD), or Best disease, is an autosomal dominant macular dystrophy caused by BEST1 gene mutations. It presents with bilateral yellow vitelliform lesions, progressing through previtelliform, vitelliform, pseudohypopyon, vitelloruptive, atrophic, and choroidal neovascularization (CNV) stages. Central vision loss is gradual, with preserved peripheral vision. Electrooculography (EOG) shows a reduced Arden ratio (<1.5), while ERG remains normal. Complications include CNV (20% of cases) and geographic atrophy [1][2][6][9][12].
Population
Prevalence: ~1 in 127,000 globally, higher in Arab Muslim populations (1:76,000) [6].
Onset: Typically childhood (3–15 years), though delayed diagnosis is common due to preserved vision in early stages [1][6][10].
Inheritance: Autosomal dominant BEST1 mutations with variable expressivity and incomplete penetrance [2][9].
Burden
Vision Loss: Central acuity declines to ≤20/200 in 30–50% of advanced cases, impacting reading and facial recognition [9][11][14].
CNV Risk: ~20% develop CNV, requiring urgent intervention to prevent rapid vision loss [2][10][12].
Lifelong Impact: Slow progression demands decades of surveillance, with psychosocial and occupational challenges due to variable disease severity [6][9][13].
Therapies
Monitoring: Annual ophthalmologic exams, OCT, and self-monitoring (e.g., Amsler grid) for CNV detection [5][12].
CNV Treatment: Intravitreal anti-VEGF agents (e.g., ranibizumab) or photodynamic therapy [5][12][14].
Emerging Therapies: Gene augmentation (AAV-mediated BEST1 delivery) and pharmacologic agents (valproic acid, proteasome inhibitors) in preclinical trials [2][3][7].
Categories: rare genetic diseases, rare ophthalmic disorders
Research Papers
114 drug discovery papers about Best vitelliform macular dystrophy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
114 drug discovery papers about Best vitelliform macular dystrophy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2023-04-08 | Tadalafil Rescues the p.M325T Mutant of Best1 Chloride Channel
Bestrophin 1 (Best1) is a chloride channel that localises to the plasma membrane of retinal pigment epithelium (RPE) cells. Mutations in the BEST1 gene are associated with a group of untreatable inherited retinal dystrophies (IRDs) called bestrophinopathies, caused by protein instability and loss-of-function of the Best1 protein. 4PBA and 2-NOAA have been shown to rescue the function, expression, and localisation of Best1 mutants; however, it is of interest to find more potent analogues as the concentration of the drugs required is too high (2.5 mM) to be given therapeutically. A virtual docking model of the COPII Sec24a site, where 4PBA has been shown to bind, was generated and a library of 1416 FDA-approved compounds was screened at the site. The top binding compounds were tested in vitro in whole-cell patch-clamp experiments of HEK293T cells expressing mutant Best1. The application of 25 μM tadalafil resulted in full rescue of Cl- conductance, comparable to wild type Best1 levels, for p.M325T mutant Best1 but not for p.R141H or p.L234V mutants.
2022-09-26 | SPACR Encoded by IMPG1 Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium.
Several pathogenic variants have been reported in the IMPG1 gene associated with the inherited retinal disorders vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). IMPG1 and its paralog IMPG2 encode for two proteoglycans, SPACR and SPACRCAN, respectively, which are the main components of the interphotoreceptor matrix (IPM), the extracellular matrix surrounding the photoreceptor cells. To determine the role of SPACR in the pathological mechanisms leading to RP and VMD, we generated a knockout mouse model lacking Impg1, the mouse ortholog. Impg1-deficient mice show abnormal accumulation of autofluorescent deposits visible by fundus imaging and spectral-domain optical coherence tomography (SD-OCT) and attenuated electroretinogram responses from 9 months of age. Furthermore, SD-OCT of Impg1-/- mice shows a degeneration of the photoreceptor layer, and transmission electron microscopy shows a disruption of the IPM and the retinal pigment epithelial cells. The decrease in the concentration of the chromophore 11-cis-retinal supports this loss of photoreceptors. In conclusion, our results demonstrate the essential role of SPACR in maintaining photoreceptors. Impg1-/- mice provide a novel model for mechanistic investigations and the development of therapies for VMD and RP caused by IMPG1 pathogenic variants.
2021-12-08 | Long-Term Maintenance of Vision and Resolution of Vitelliform Lesions with Systemic Phosphodiesterase 5/6 Treatment (Sildenafil)
BACKGROUND: Adult vitelliform macular dystrophy results in loss of central vision. The use of systemic sildenafil has been proven to increase choroidal blood flow. This is a report of a favorable long-term treatment outcome using systemic sildenafil for a patient with adult onset vitelliform macular dystrophy. CASE PRESENTATION: A 55-year-old woman presenting with bilateral subretinal vitelliform lesions was initially assessed by full-field electroretinogram, electro-oculogram and direct sequencing of the RDS/PRPH2 and BEST1 genes. Best-corrected visual acuity, spectral domain-optical coherence tomography and color fundus photography were obtained and analyzed over a 5-year treatment course which included bevacizumab (Avastin) injections in the right eye and left eye and subsequent ranibizumab (Lucentis) treatments in the left eye. Lipid resolution in the right eye was seen with bevacizumab after two months of treatment, while the left eye was unresponsive to eight subsequent injections of bevacizumab, followed by ranibizumab over a period of twenty months. Systemic sildenafil was started, off label, at 20 months following course of intravitreal injections. Following initiation of sildenafil, there were both measured and patient-reported improvements in the left eye following after two months of sildenafil. CONCLUSIONS: Systemic phosphodiesterase (PDE)-5 and -6 inhibitors may facilitate the removal of lipid and waste from the subretinal space by increasing perfusion in patients with vitelliform lesions and aid in maintaining and/or recovering photoreceptor function.
2021-08-18 | Disease-causing mutations associated with bestrophinopathies promote apoptosis in retinal pigment epithelium cells.
Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) are two kinds of bestrophinopathies which are caused by BEST1 mutations and characterized by accumulation of lipofuscin-like materials on the retinal pigment epithelium cell-photoreceptor interface. In the past two decades, research about the pathogenesis of bestrophinopathies was mainly focused on the anion channel and intracellular Ca2+ signaling, but seldom concentrated on the function of retinal pigment epithelium (RPE) cells. In this study, we explored the possible effect of the three BEST1 mutations p.V143F, p.S142G, and p.A146T on the apoptosis in human fetal RPE cells. Wild-type plasmid and mutant plasmids BEST1-pcDNA3.1 p.V143F, p.S142G, and p.A146T were transfected to human fetal RPE cells. The molecules caspase-3, phospho-Bcl-2, BAX, PARP, and AIF associated with apoptosis were determined by quantitative PCR and Western blot. Apoptotic rate and active Caspase-3 staining were analyzed by flow cytometry. Caspase-3 and PARP expression were significantly increased in BEST1-pcDNA3.1 p.S142G and p.A146T group. Flow cytometry showed that the apoptosis rates were significantly increased in the BEST1-pcDNA3.1 p.V143F, p.S142G, and p.A146T group compared with the wild-type group. For the first time, we found that the three mutations promoted RPE cell apoptosis. Furthermore, the results indicated that BEST1 mutations p.S142G and p.A146T may contribute apoptosis of RPE cells by targeting Caspase 3. Our observations suggested that the apoptosis of RPE cells may be one of the mechanisms in bestrophinopathies, which may provide a new potential therapeutic target for the treatment of this disease.
2021-06-21 | Optical coherence tomography angiography cyclic remodeling of CNV in patients affected by Best macular dystrophy.
To evaluate the effect of photodynamic therapy and/or intravitreal injections on choroidal neovascularization in treatment-naïve patients affected by Best Macular Dystrophy using OCT-A. BMD patients with CNV treated using PDT and/or IV were included in the study. All patients underwent a complete ophthalmological examination, OCT and 3 × 3 mm OCT-A. The OCT-A images were analyzed using an open-source software (ImageJ) to assess the CNV membrane area (CNV-MA), the CNV vessel area (CNV-VA), and vessel density (VD) at the follow-ups (3 months after PDT and 1 month after IV). Five eyes of four patients with CNV were included. All eyes received PDT as first-line therapy; 4 eyes underwent more than 1 treatment session: three eyes received 1 IV, whereas one eye had one further PDT. After PDT, the CNV-MA, CNV-VA, and VD quantitative parameters were obtained for four out of five eyes: in three eyes of two patients CNV-MA, CNV-VA, and VD first decreased and then gradually increased during follow-up, whereas in one eye of one patient CNV-MA, CNV-VA, and VD slightly increased. After IV the CNV-MA, CNV-VA, and VD had significantly decreased at the 1-month follow-up in three eyes of three patients. OCT-A is an important tool for the diagnosis of both naïve and fibrotic CNV in BMD patients; it is a non-invasive method for the qualitative and quantitative analysis of neovascular lesions during follow-up. Our results have shown a cyclic remodeling of treated CNV in BMD patients using both PDT and IV.
gene therapies
2026-07-15 | Allele-specific correction of dominant Best vitelliform macular dystrophy in patient-derived retinal pigment epithelium
ABSTRACT Autosomal dominant Best vitelliform macular dystrophy (BVMD) caused by variants in the BEST1 gene is characterized by dysfunction of the macular retinal pigment epithelium (RPE) and secondary degeneration of the photoreceptors. There are currently no approved treatments for BVMD, and owing to its dominant nature, there remains uncertainty regarding the utility of traditional gene augmentation. Here we evaluated whether a dominant pathogenic BEST1 allele can be corrected by base editing in differentiated RPE cells. We identified a patient with a likely pathogenic BEST1 c.851A>G (p. Tyr284Cys) variant that was amenable to cytidine base editing. After establishing patient-derived induced pluripotent stem cells (iPSCs), we corrected the pathogenic variant in the iPSCs to obtain corrected iPSCs with the same genetic background. Corrected iPSC-derived RPE exhibited normalized monolayer appearance, improved barrier integrity, reduced cell death, and restored RPE-specific transcriptome. We then used a dual adeno-associated virus (AAV) split-intein system to deliver a CRISPR-associated protein 9 cytidine base editor (SpCas9-CBE) to BEST1 c.851A>G mutant RPE monolayers and achieved editing of the pathogenic allele with a maximum efficiency of 13.42 ± 3.64% (mean ± SD). Together, these results demonstrate progress towards allele-specific base editing in a dominantly inherited retinal disorder.
2026-07-07 | Evaluation of the Toxicity and Efficacy of an Adeno-Associated Viral Vector Expressing BEST1 Delivered by Subretinal Injection in a Canine Model of Human Bestrophinopathy.
To treat patients affected with bestrophinopathies caused by mutations in the BEST1 gene, a recombinant adeno-associated virus vector (OPGx-BEST1 or rAAV2/2-VMD2-BEST1) is being developed. The vector construct includes the human BEST1 cDNA under control of the VMD2/BEST1 promoter and is packaged in an AAV2 capsid. This study evaluated the efficacy and toxicity of OPGx-BEST1 administered by subretinal injection in dogs that were homozygous mutant or compound heterozygotes for 3 naturally occurring mutations in BEST1. Twelve BEST1-mutant dogs were divided into 4 groups of 3 animals each, and they received in their left eye a subretinal injection of 0.15 mL of OPGx-BEST1 at 1 of 3 concentrations (9.5 × 109 vector genome [vg]/mL; 3.0 × 1010 vg/mL; or 3.0 × 1011 vg/mL) of OPGx-BEST1, resulting, respectively, in a low (1.4 × 109 vg), high (4.5 × 109 vg), and highest (4.5 × 1010 vg) dose or vehicle control. The right eyes were not injected. Subretinal injections were well tolerated and were not associated with any systemic or ocular toxicity. Electroretinography showed improved rod- and cone-mediated responses in eyes treated with OPGx-BEST1. Noninvasive retinal imaging by optical coherence tomography showed improved structural integrity with a reduction or prevention of appearance of vitelliform lesions and reversal of microdetachments in the retinal areas treated with OPGx-BEST1. These results support the use of OPGx-BEST1 in clinical studies with patients affected with bestrophinopathies and define the no-observed-adverse-effect level at 4.5 × 1010 vg/eye (0.15 mL, 3.0 × 1011 vg/mL).
2026-06-01 | From BEST1 mutations to retinal regeneration: integrating stem cell-derived RPE models and gene correction strategies.
Retinal degenerative diseases are among the leading causes of irreversible vision loss worldwide and arise primarily from progressive dysfunction and death of photoreceptors and retinal pigment epithelial (RPE) cells. Because the mammalian retina lacks an intrinsic capacity for regeneration, current treatments remain limited and largely palliative. Recent advances in stem cell technologies and gene-based therapies, however, have opened new avenues for retinal repair and functional restoration. Among monogenic retinal disorders, BEST1-associated retinopathies provide a particularly informative paradigm for linking molecular mechanisms to emerging regenerative strategies.The human BEST1 encodes bestrophin-1 (BEST1), a calcium-activated chloride channel predominantly expressed in the RPE, where it plays essential roles in ionic homeostasis, transepithelial transport, and regulation of the visual cycle. Pathogenic variants in BEST1 give rise to a spectrum of inherited retinal diseases, including Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, and adult-onset vitelliform dystrophy. Mechanistic studies of BEST1 mutations have revealed diverse functional consequences, ranging from loss-of-function to gain-of-function effects, highlighting the importance of precise molecular diagnosis for therapeutic intervention.Here, we synthesize recent progress in stem cell-derived RPE models and gene correction strategies, using BEST1-associated retinopathies as a conceptual framework. We discuss how human induced pluripotent stem cell-derived RPE systems enable disease modeling and functional analysis of pathogenic variants, and how gene replacement and genome editing approaches are tailored to distinct mutation classes. Finally, we explore how integration of stem cell and gene therapy strategies may advance retinal regeneration and outline future directions for personalized and mechanism-based treatments of retinal degenerative diseases.
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.
2026-01-29 | Gene Augmentation Therapy for Bestrophinopathies: Targeting BEST1 in the Clinic
The bestrophin-1 (BEST1) gene encodes a calcium-dependent chloride channel, a transmembrane protein critical for the function of the retinal pigment epithelium (RPE) in the eye. Pathogenic variants in BEST1 are the underlying cause for bestrophinopathies, a group of inherited retinal diseases (IRDs) that vary in their pattern of inheritance, clinical appearance, and underlying molecular disease mechanisms. This article focuses on gene therapy strategies to treat Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB), two conditions for which there are currently no available treatments. Gene therapy represents an attractive strategy to treat BVMD and ARB, in particular gene augmentation, which has a successful track record for treating IRDs. This review examines the clinical diversity of bestrophinopathies and identifies the specific molecular disease mechanism of the pathogenic BEST1 genetic variants as an important parameter for designing future gene therapy strategies. Finally, we highlight the ongoing BIRD-1 (BEST1 Inherited Retinal Diseases) clinical trial as a significant step in translating the gene augmentation strategy into a clinical reality for treating BVMD and ARB.
antibodies
2025-10-20 | Anti-vascular endothelial growth factor therapies in ophthalmology.
Retinal diseases, including neovascular age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion, are leading causes of vision loss worldwide. The introduction of anti-vascular endothelial growth factor (anti-VEGF) therapies has dramatically changed the management of these conditions, offering targeted treatment that can preserve and even improve vision. We aimed to provide a comprehensive review of the development, clinical applications, and emerging indications of anti-VEGF therapies in ophthalmology, including biosimilar agents. A comprehensive literature search was conducted in PubMed/MEDLINE for English-language articles published up to 31 July 2025. Additional sources were identified through manual screening of reference lists. Included studies spanned various designs: clinical trials, meta-analyses, observational studies, and preclinical research. Keywords used in the search strategy included terms such as "anti-VEGF therapy", "biosimilar pharmaceuticals", "intravitreal and intrastromal anti-VEGF injections", "retinal diseases" including "macular degeneration" and "retinal neovascularization", "ranibizumab", and "bevacizumab", as well as relevant MeSH terms where applicable. Anti-VEGF agents have transformed the management of retinal diseases such as neovascular age-related macular degeneration, diabetic macular edema, proliferative diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. Newer agents such as brolucizumab and faricimab offer prolonged durability and enhanced anatomic outcomes, while biosimilars provide cost-effective alternatives. Anti-VEGF therapy has also shown promise in off-label or emerging indications such as neovascular glaucoma, corneal neovascularization, and other retinal or choroidal disorders including secondary macular edema and/or macular neovascularization associated with various forms of uveitis, diffuse choroidal hemangioma in Sturge-Weber Syndrome, hereditary retinal disorders such as fundus flavimaculatus, Coats-Like retinitis pigmentosa, Peripherin-2-associated retinopathy, immune checkpoint inhibitor use, radiation retinopathy, retinitis pigmentosa, Bietti crystalline dystrophy, autosomal recessive bestrophinopathy, melanocytoma-associated macular neovascular membrane, Best disease, Wyburn-Mason syndrome, choroidal osteoma, peripheral exudative hemorrhagic chorioretinopathy, traumatic choroidal rupture, torpedo maculopathy, optic disc melanocytoma, type 2 proliferative macular telangiectasia, and Coats disease. High-dose formulations and innovative delivery systems are under active investigation to reduce the treatment burden and extend dosing intervals. Anti-VEGF therapies have revolutionized the field of ophthalmology, providing sight-saving treatment for a range of retinal diseases that were once considered untreatable or inevitably blinding. Today, anti-VEGF drugs are the go-to option for managing neovascular retinal disorders, thanks to their proven efficacy, favorable safety profile, and transformative impact on modern eye care.
2025-03-26 | Combined ocular involvement in juvenile glaucoma and Best disease
PURPOSE. Monitoring of a patient with a rare combined pathology of juvenile open-angle glaucoma (JOAG) and Best disease (Best vitelliform macular dystrophy, BVMD). METHODS. Visometry, autorefractometry, tonometry, gonioscopy, biomicroscopy, ophthalmoscopy, ocular ultrasound, digital fundus photography, optical coherence tomography angiography (OCT-A). RESULTS. A 32-year-old male patient reported a long-standing fog before his right eye, a spot, progressive visual impairment in both eyes (more pronounced in the right eye), eye redness, and poor tolerance to hypotensive eye drops. He was previously diagnosed with Best disease and JOAG in both eyes. Fundus photography and OCT-A revealed retinal changes characteristic of JOAG. The patient exhibited poor tolerance to topical glaucoma medications, experiencing significant conjunctival hyperemia and ocular pain. A well-tolerated antiglaucoma regimen was established, consisting of a fixed combination of bimatoprost 0.3 mg/ml and timolol 5 mg/ml (BIMOKKO-SZ); dorzolamide 20 mg/ml (Dorzolamide-SZ); and brimonidine 2 mg/ml (Brimonidine-SZ) (all manufactured by NAO Severnaya Zvezda, Russia). Vision, intraocular pressure, and OCT-A parameters stabilized.During the follow-up, retinal thickening exceeding 700 µm was observed, with a risk of inner retinal layer rupture and macular hole formation. Emergence of new choroidal vessels and active choroidal neovascularization were oserved. Intravitreal aflibercept injection was administered, resulting in disease stabilization. CONCLUSION. The combination of JOAG and Best disease requires personalized monitoring and treatment selection, including conservative, laser, surgical, and antiangiogenic therapies as needed. Patient follow-up is ongoing.
2024-11-25 | Adult Onset Foveomacular Vitelliform Dystrophy Shows Genetic Overlap With Age-Related Macular Degeneration.
Adult-onset foveomacular vitelliform dystrophy (AFVD) shares phenotypic similarities with age-related macular degeneration (AMD). The genetic factors associated with AFVD are unknown in >80% of cases. This study evaluated the association of known AMD genetic risk variants with AFVD and compared systemic complement activation in these conditions. Clinical, imaging, and genetic data were collected from 50 patients with AFVD (men/women = 25/25, mean age ± SD 73 ± 10 years), 917 patients with AMD (men/women = 377/540, mean age ± SD 77 ± 9 years), and 432 unaffected healthy controls (men/women = 202/230, mean age ± SD 71 ± 8 years). Genotyping focused on 52 single nucleotide polymorphisms (SNPs) linked to AMD. Weighted genetic risk scores (GRS) for 19 complement system associated variants, 7 lipid metabolism associated variants, the remaining 26 variants (other pathways GRS), and for all 52 variants (global score) were derived and correlated with phenotype. Of the 52 SNPs evaluated, CFH (rs570618) and C2/CFB/SKIV2L (rs116503776 and rs114254831) were associated with AFVD compared with healthy controls (odds ratio [OR] = 2.73, 95% confidence interval [CI] = 1.32-5.73, P = 0.01; OR = 0.31, 95% CI = 0.14-0.71, P = 0.0036; and OR = 0.41, 95% CI = 0.22-0.74, P = 0.0025, respectively). MIR6130/RORB (rs10781182) was negatively associated with AFVD compared with the healthy controls (OR = 0.13, CI = 0.06-0.25, P < 0.0001) and AMD (OR = 0.19, CI = 0.10-0.34, P < 0.0001). Regression analysis showed complement GRS was positively associated with AFVD compared with controls (OR = 1.42, 95% CI = 1.04-1.95, P = 0.03), whereas the other pathways' GRS was negatively associated (OR = 0.46, 95% CI = 0.21-0.98, P = 0.04). AMD was positively associated with the complement score, global score, and ARMS2/HTRA1 compared with controls. Non-monogenic AFVD is associated with AMD risk alleles in the complement cascade, but not in other pathways. Further research is needed to explore complement inhibition for AFVD.
2024-07-18 | Best Vitelliform Macular Dystrophy Presenting with Choroidal Neovascular Membrane in an Adolescent: A Case Report and a Review of the Literature
Abstract An 11-year-old boy presented to the retina outpatient clinic with a -5-year history of poor vision in the left eye. The best corrected visual acuity at presentation was 6/5 and 6/36, respectively, in the right and left eyes. Ocular examination revealed normal anterior segments in both eyes. Binocular indirect ophthalmoscopy of the right eye revealed a pink disc with a cup disc ratio (CDR) of 0.3, normal vessels while the macula had a yellowish lesion with a scrambled egg appearance and surrounding dome-shaped subretinal fluid with a flat retina and no treatable peripheral retinal lesions. The left eye had a pink disc with CDR O.3, normal vessels with a hyperpigmented lesion at the macula surrounded by a small cuff of subretinal fluid with a flat retina and no treatable peripheral retinal lesions. Optical coherence tomography scan revealed subretinal fluid in both eyes with an active choroidal neovascular membrane in the left eye. He was advised on the need for left intravitreal anti-vascular endothelial growth factor injections.
2024-07-11 | An Overview of Best Disease
The German ophthalmologist Friedrich Best named Best vitelliform macular dystrophy (BVD), sometimes referred to as Best disease, in 1905 when he discovered a family with a history of early-onset macular degeneration. A Swedish study assessed the frequency of BVMD to be 2 in 10,000, whereas a Danish examination found 1.5 in 100,000 cases. If a parent with the condition has a kid with an unaffected spouse, there is a 50% chance that the child will inherit the condition from the parent. The syndrome is caused by a mutation in the VMD2 or BEST1 gene found at chromosome 11q12-q13. It is yet unclear how bestrophinopathies pathophysiologically operate. An ionic imbalance in the RPE milieu, which BEST1 gene mutations can bring on, can lead to impaired RPE functions. The best sickness is in five phases. There is currently no recognized treatment for the best sickness. One treatment option for CNV is VEFG injections, either used alone or in conjunction with photodynamic therapy (PDT). Anti-vascular endothelial growth factor (Anti- VEGF) treatments can prevent or reduce the creation of new blood vessels. This can postpone the onset of blindness and slow down the rate at which they leak.
oligonucleotides
2026-02-02 | Clinical and genetic characterization of BEST1-associated retinal dystrophies in the Norwegian population.
BEST1 variants are the third leading cause of inherited retinal dystrophies in Norway. The purpose of this study was to describe the BEST1-associated retinal dystrophy (BEST1-RD) population genetically and clinically, and to determine the prevalence of BEST1-RD in Southern and Eastern Norway. This registry-based study used the Oslo University Hospital Inherited Retinal Disease registry for genetic data and extracted clinical data from medical records. Sixty patients were included. The prevalence of BEST1-RD in Southern and Eastern Norway was between 1:64 600 and 1:43 700. Forty-one patients were diagnosed with Best's vitelliform macular dystrophy (BVMD), 15 with autosomal recessive bestrophinopathy (ARB) and 4 with autosomal dominant vitreoretinochoroidopathy (ADVIRC). The two most common genotypes were c.403G>A and c.89A>G. These variants were associated with BVMD and a later age of onset compared with other BVMD-associated genotypes. The prevalence of BEST1-RD in Southern and Eastern Norway was between 1:64 600 and 1:43 700. BVMD patients carrying c.403G>A or c.89A>G had a later age of onset than BVMD patients carrying other variants.
2025-07-30 | Best Vitelliform Macular Dystrophy.
Autosomal recessive bestrophinopathy (ARB) results from a total absence of functional bestrophin-1 protein owing to two BEST1 mutations, one on each of the chromosomes.
2025-07-30 | Best Vitelliform Macular Dystrophy.
Best vitelliform macular dystrophy (VMD or BVMD) is one of the most common macular dystrophies, affecting 1 in 10,000 individuals. The clinical presentation varies, depending on the stage of the disease at which the patient presents, usually one of these five stages.
2025-01-01 | StoneRounds Case: SR2904
StoneRounds Case SR2904 was diagnosed with Best Disease likely caused by mutations in the gene: BEST1.
2020-12-01 | Natural course of the vitelliform stage in best vitelliform macular dystrophy: a five-year follow-up study.
The vitelliform stage is the typical phenotypic manifestation of Best vitelliform macular dystrophy (BVMD). As yet, no study has focused specifically on the clinical changes occurring in the vitelliform stage over the follow-up. The survey takes the form of a prospective observational study with a 5-year follow-up. Twenty-one eyes of 11 patients in the vitelliform stage were examined annually. The primary outcome was the identification of the changes in the vitelliform lesion over a 5-year follow-up. Secondary outcomes included changes in structural optical coherence tomography (OCT) parameters and the correlation with the BCVA variation over the follow-up. Spectral domain OCT at baseline showed one subform characterized by solid vitelliform deposition, in 81% of eyes, and another subform characterized by a combination of solid deposition and subretinal fluid, in 19% of eyes. Overall, 62% of eyes showed an increase in the area of vitelliform deposition. Once the maximal area was reached, a progressive flattening of the vitelliform deposition took place, with subsequent flattening of the vitelliform lesion and formation of subretinal fluid. Hyperreflective foci (HF) increased in number as long as the vitelliform area continued to expand, with no variation in HF when the vitelliform lesion flattened or the subretinal fluid formed. The vitelliform stage reveals more subforms with clinical variations over the follow-up. Our data suggest that the substage before the flattening of the lesion, thus before the so-called subretinal fluid accumulates and when the visual acuity is still high, might offer the best opportunity for an optimal therapeutic approach.
other
2025-11-04 | Augmented Innate Silence (AIS) as a Personalised Translational Strategy in Inherited Retinal Diseases
Inherited retinal diseases (IRDs) represent a major unmet clinical challenge, characterised by extensive genetic heterogeneity, variable penetrance, and unpredictable progression. While recent advances in gene replacement and gene-editing therapies have transformed selected conditions, most current disease-modifying strategies remain focused on correcting known pathogenic mechanisms after clinical manifestation, often within a limited therapeutic window.Augmented Innate Silence (AIS) is introduced as a novel, personalised translational framework that shifts the investigative focus from disease causation to disease suppression. The concept originates from the author’s clinical and electrophysiological work in inherited retinal dystrophies, where repeated observations of unilateral or highly asymmetric disease—despite shared genetic risk—prompted a fundamental question: what endogenous (innate) mechanisms allow one eye to remain clinically silent? A key clinical inspiration for this framework was the first reported case of unilateral Best disease from Sri Lanka, documented in an extended mini-publication and oral presentation(Lindamulage SD, The First Case Report of Unilateral Best Disease from Sri Lanka: Oral Presentation with Extended Mini-Publication, Figshare, https://doi.org/10.6084/m9.figshare.30090424).Rather than treating asymmetric or unilateral phenotypes as anomalies, AIS reframes them as natural experiments of resilience. The framework proposes that genetically predisposed yet unaffected or minimally affected eyes harbour protective modifiers—genetic, molecular, epigenetic, metabolic, or systemic—that actively suppress disease expression. AIS is therefore positioned as a discovery-driven paradigm, complementary to established genetic mechanisms, with the explicit goal of identifying actionable targets for therapeutic augmentation.This work was presented as a poster at the Personalised Medicine Conference, Aarhus, Denmark (2025)—a multidisciplinary forum bringing together clinicians, geneticists, molecular biologists, data scientists, and industry partners focused on precision and translational medicine. Within this context, AIS was discussed as a conceptual bridge between clinical observation and next-generation therapeutic discovery, aligning with emerging interests in disease modifiers, resilience biology, and patient-stratified interventions.The author proposes a structured research pathway for AIS, incorporating comparative multi-omics analyses of silent versus affected tissue, longitudinal phenotyping, and integrative systems biology approaches. By prioritising endogenous protection rather than defect correction alone, AIS offers a complementary route toward preventative, stabilising, and early-intervention strategies for IRDs—particularly for conditions where conventional gene therapy has limited applicability.This Figshare entry serves both as a permanent scholarly record of the AIS concept and as an open invitation to the scientific community. Researchers in retinal genetics, molecular biology, systems medicine, bioinformatics, and translational therapeutics are encouraged to engage with, test, refine, and expand this framework. Collaborative efforts are essential to transform clinically observed resilience into scalable translational strategies capable of preserving vision in inherited retinal diseases.
2025-01-20 | Characterizing iPSC‐derived organoid models from the most prevalent retinal dystrophies
Aims/Purpose: To establish novel retina cell models to investigate the mechanisms that lead to cell death in IRD. Methods: We generated induced pluripotent stems cells (iPSC) from a cohort of patients with some of the most prevalent IRDs: Retinitis Pigmentosa (RP), Stargardt Disease, Best Disease and Achromatopsia. We differentiated them into PR precursors, retinal organoids (RO) or retinal pigment epithelium cells (RPE) and analyzed the functional implications of each gene and pathogenic variant. Results: All cell models generated from 6 iPSC lines allowed for a better understanding of the molecular mechanisms of IRD. Specifically, in the Best Disease model, we determined using RPE cells that a particular dominant mutation in BEST1 is responsible for a defective closure of the bestrophin pentameric channel. The mutation responsible for RP in RHO shows rhodopsin accumulation and mislocalization, along with an increase of autophagy and ER stress. RO models with mutations in the genes PDE6A and PDE6C , causing respectively RP and Achromatopsia, suggest that expression levels of the pathogenic proteins are diminished. Finally, RPE and RO from two distinct Stargardt Disease patient lines show affectations in bisretinoid disposal, phagocytosis reduction and cell death. Interestingly, those results correlate with the severity of the phenotypes. Conclusions: We show that a wide range of mutations responsible for IRD can be studied using iPSC‐derived retinal models. This opens the door to a deeper understanding of retinal diseases and are key for the development of successful gene and cell therapies. References: Inherited retinal dystrophies (IRD) are a group of rare diseases where photoreceptor (PR) cell death leads to partial or total visual impairment. Over 300 genes have been determined to cause these dystrophies, but most of the molecular mechanisms underlying the start and development of the pathology are still waiting to be unraveled.
2015-10-01 | Personalized Medicine: Cell and Gene Therapy Based on Patient-Specific iPSC-Derived Retinal Pigment Epithelium Cells
Interest in generating human induced pluripotent stem (iPS) cells for stem cell modeling of diseases has overtaken that of patient-specific human embryonic stem cells due to the ethical, technical, and political concerns associated with the latter. In ophthalmology, researchers are currently using iPS cells to explore various applications, including: (1) modeling of retinal diseases using patient-specific iPS cells; (2) autologous transplantation of differentiated retinal cells that undergo gene correction at the iPS cell stage via gene editing tools (e.g., CRISPR/Cas9, TALENs and ZFNs); and (3) autologous transplantation of patient-specific iPS-derived retinal cells treated with gene therapy. In this review, we will discuss the uses of patient-specific iPS cells for differentiating into retinal pigment epithelium (RPE) cells, uncovering disease pathophysiology, and developing new treatments such as gene therapy and cell replacement therapy via autologous transplantation.
small molecules
2023-04-08 | Tadalafil Rescues the p.M325T Mutant of Best1 Chloride Channel
Bestrophin 1 (Best1) is a chloride channel that localises to the plasma membrane of retinal pigment epithelium (RPE) cells. Mutations in the BEST1 gene are associated with a group of untreatable inherited retinal dystrophies (IRDs) called bestrophinopathies, caused by protein instability and loss-of-function of the Best1 protein. 4PBA and 2-NOAA have been shown to rescue the function, expression, and localisation of Best1 mutants; however, it is of interest to find more potent analogues as the concentration of the drugs required is too high (2.5 mM) to be given therapeutically. A virtual docking model of the COPII Sec24a site, where 4PBA has been shown to bind, was generated and a library of 1416 FDA-approved compounds was screened at the site. The top binding compounds were tested in vitro in whole-cell patch-clamp experiments of HEK293T cells expressing mutant Best1. The application of 25 μM tadalafil resulted in full rescue of Cl- conductance, comparable to wild type Best1 levels, for p.M325T mutant Best1 but not for p.R141H or p.L234V mutants.
2022-09-26 | SPACR Encoded by IMPG1 Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium.
Several pathogenic variants have been reported in the IMPG1 gene associated with the inherited retinal disorders vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). IMPG1 and its paralog IMPG2 encode for two proteoglycans, SPACR and SPACRCAN, respectively, which are the main components of the interphotoreceptor matrix (IPM), the extracellular matrix surrounding the photoreceptor cells. To determine the role of SPACR in the pathological mechanisms leading to RP and VMD, we generated a knockout mouse model lacking Impg1, the mouse ortholog. Impg1-deficient mice show abnormal accumulation of autofluorescent deposits visible by fundus imaging and spectral-domain optical coherence tomography (SD-OCT) and attenuated electroretinogram responses from 9 months of age. Furthermore, SD-OCT of Impg1-/- mice shows a degeneration of the photoreceptor layer, and transmission electron microscopy shows a disruption of the IPM and the retinal pigment epithelial cells. The decrease in the concentration of the chromophore 11-cis-retinal supports this loss of photoreceptors. In conclusion, our results demonstrate the essential role of SPACR in maintaining photoreceptors. Impg1-/- mice provide a novel model for mechanistic investigations and the development of therapies for VMD and RP caused by IMPG1 pathogenic variants.
2021-12-08 | Long-Term Maintenance of Vision and Resolution of Vitelliform Lesions with Systemic Phosphodiesterase 5/6 Treatment (Sildenafil)
BACKGROUND: Adult vitelliform macular dystrophy results in loss of central vision. The use of systemic sildenafil has been proven to increase choroidal blood flow. This is a report of a favorable long-term treatment outcome using systemic sildenafil for a patient with adult onset vitelliform macular dystrophy. CASE PRESENTATION: A 55-year-old woman presenting with bilateral subretinal vitelliform lesions was initially assessed by full-field electroretinogram, electro-oculogram and direct sequencing of the RDS/PRPH2 and BEST1 genes. Best-corrected visual acuity, spectral domain-optical coherence tomography and color fundus photography were obtained and analyzed over a 5-year treatment course which included bevacizumab (Avastin) injections in the right eye and left eye and subsequent ranibizumab (Lucentis) treatments in the left eye. Lipid resolution in the right eye was seen with bevacizumab after two months of treatment, while the left eye was unresponsive to eight subsequent injections of bevacizumab, followed by ranibizumab over a period of twenty months. Systemic sildenafil was started, off label, at 20 months following course of intravitreal injections. Following initiation of sildenafil, there were both measured and patient-reported improvements in the left eye following after two months of sildenafil. CONCLUSIONS: Systemic phosphodiesterase (PDE)-5 and -6 inhibitors may facilitate the removal of lipid and waste from the subretinal space by increasing perfusion in patients with vitelliform lesions and aid in maintaining and/or recovering photoreceptor function.
2021-08-18 | Disease-causing mutations associated with bestrophinopathies promote apoptosis in retinal pigment epithelium cells.
Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) are two kinds of bestrophinopathies which are caused by BEST1 mutations and characterized by accumulation of lipofuscin-like materials on the retinal pigment epithelium cell-photoreceptor interface. In the past two decades, research about the pathogenesis of bestrophinopathies was mainly focused on the anion channel and intracellular Ca2+ signaling, but seldom concentrated on the function of retinal pigment epithelium (RPE) cells. In this study, we explored the possible effect of the three BEST1 mutations p.V143F, p.S142G, and p.A146T on the apoptosis in human fetal RPE cells. Wild-type plasmid and mutant plasmids BEST1-pcDNA3.1 p.V143F, p.S142G, and p.A146T were transfected to human fetal RPE cells. The molecules caspase-3, phospho-Bcl-2, BAX, PARP, and AIF associated with apoptosis were determined by quantitative PCR and Western blot. Apoptotic rate and active Caspase-3 staining were analyzed by flow cytometry. Caspase-3 and PARP expression were significantly increased in BEST1-pcDNA3.1 p.S142G and p.A146T group. Flow cytometry showed that the apoptosis rates were significantly increased in the BEST1-pcDNA3.1 p.V143F, p.S142G, and p.A146T group compared with the wild-type group. For the first time, we found that the three mutations promoted RPE cell apoptosis. Furthermore, the results indicated that BEST1 mutations p.S142G and p.A146T may contribute apoptosis of RPE cells by targeting Caspase 3. Our observations suggested that the apoptosis of RPE cells may be one of the mechanisms in bestrophinopathies, which may provide a new potential therapeutic target for the treatment of this disease.
2021-06-21 | Optical coherence tomography angiography cyclic remodeling of CNV in patients affected by Best macular dystrophy.
To evaluate the effect of photodynamic therapy and/or intravitreal injections on choroidal neovascularization in treatment-naïve patients affected by Best Macular Dystrophy using OCT-A. BMD patients with CNV treated using PDT and/or IV were included in the study. All patients underwent a complete ophthalmological examination, OCT and 3 × 3 mm OCT-A. The OCT-A images were analyzed using an open-source software (ImageJ) to assess the CNV membrane area (CNV-MA), the CNV vessel area (CNV-VA), and vessel density (VD) at the follow-ups (3 months after PDT and 1 month after IV). Five eyes of four patients with CNV were included. All eyes received PDT as first-line therapy; 4 eyes underwent more than 1 treatment session: three eyes received 1 IV, whereas one eye had one further PDT. After PDT, the CNV-MA, CNV-VA, and VD quantitative parameters were obtained for four out of five eyes: in three eyes of two patients CNV-MA, CNV-VA, and VD first decreased and then gradually increased during follow-up, whereas in one eye of one patient CNV-MA, CNV-VA, and VD slightly increased. After IV the CNV-MA, CNV-VA, and VD had significantly decreased at the 1-month follow-up in three eyes of three patients. OCT-A is an important tool for the diagnosis of both naïve and fibrotic CNV in BMD patients; it is a non-invasive method for the qualitative and quantitative analysis of neovascular lesions during follow-up. Our results have shown a cyclic remodeling of treated CNV in BMD patients using both PDT and IV.
gene therapies
2026-07-15 | Allele-specific correction of dominant Best vitelliform macular dystrophy in patient-derived retinal pigment epithelium
ABSTRACT Autosomal dominant Best vitelliform macular dystrophy (BVMD) caused by variants in the BEST1 gene is characterized by dysfunction of the macular retinal pigment epithelium (RPE) and secondary degeneration of the photoreceptors. There are currently no approved treatments for BVMD, and owing to its dominant nature, there remains uncertainty regarding the utility of traditional gene augmentation. Here we evaluated whether a dominant pathogenic BEST1 allele can be corrected by base editing in differentiated RPE cells. We identified a patient with a likely pathogenic BEST1 c.851A>G (p. Tyr284Cys) variant that was amenable to cytidine base editing. After establishing patient-derived induced pluripotent stem cells (iPSCs), we corrected the pathogenic variant in the iPSCs to obtain corrected iPSCs with the same genetic background. Corrected iPSC-derived RPE exhibited normalized monolayer appearance, improved barrier integrity, reduced cell death, and restored RPE-specific transcriptome. We then used a dual adeno-associated virus (AAV) split-intein system to deliver a CRISPR-associated protein 9 cytidine base editor (SpCas9-CBE) to BEST1 c.851A>G mutant RPE monolayers and achieved editing of the pathogenic allele with a maximum efficiency of 13.42 ± 3.64% (mean ± SD). Together, these results demonstrate progress towards allele-specific base editing in a dominantly inherited retinal disorder.
2026-07-07 | Evaluation of the Toxicity and Efficacy of an Adeno-Associated Viral Vector Expressing BEST1 Delivered by Subretinal Injection in a Canine Model of Human Bestrophinopathy.
To treat patients affected with bestrophinopathies caused by mutations in the BEST1 gene, a recombinant adeno-associated virus vector (OPGx-BEST1 or rAAV2/2-VMD2-BEST1) is being developed. The vector construct includes the human BEST1 cDNA under control of the VMD2/BEST1 promoter and is packaged in an AAV2 capsid. This study evaluated the efficacy and toxicity of OPGx-BEST1 administered by subretinal injection in dogs that were homozygous mutant or compound heterozygotes for 3 naturally occurring mutations in BEST1. Twelve BEST1-mutant dogs were divided into 4 groups of 3 animals each, and they received in their left eye a subretinal injection of 0.15 mL of OPGx-BEST1 at 1 of 3 concentrations (9.5 × 109 vector genome [vg]/mL; 3.0 × 1010 vg/mL; or 3.0 × 1011 vg/mL) of OPGx-BEST1, resulting, respectively, in a low (1.4 × 109 vg), high (4.5 × 109 vg), and highest (4.5 × 1010 vg) dose or vehicle control. The right eyes were not injected. Subretinal injections were well tolerated and were not associated with any systemic or ocular toxicity. Electroretinography showed improved rod- and cone-mediated responses in eyes treated with OPGx-BEST1. Noninvasive retinal imaging by optical coherence tomography showed improved structural integrity with a reduction or prevention of appearance of vitelliform lesions and reversal of microdetachments in the retinal areas treated with OPGx-BEST1. These results support the use of OPGx-BEST1 in clinical studies with patients affected with bestrophinopathies and define the no-observed-adverse-effect level at 4.5 × 1010 vg/eye (0.15 mL, 3.0 × 1011 vg/mL).
2026-06-01 | From BEST1 mutations to retinal regeneration: integrating stem cell-derived RPE models and gene correction strategies.
Retinal degenerative diseases are among the leading causes of irreversible vision loss worldwide and arise primarily from progressive dysfunction and death of photoreceptors and retinal pigment epithelial (RPE) cells. Because the mammalian retina lacks an intrinsic capacity for regeneration, current treatments remain limited and largely palliative. Recent advances in stem cell technologies and gene-based therapies, however, have opened new avenues for retinal repair and functional restoration. Among monogenic retinal disorders, BEST1-associated retinopathies provide a particularly informative paradigm for linking molecular mechanisms to emerging regenerative strategies.The human BEST1 encodes bestrophin-1 (BEST1), a calcium-activated chloride channel predominantly expressed in the RPE, where it plays essential roles in ionic homeostasis, transepithelial transport, and regulation of the visual cycle. Pathogenic variants in BEST1 give rise to a spectrum of inherited retinal diseases, including Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, and adult-onset vitelliform dystrophy. Mechanistic studies of BEST1 mutations have revealed diverse functional consequences, ranging from loss-of-function to gain-of-function effects, highlighting the importance of precise molecular diagnosis for therapeutic intervention.Here, we synthesize recent progress in stem cell-derived RPE models and gene correction strategies, using BEST1-associated retinopathies as a conceptual framework. We discuss how human induced pluripotent stem cell-derived RPE systems enable disease modeling and functional analysis of pathogenic variants, and how gene replacement and genome editing approaches are tailored to distinct mutation classes. Finally, we explore how integration of stem cell and gene therapy strategies may advance retinal regeneration and outline future directions for personalized and mechanism-based treatments of retinal degenerative diseases.
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.
2026-01-29 | Gene Augmentation Therapy for Bestrophinopathies: Targeting BEST1 in the Clinic
The bestrophin-1 (BEST1) gene encodes a calcium-dependent chloride channel, a transmembrane protein critical for the function of the retinal pigment epithelium (RPE) in the eye. Pathogenic variants in BEST1 are the underlying cause for bestrophinopathies, a group of inherited retinal diseases (IRDs) that vary in their pattern of inheritance, clinical appearance, and underlying molecular disease mechanisms. This article focuses on gene therapy strategies to treat Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB), two conditions for which there are currently no available treatments. Gene therapy represents an attractive strategy to treat BVMD and ARB, in particular gene augmentation, which has a successful track record for treating IRDs. This review examines the clinical diversity of bestrophinopathies and identifies the specific molecular disease mechanism of the pathogenic BEST1 genetic variants as an important parameter for designing future gene therapy strategies. Finally, we highlight the ongoing BIRD-1 (BEST1 Inherited Retinal Diseases) clinical trial as a significant step in translating the gene augmentation strategy into a clinical reality for treating BVMD and ARB.
antibodies
2025-10-20 | Anti-vascular endothelial growth factor therapies in ophthalmology.
Retinal diseases, including neovascular age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion, are leading causes of vision loss worldwide. The introduction of anti-vascular endothelial growth factor (anti-VEGF) therapies has dramatically changed the management of these conditions, offering targeted treatment that can preserve and even improve vision. We aimed to provide a comprehensive review of the development, clinical applications, and emerging indications of anti-VEGF therapies in ophthalmology, including biosimilar agents. A comprehensive literature search was conducted in PubMed/MEDLINE for English-language articles published up to 31 July 2025. Additional sources were identified through manual screening of reference lists. Included studies spanned various designs: clinical trials, meta-analyses, observational studies, and preclinical research. Keywords used in the search strategy included terms such as "anti-VEGF therapy", "biosimilar pharmaceuticals", "intravitreal and intrastromal anti-VEGF injections", "retinal diseases" including "macular degeneration" and "retinal neovascularization", "ranibizumab", and "bevacizumab", as well as relevant MeSH terms where applicable. Anti-VEGF agents have transformed the management of retinal diseases such as neovascular age-related macular degeneration, diabetic macular edema, proliferative diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. Newer agents such as brolucizumab and faricimab offer prolonged durability and enhanced anatomic outcomes, while biosimilars provide cost-effective alternatives. Anti-VEGF therapy has also shown promise in off-label or emerging indications such as neovascular glaucoma, corneal neovascularization, and other retinal or choroidal disorders including secondary macular edema and/or macular neovascularization associated with various forms of uveitis, diffuse choroidal hemangioma in Sturge-Weber Syndrome, hereditary retinal disorders such as fundus flavimaculatus, Coats-Like retinitis pigmentosa, Peripherin-2-associated retinopathy, immune checkpoint inhibitor use, radiation retinopathy, retinitis pigmentosa, Bietti crystalline dystrophy, autosomal recessive bestrophinopathy, melanocytoma-associated macular neovascular membrane, Best disease, Wyburn-Mason syndrome, choroidal osteoma, peripheral exudative hemorrhagic chorioretinopathy, traumatic choroidal rupture, torpedo maculopathy, optic disc melanocytoma, type 2 proliferative macular telangiectasia, and Coats disease. High-dose formulations and innovative delivery systems are under active investigation to reduce the treatment burden and extend dosing intervals. Anti-VEGF therapies have revolutionized the field of ophthalmology, providing sight-saving treatment for a range of retinal diseases that were once considered untreatable or inevitably blinding. Today, anti-VEGF drugs are the go-to option for managing neovascular retinal disorders, thanks to their proven efficacy, favorable safety profile, and transformative impact on modern eye care.
2025-03-26 | Combined ocular involvement in juvenile glaucoma and Best disease
PURPOSE. Monitoring of a patient with a rare combined pathology of juvenile open-angle glaucoma (JOAG) and Best disease (Best vitelliform macular dystrophy, BVMD). METHODS. Visometry, autorefractometry, tonometry, gonioscopy, biomicroscopy, ophthalmoscopy, ocular ultrasound, digital fundus photography, optical coherence tomography angiography (OCT-A). RESULTS. A 32-year-old male patient reported a long-standing fog before his right eye, a spot, progressive visual impairment in both eyes (more pronounced in the right eye), eye redness, and poor tolerance to hypotensive eye drops. He was previously diagnosed with Best disease and JOAG in both eyes. Fundus photography and OCT-A revealed retinal changes characteristic of JOAG. The patient exhibited poor tolerance to topical glaucoma medications, experiencing significant conjunctival hyperemia and ocular pain. A well-tolerated antiglaucoma regimen was established, consisting of a fixed combination of bimatoprost 0.3 mg/ml and timolol 5 mg/ml (BIMOKKO-SZ); dorzolamide 20 mg/ml (Dorzolamide-SZ); and brimonidine 2 mg/ml (Brimonidine-SZ) (all manufactured by NAO Severnaya Zvezda, Russia). Vision, intraocular pressure, and OCT-A parameters stabilized.During the follow-up, retinal thickening exceeding 700 µm was observed, with a risk of inner retinal layer rupture and macular hole formation. Emergence of new choroidal vessels and active choroidal neovascularization were oserved. Intravitreal aflibercept injection was administered, resulting in disease stabilization. CONCLUSION. The combination of JOAG and Best disease requires personalized monitoring and treatment selection, including conservative, laser, surgical, and antiangiogenic therapies as needed. Patient follow-up is ongoing.
2024-11-25 | Adult Onset Foveomacular Vitelliform Dystrophy Shows Genetic Overlap With Age-Related Macular Degeneration.
Adult-onset foveomacular vitelliform dystrophy (AFVD) shares phenotypic similarities with age-related macular degeneration (AMD). The genetic factors associated with AFVD are unknown in >80% of cases. This study evaluated the association of known AMD genetic risk variants with AFVD and compared systemic complement activation in these conditions. Clinical, imaging, and genetic data were collected from 50 patients with AFVD (men/women = 25/25, mean age ± SD 73 ± 10 years), 917 patients with AMD (men/women = 377/540, mean age ± SD 77 ± 9 years), and 432 unaffected healthy controls (men/women = 202/230, mean age ± SD 71 ± 8 years). Genotyping focused on 52 single nucleotide polymorphisms (SNPs) linked to AMD. Weighted genetic risk scores (GRS) for 19 complement system associated variants, 7 lipid metabolism associated variants, the remaining 26 variants (other pathways GRS), and for all 52 variants (global score) were derived and correlated with phenotype. Of the 52 SNPs evaluated, CFH (rs570618) and C2/CFB/SKIV2L (rs116503776 and rs114254831) were associated with AFVD compared with healthy controls (odds ratio [OR] = 2.73, 95% confidence interval [CI] = 1.32-5.73, P = 0.01; OR = 0.31, 95% CI = 0.14-0.71, P = 0.0036; and OR = 0.41, 95% CI = 0.22-0.74, P = 0.0025, respectively). MIR6130/RORB (rs10781182) was negatively associated with AFVD compared with the healthy controls (OR = 0.13, CI = 0.06-0.25, P < 0.0001) and AMD (OR = 0.19, CI = 0.10-0.34, P < 0.0001). Regression analysis showed complement GRS was positively associated with AFVD compared with controls (OR = 1.42, 95% CI = 1.04-1.95, P = 0.03), whereas the other pathways' GRS was negatively associated (OR = 0.46, 95% CI = 0.21-0.98, P = 0.04). AMD was positively associated with the complement score, global score, and ARMS2/HTRA1 compared with controls. Non-monogenic AFVD is associated with AMD risk alleles in the complement cascade, but not in other pathways. Further research is needed to explore complement inhibition for AFVD.
2024-07-18 | Best Vitelliform Macular Dystrophy Presenting with Choroidal Neovascular Membrane in an Adolescent: A Case Report and a Review of the Literature
Abstract An 11-year-old boy presented to the retina outpatient clinic with a -5-year history of poor vision in the left eye. The best corrected visual acuity at presentation was 6/5 and 6/36, respectively, in the right and left eyes. Ocular examination revealed normal anterior segments in both eyes. Binocular indirect ophthalmoscopy of the right eye revealed a pink disc with a cup disc ratio (CDR) of 0.3, normal vessels while the macula had a yellowish lesion with a scrambled egg appearance and surrounding dome-shaped subretinal fluid with a flat retina and no treatable peripheral retinal lesions. The left eye had a pink disc with CDR O.3, normal vessels with a hyperpigmented lesion at the macula surrounded by a small cuff of subretinal fluid with a flat retina and no treatable peripheral retinal lesions. Optical coherence tomography scan revealed subretinal fluid in both eyes with an active choroidal neovascular membrane in the left eye. He was advised on the need for left intravitreal anti-vascular endothelial growth factor injections.
2024-07-11 | An Overview of Best Disease
The German ophthalmologist Friedrich Best named Best vitelliform macular dystrophy (BVD), sometimes referred to as Best disease, in 1905 when he discovered a family with a history of early-onset macular degeneration. A Swedish study assessed the frequency of BVMD to be 2 in 10,000, whereas a Danish examination found 1.5 in 100,000 cases. If a parent with the condition has a kid with an unaffected spouse, there is a 50% chance that the child will inherit the condition from the parent. The syndrome is caused by a mutation in the VMD2 or BEST1 gene found at chromosome 11q12-q13. It is yet unclear how bestrophinopathies pathophysiologically operate. An ionic imbalance in the RPE milieu, which BEST1 gene mutations can bring on, can lead to impaired RPE functions. The best sickness is in five phases. There is currently no recognized treatment for the best sickness. One treatment option for CNV is VEFG injections, either used alone or in conjunction with photodynamic therapy (PDT). Anti-vascular endothelial growth factor (Anti- VEGF) treatments can prevent or reduce the creation of new blood vessels. This can postpone the onset of blindness and slow down the rate at which they leak.
oligonucleotides
2026-02-02 | Clinical and genetic characterization of BEST1-associated retinal dystrophies in the Norwegian population.
BEST1 variants are the third leading cause of inherited retinal dystrophies in Norway. The purpose of this study was to describe the BEST1-associated retinal dystrophy (BEST1-RD) population genetically and clinically, and to determine the prevalence of BEST1-RD in Southern and Eastern Norway. This registry-based study used the Oslo University Hospital Inherited Retinal Disease registry for genetic data and extracted clinical data from medical records. Sixty patients were included. The prevalence of BEST1-RD in Southern and Eastern Norway was between 1:64 600 and 1:43 700. Forty-one patients were diagnosed with Best's vitelliform macular dystrophy (BVMD), 15 with autosomal recessive bestrophinopathy (ARB) and 4 with autosomal dominant vitreoretinochoroidopathy (ADVIRC). The two most common genotypes were c.403G>A and c.89A>G. These variants were associated with BVMD and a later age of onset compared with other BVMD-associated genotypes. The prevalence of BEST1-RD in Southern and Eastern Norway was between 1:64 600 and 1:43 700. BVMD patients carrying c.403G>A or c.89A>G had a later age of onset than BVMD patients carrying other variants.
2025-07-30 | Best Vitelliform Macular Dystrophy.
Autosomal recessive bestrophinopathy (ARB) results from a total absence of functional bestrophin-1 protein owing to two BEST1 mutations, one on each of the chromosomes.
2025-07-30 | Best Vitelliform Macular Dystrophy.
Best vitelliform macular dystrophy (VMD or BVMD) is one of the most common macular dystrophies, affecting 1 in 10,000 individuals. The clinical presentation varies, depending on the stage of the disease at which the patient presents, usually one of these five stages.
2025-01-01 | StoneRounds Case: SR2904
StoneRounds Case SR2904 was diagnosed with Best Disease likely caused by mutations in the gene: BEST1.
2020-12-01 | Natural course of the vitelliform stage in best vitelliform macular dystrophy: a five-year follow-up study.
The vitelliform stage is the typical phenotypic manifestation of Best vitelliform macular dystrophy (BVMD). As yet, no study has focused specifically on the clinical changes occurring in the vitelliform stage over the follow-up. The survey takes the form of a prospective observational study with a 5-year follow-up. Twenty-one eyes of 11 patients in the vitelliform stage were examined annually. The primary outcome was the identification of the changes in the vitelliform lesion over a 5-year follow-up. Secondary outcomes included changes in structural optical coherence tomography (OCT) parameters and the correlation with the BCVA variation over the follow-up. Spectral domain OCT at baseline showed one subform characterized by solid vitelliform deposition, in 81% of eyes, and another subform characterized by a combination of solid deposition and subretinal fluid, in 19% of eyes. Overall, 62% of eyes showed an increase in the area of vitelliform deposition. Once the maximal area was reached, a progressive flattening of the vitelliform deposition took place, with subsequent flattening of the vitelliform lesion and formation of subretinal fluid. Hyperreflective foci (HF) increased in number as long as the vitelliform area continued to expand, with no variation in HF when the vitelliform lesion flattened or the subretinal fluid formed. The vitelliform stage reveals more subforms with clinical variations over the follow-up. Our data suggest that the substage before the flattening of the lesion, thus before the so-called subretinal fluid accumulates and when the visual acuity is still high, might offer the best opportunity for an optimal therapeutic approach.
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2025-11-04 | Augmented Innate Silence (AIS) as a Personalised Translational Strategy in Inherited Retinal Diseases
Inherited retinal diseases (IRDs) represent a major unmet clinical challenge, characterised by extensive genetic heterogeneity, variable penetrance, and unpredictable progression. While recent advances in gene replacement and gene-editing therapies have transformed selected conditions, most current disease-modifying strategies remain focused on correcting known pathogenic mechanisms after clinical manifestation, often within a limited therapeutic window.Augmented Innate Silence (AIS) is introduced as a novel, personalised translational framework that shifts the investigative focus from disease causation to disease suppression. The concept originates from the author’s clinical and electrophysiological work in inherited retinal dystrophies, where repeated observations of unilateral or highly asymmetric disease—despite shared genetic risk—prompted a fundamental question: what endogenous (innate) mechanisms allow one eye to remain clinically silent? A key clinical inspiration for this framework was the first reported case of unilateral Best disease from Sri Lanka, documented in an extended mini-publication and oral presentation(Lindamulage SD, The First Case Report of Unilateral Best Disease from Sri Lanka: Oral Presentation with Extended Mini-Publication, Figshare, https://doi.org/10.6084/m9.figshare.30090424).Rather than treating asymmetric or unilateral phenotypes as anomalies, AIS reframes them as natural experiments of resilience. The framework proposes that genetically predisposed yet unaffected or minimally affected eyes harbour protective modifiers—genetic, molecular, epigenetic, metabolic, or systemic—that actively suppress disease expression. AIS is therefore positioned as a discovery-driven paradigm, complementary to established genetic mechanisms, with the explicit goal of identifying actionable targets for therapeutic augmentation.This work was presented as a poster at the Personalised Medicine Conference, Aarhus, Denmark (2025)—a multidisciplinary forum bringing together clinicians, geneticists, molecular biologists, data scientists, and industry partners focused on precision and translational medicine. Within this context, AIS was discussed as a conceptual bridge between clinical observation and next-generation therapeutic discovery, aligning with emerging interests in disease modifiers, resilience biology, and patient-stratified interventions.The author proposes a structured research pathway for AIS, incorporating comparative multi-omics analyses of silent versus affected tissue, longitudinal phenotyping, and integrative systems biology approaches. By prioritising endogenous protection rather than defect correction alone, AIS offers a complementary route toward preventative, stabilising, and early-intervention strategies for IRDs—particularly for conditions where conventional gene therapy has limited applicability.This Figshare entry serves both as a permanent scholarly record of the AIS concept and as an open invitation to the scientific community. Researchers in retinal genetics, molecular biology, systems medicine, bioinformatics, and translational therapeutics are encouraged to engage with, test, refine, and expand this framework. Collaborative efforts are essential to transform clinically observed resilience into scalable translational strategies capable of preserving vision in inherited retinal diseases.
2025-01-20 | Characterizing iPSC‐derived organoid models from the most prevalent retinal dystrophies
Aims/Purpose: To establish novel retina cell models to investigate the mechanisms that lead to cell death in IRD. Methods: We generated induced pluripotent stems cells (iPSC) from a cohort of patients with some of the most prevalent IRDs: Retinitis Pigmentosa (RP), Stargardt Disease, Best Disease and Achromatopsia. We differentiated them into PR precursors, retinal organoids (RO) or retinal pigment epithelium cells (RPE) and analyzed the functional implications of each gene and pathogenic variant. Results: All cell models generated from 6 iPSC lines allowed for a better understanding of the molecular mechanisms of IRD. Specifically, in the Best Disease model, we determined using RPE cells that a particular dominant mutation in BEST1 is responsible for a defective closure of the bestrophin pentameric channel. The mutation responsible for RP in RHO shows rhodopsin accumulation and mislocalization, along with an increase of autophagy and ER stress. RO models with mutations in the genes PDE6A and PDE6C , causing respectively RP and Achromatopsia, suggest that expression levels of the pathogenic proteins are diminished. Finally, RPE and RO from two distinct Stargardt Disease patient lines show affectations in bisretinoid disposal, phagocytosis reduction and cell death. Interestingly, those results correlate with the severity of the phenotypes. Conclusions: We show that a wide range of mutations responsible for IRD can be studied using iPSC‐derived retinal models. This opens the door to a deeper understanding of retinal diseases and are key for the development of successful gene and cell therapies. References: Inherited retinal dystrophies (IRD) are a group of rare diseases where photoreceptor (PR) cell death leads to partial or total visual impairment. Over 300 genes have been determined to cause these dystrophies, but most of the molecular mechanisms underlying the start and development of the pathology are still waiting to be unraveled.
2015-10-01 | Personalized Medicine: Cell and Gene Therapy Based on Patient-Specific iPSC-Derived Retinal Pigment Epithelium Cells
Interest in generating human induced pluripotent stem (iPS) cells for stem cell modeling of diseases has overtaken that of patient-specific human embryonic stem cells due to the ethical, technical, and political concerns associated with the latter. In ophthalmology, researchers are currently using iPS cells to explore various applications, including: (1) modeling of retinal diseases using patient-specific iPS cells; (2) autologous transplantation of differentiated retinal cells that undergo gene correction at the iPS cell stage via gene editing tools (e.g., CRISPR/Cas9, TALENs and ZFNs); and (3) autologous transplantation of patient-specific iPS-derived retinal cells treated with gene therapy. In this review, we will discuss the uses of patient-specific iPS cells for differentiating into retinal pigment epithelium (RPE) cells, uncovering disease pathophysiology, and developing new treatments such as gene therapy and cell replacement therapy via autologous transplantation.
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