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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
0
drugs
With orphan designations
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
113 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:
113 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:
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.
2026-07-07 | 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.
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