BEST1-Related Dominant Retinopathy

1. Disease Information

Overview

BEST1-related dominant retinopathy encompasses a group of inherited retinal dystrophies caused by heterozygous pathogenic variants in the BEST1 gene (formerly VMD2), which encodes bestrophin-1, a calcium-activated chloride channel expressed exclusively in the retinal pigment epithelium (RPE) (amato2023genetherapyin pages 2-3, navinesferrer2022impairedbestrophinchannel pages 1-2). The most common dominant phenotype is Best vitelliform macular dystrophy (BVMD, or Best disease), first described by Dr. Friedrich Best in 1905 (haldrup2025genetherapystrategies pages 3-5). BVMD is characterized by the bilateral accumulation of yellow, lipofuscin-rich vitelliform material beneath the neurosensory retina in the macular region, leading to progressive central visual impairment (beryozkin2024bestdiseaseglobal pages 1-2, bianco2024multimodalimagingin pages 1-2).

Other BEST1-associated dominant retinopathies include adult-onset foveomacular vitelliform dystrophy (AOFVD/AVMD) and autosomal dominant vitreoretinochoroidopathy (ADVIRC) (yang2023best1novelmutation pages 1-2, amato2023genetherapyin pages 1-2). While biallelic BEST1 variants cause autosomal recessive bestrophinopathy (ARB), this report focuses on the dominantly inherited forms.

Disease Identifiers and Synonyms

The following table summarizes the key identifiers, synonyms, and related phenotypes for BEST1-related dominant retinopathy:

Table: This table compiles the main disease and gene identifiers used for BEST1-related dominant retinopathy, centered on Best vitelliform macular dystrophy. It also summarizes key synonyms, related BEST1 phenotypes, and inheritance details useful for database curation.

Common Synonyms: Best disease, Best vitelliform macular dystrophy (BVMD), VMD2-associated macular dystrophy, bestrophinopathy, BEST1-related bestrophinopathy.

Information Sources: This report synthesizes data from aggregated disease-level resources including OMIM, Orphanet, OpenTargets (OpenTargets Search: -BEST1), ClinicalTrials.gov (NCT05809635 chunk 1, NCT07185256 chunk 1), and primary peer-reviewed literature.

2. Etiology

Disease Causal Factors

BEST1-related dominant retinopathy is a Mendelian genetic disorder caused by heterozygous pathogenic variants in the BEST1 gene located on chromosome 11q12-q13.1 (nowomiejska2022diseaseexpressioncaused pages 1-2, NCT07185256 chunk 1). The disease is exclusively genetic in origin, with no known environmental or infectious causes.

Genetic Risk Factors

• Causal Gene: BEST1 (HGNC symbol; Ensembl: ENSG00000167995; OMIM gene: 607854) (OpenTargets Search: -BEST1, yang2023best1novelmutation pages 1-2).
• Variant Spectrum: Over 250–300 individual pathogenic mutations have been identified in BEST1, with the majority being missense variants in functional domains of the protein (grewal2021bestrophinopathiesperspectiveson pages 1-2, nowomiejska2022diseaseexpressioncaused pages 1-2). In an 18-year single-center DNA diagnostics study of over 7,000 inherited retinal dystrophy patients, BEST1 accounted for 7.8% of all disease-causing variants, making it the second most frequently implicated gene after ABCA4 (nowomiejska2022diseaseexpressioncaused pages 1-2).
• Critical Conserved Domains: Disease-causing dominant missense mutations cluster in transmembrane domains and the intracellular Ca²⁺-binding domain of the BEST1 protein (beryozkin2024bestdiseaseglobal pages 1-2). Dominant variants specifically cluster around the Ca²⁺-clasp and gating apparatus regions of the ion pore (haldrup2025genetherapystrategies pages 1-3).
• Inheritance Pattern: Autosomal dominant with variable expressivity and incomplete penetrance (grewal2021bestrophinopathiesperspectiveson pages 1-2, beryozkin2024bestdiseaseglobal pages 1-2, haldrup2025genetherapystrategies pages 3-5).

Protective and Environmental Factors

No specific genetic protective factors, modifier genes, or environmental factors that influence disease risk or expression have been conclusively identified for BEST1-related dominant retinopathy in the current literature. The phenotypic variability observed is attributed primarily to the specific pathogenic variant and stochastic biological factors rather than known gene-environment interactions (grewal2021bestrophinopathiesperspectiveson pages 1-2, nowomiejska2022diseaseexpressioncaused pages 1-2).

3. Phenotypes

Clinical Features and Staging

BVMD progresses through five classic clinical stages, originally described by Gass and subsequently refined with modern imaging:

Table: This table summarizes the five classic clinical stages of Best vitelliform macular dystrophy, integrating fundus, OCT, FAF, and functional features. It is useful for disease characterization, differential diagnosis, and structuring natural history or trial-readiness annotations.

Key Phenotypic Features

• Vitelliform macular lesion: Bilateral, yellow, "egg-yolk" appearance at the macula; the hallmark of BVMD (navinesferrer2022impairedbestrophinchannel pages 1-2, bianco2024multimodalimagingin pages 1-2). HPO: HP:0007754 (Macular dystrophy).
• Reduced visual acuity: Progressive central vision loss, particularly in advanced stages (haldrup2025genetherapystrategies pages 3-5). HPO: HP:0000572 (Visual loss).
• Metamorphopsia: Distortion of central vision reported in some patients (haldrup2025genetherapystrategies pages 3-5, shi2023comprehensivegeneticanalysis pages 5-8). HPO: HP:0012508 (Metamorphopsia).
• Photophobia: Reported in vitelliform stage (haldrup2025genetherapystrategies pages 3-5). HPO: HP:0000613 (Photophobia).
• Nyctalopia (night blindness): Reported variably (haldrup2025genetherapystrategies pages 3-5, shi2023comprehensivegeneticanalysis pages 5-8). HPO: HP:0000662 (Nyctalopia).
• Abnormal EOG: Markedly reduced Arden ratio (≤1.5); pathognomonic (bianco2024multimodalimagingin pages 1-2, haldrup2025genetherapystrategies pages 3-5). HPO: HP:0000495 (Abnormality of the electrooculogram).
• Lipofuscin accumulation: Subretinal deposition of lipofuscin and unphagocytosed photoreceptor outer segments (bianco2024multimodalimagingin pages 1-2). HPO: HP:0007807 (Vitelliform (egg-yolk) macular lesion).
• Choroidal neovascularization (CNV): May complicate late-stage disease (bianco2024multimodalimagingin pages 1-2, padhy2026reviewofthe pages 2-4). HPO: HP:0011506 (Choroidal neovascularization).
• Hyperopia and astigmatism: Associated refractive errors have been reported (haldrup2025genetherapystrategies pages 3-5).

Phenotype Characteristics

• Age of onset: Typically childhood to early adulthood (ages 3–15 years for BVMD); AVMD presents after age 40 (yang2023best1novelmutation pages 1-2, navinesferrer2022impairedbestrophinchannel pages 1-2).
• Severity: Highly variable, even among family members carrying the same mutation (grewal2021bestrophinopathiesperspectiveson pages 1-2, yang2023best1novelmutation pages 4-5).
• Progression: Slow and unpredictable; not all patients progress through all stages sequentially (amato2023genetherapyin pages 2-3, bianco2024multimodalimagingin pages 1-2).
• Quality of life: Central vision loss affects reading, driving, and fine visual tasks; 75% of patients under age 40 maintain visual acuity of 6/12 (20/40) or better in at least one eye (haldrup2025genetherapystrategies pages 3-5).

4. Genetic/Molecular Information

Causal Gene

BEST1 (bestrophin 1): Located on chromosome 11q12-q13.1, comprising 11 exons (of which 10 encode the protein), the gene encodes bestrophin-1, a 585-amino acid, 68 kDa protein that forms a homopentameric calcium-activated chloride channel (CaCC) (amato2023genetherapyin pages 2-3, navinesferrer2022impairedbestrophinchannel pages 1-2, amato2023genetherapyin pages 1-2).

Pathogenic Variants

• Variant types: Predominantly missense variants for dominant forms; nonsense, frameshift, splice-site, and structural variants are more common in recessive disease (haldrup2025genetherapystrategies pages 1-3, nowomiejska2022diseaseexpressioncaused pages 1-2).
• Variant classification: Pathogenic and likely pathogenic per ACMG/AMP guidelines; the BIRD-1 clinical trial (NCT07185256) requires ACMG/AMP-classified pathogenic or likely pathogenic variants for enrollment (NCT07185256 chunk 1).
• Functional consequences: Three major categories have been identified (amato2023genetherapyin pages 1-2, haldrup2025genetherapystrategies pages 5-7):
• Loss of function (LOF): Destabilized protein, non-functional channels, or reduced function; can occur throughout the gene.
• Dominant negative (DN): Mutant subunits incorporate into pentameric channels and impair overall channel function; since BEST1 forms pentamers containing both wild-type and mutant subunits, even a 4:1 WT:mutant ratio can cause substantial dysfunction (navinesferrer2022impairedbestrophinchannel pages 10-11). This is the most common mechanism in dominant BVMD.
• Gain of function (GOF): Increased or aberrant channel activity; a smaller subset of variants, exemplified by p.Pro77Ser which increases anion permeability (navinesferrer2022impairedbestrophinchannel pages 10-11).
• Allelic expression imbalance: At the BEST1 locus, mutant alleles may be transcribed at higher levels than wildtype alleles in human RPE cells, promoting dominant negative effects (haldrup2025genetherapystrategies pages 5-7).
• Somatic vs. germline: All described BEST1 pathogenic variants are germline in origin.

Specific Variant Examples

Multiple specific pathogenic variants have been characterized functionally: R218C shows correct basolateral localization but impaired function; W93C and V9M show intracellular mislocalization; Y85H, Q96R, L100R, Y227N, T6P, L21V, W24C, L224M, T237R, F305S, and V311G show trafficking errors on the cytoplasmic face; S79C, F80L, L82V, and A243T affect membrane domain function (padhy2026reviewofthe pages 2-4).

Modifier Genes and Epigenetics

No confirmed modifier genes or disease-associated epigenetic changes have been identified specifically for BEST1-related dominant retinopathy in the current literature.

5. Environmental Information

No environmental factors, lifestyle factors, or infectious agents have been identified as contributing to BEST1-related dominant retinopathy. This is a purely genetic, Mendelian disorder.

6. Mechanism / Pathophysiology

Molecular Pathways

Bestrophin-1 functions as a calcium-dependent chloride channel (CaCC) that controls chloride-ion current across the RPE basolateral membrane (haldrup2025genetherapystrategies pages 1-3). The protein's Ca²⁺-clasps regulate calcium-dependent opening and closing through conformational changes. Additionally, bestrophin-1 regulates intracellular calcium signaling, calcium release from endoplasmic reticulum stores, and cell volume homeostasis in RPE cells (haldrup2025genetherapystrategies pages 3-5, amato2023genetherapyin pages 2-3).

Relevant GO Biological Process terms: - GO:0005229 (intracellular calcium activated chloride channel activity) - GO:0006821 (chloride transport) - GO:0007601 (visual perception) - GO:0055085 (transmembrane transport)

Causal Chain from Initial Trigger to Clinical Manifestation

1. Initial trigger: Heterozygous pathogenic variant in BEST1 leads to production of mutant bestrophin-1 subunits (amato2023genetherapyin pages 1-2).
2. Protein dysfunction: Mutant subunits incorporate into pentameric channel complexes, causing dominant negative effects (most commonly), loss of function, or gain of function depending on the specific variant (navinesferrer2022impairedbestrophinchannel pages 10-11, haldrup2025genetherapystrategies pages 5-7). Some variants cause protein mislocalization from the basolateral membrane to intracellular compartments (padhy2026reviewofthe pages 2-4).
3. RPE dysfunction: Impaired chloride transport disrupts RPE transepithelial potential (measured as reduced EOG light rise), fluid transport, and calcium homeostasis (padhy2026reviewofthe pages 2-4, haldrup2025genetherapystrategies pages 1-3).
4. RPE-photoreceptor interaction failure: Loss of normal apposition between RPE apical microvilli and photoreceptor outer segments leads to impaired phagocytosis of shed outer segments (navinesferrer2022impairedbestrophinchannel pages 11-13, bianco2024multimodalimagingin pages 1-2).
5. Vitelliform material accumulation: Unphagocytosed photoreceptor outer segments and lipofuscin accumulate in the subretinal space, forming the characteristic vitelliform lesion (bianco2024multimodalimagingin pages 1-2).
6. Progressive photoreceptor damage: Cone mosaic changes, outer nuclear layer thinning, and ellipsoid zone disruption develop over time (bianco2024multimodalimagingin pages 1-2).
7. End-stage disease: RPE death, photoreceptor loss, geographic atrophy, and potential choroidal neovascularization result in irreversible central vision loss (padhy2026reviewofthe pages 2-4, grewal2021bestrophinopathiesperspectiveson pages 1-2).

Cell Types Involved

• Retinal pigment epithelium (RPE): Primary cell type expressing BEST1 and site of initial pathology. CL:0002586 (retinal pigment epithelial cell).
• Cone photoreceptors: Secondary damage from RPE dysfunction, particularly in the macula. CL:0000573 (cone photoreceptor cell).
• Rod photoreceptors: May also be affected in later stages. CL:0000604 (rod photoreceptor cell).

Biochemical Abnormalities

• Ion channel defect: Impaired calcium-activated chloride channel activity at the RPE basolateral membrane (amato2023genetherapyin pages 2-3, navinesferrer2022impairedbestrophinchannel pages 10-11).
• Calcium signaling disruption: Altered intracellular calcium dynamics in RPE cells (amato2023genetherapyin pages 2-3).
• Phagocytosis defect: Impaired photoreceptor outer segment phagocytosis by RPE (navinesferrer2022impairedbestrophinchannel pages 11-13, xu2024ionchannelsresearch pages 4-5).
• Transepithelial fluid transport deficiency: Reduced subretinal fluid clearance (xu2024ionchannelsresearch pages 4-5).

7. Anatomical Structures Affected

Organ Level

• Primary organ: Eye (UBERON:0000970)
• Primary structure: Retina (UBERON:0000966), specifically the macula (UBERON:0000053)
• Body system: Visual/nervous system

Tissue and Cell Level

• Retinal pigment epithelium (RPE): Primary tissue directly affected; site of bestrophin-1 expression and initial pathology (UBERON:0001782) (amato2023genetherapyin pages 2-3, padhy2026reviewofthe pages 2-4).
• Photoreceptor layer: Secondary damage to cone and rod photoreceptors (UBERON:0001789) (bianco2024multimodalimagingin pages 1-2).
• Subretinal space: Site of vitelliform material accumulation (bianco2024multimodalimagingin pages 1-2).

Subcellular Level

• Basolateral plasma membrane: Primary localization of bestrophin-1 (GO:0016323) (amato2023genetherapyin pages 2-3, padhy2026reviewofthe pages 2-4).
• Endoplasmic reticulum: Secondary localization of bestrophin-1; involved in calcium release regulation (GO:0005783) (amato2023genetherapyin pages 2-3, padhy2026reviewofthe pages 2-4).

Localization

• Bilateral involvement: Typically bilateral and symmetrical, though asymmetric presentation occurs (haldrup2025genetherapystrategies pages 3-5).
• Macular predominance: Vitelliform lesions primarily affect the central macula, with some patients showing extramacular deposits (yang2023best1novelmutation pages 1-2, bianco2024multimodalimagingin pages 1-2).

8. Temporal Development

Onset

• Typical age of onset: Childhood to early adulthood for BVMD (ages 3–15 years); AVMD presents after age 40 (yang2023best1novelmutation pages 1-2, navinesferrer2022impairedbestrophinchannel pages 1-2, nowomiejska2022diseaseexpressioncaused pages 1-2).
• Onset pattern: Insidious; pre-vitelliform stage may be detected on imaging before symptoms develop (padhy2026reviewofthe pages 2-4, amato2023genetherapyin pages 2-3).

Progression

• Disease course: Slowly progressive over decades; photoreceptors can remain viable for extended periods despite subretinal material accumulation (amato2023genetherapyin pages 2-3, amato2023genetherapyin pages 6-7).
• Progression rate: Highly variable and unpredictable; not all patients progress through all five stages sequentially (bianco2024multimodalimagingin pages 1-2, amato2023genetherapyin pages 2-3).
• Duration: Chronic, lifelong condition.
• Critical periods: The slow progression provides a wide therapeutic window for gene therapy intervention, as central photoreceptors usually remain viable for decades (amato2023genetherapyin pages 2-3, amato2023genetherapyin pages 6-7).

9. Inheritance and Population

Inheritance Pattern

• Mode: Autosomal dominant with variable expressivity and incomplete/reduced penetrance (grewal2021bestrophinopathiesperspectiveson pages 1-2, beryozkin2024bestdiseaseglobal pages 1-2, haldrup2025genetherapystrategies pages 3-5).
• Penetrance: Incomplete; many BEST1 pathogenic variants show reduced penetrance, meaning not all carriers develop clinical disease (grewal2021bestrophinopathiesperspectiveson pages 1-2).
• Expressivity: Highly variable, even within families carrying the same mutation; intrafamilial phenotypic diversity is a hallmark (grewal2021bestrophinopathiesperspectiveson pages 1-2, yang2023best1novelmutation pages 4-5).

Epidemiology

• Prevalence estimates: Widely variable across studies:
• General estimates range from 1:5,000 to 1:67,000 (grewal2021bestrophinopathiesperspectiveson pages 1-2, navinesferrer2022impairedbestrophinchannel pages 1-2, haldrup2025genetherapystrategies pages 3-5).
• Israel: 1 in 127,000 overall; 1 in 76,000 among Arab Muslims; 1 in 145,000 among Jews (beryozkin2024bestdiseaseglobal pages 2-3, beryozkin2024bestdiseaseglobal pages 1-2).
• Denmark: 0.8–1.5 per 100,000 (beryozkin2024bestdiseaseglobal pages 4-7).
• Northern Sweden: 2 per 10,000 (beryozkin2024bestdiseaseglobal pages 4-7).
• Minnesota (USA): 1:16,500 to 1:21,000 (beryozkin2024bestdiseaseglobal pages 4-7).
• BVMD prevalence of approximately 1:50,000 has been cited (nowomiejska2022diseaseexpressioncaused pages 1-2).
• Population variation: Higher prevalence in populations with higher consanguinity rates (for recessive forms); Arab Muslim populations in Israel showed higher prevalence than Jewish populations (42% vs. ≤13.6% consanguinity rates) (beryozkin2024bestdiseaseglobal pages 7-8).
• Founder effects: Population-specific founder variants have been identified, including a founder variant c.867+97G>A in Chinese patients with ARB (allele frequency 16%) (shi2023comprehensivegeneticanalysis pages 5-8) and a founder variant p.Arg122Pro in Egyptian families (from Elbagoury et al. 2025).

Sex Ratio

No significant sex predilection has been established for BEST1-related dominant retinopathy; the clinical trials include participants of all sexes (NCT05809635 chunk 1, NCT07185256 chunk 1).

10. Diagnostics

Clinical Tests

• Electrooculogram (EOG): The hallmark diagnostic test; markedly reduced Arden ratio (typically ≤1.5, pathognomonic) reflecting impaired RPE function (bianco2024multimodalimagingin pages 1-2, nowomiejska2022diseaseexpressioncaused pages 1-2, haldrup2025genetherapystrategies pages 3-5). MAXO: MAXO:0000930 (electrooculography).
• Full-field electroretinogram (ERG): Usually normal in BVMD, distinguishing it from other retinal dystrophies; may show progressive amplitude reductions in advanced stages (bianco2024multimodalimagingin pages 1-2, padhy2026reviewofthe pages 2-4).
• Multifocal ERG (mfERG): Reduced central ring amplitudes correlating with subretinal fluid (padhy2026reviewofthe pages 2-4).
• Optical coherence tomography (OCT): Reveals subretinal hyperreflective material, dome-shaped lesions, outer retinal layer disruption, and cystoid changes; an OCT-based staging system has been developed (bianco2024multimodalimagingin pages 1-2, amato2023genetherapyin pages 2-3). MAXO: MAXO:0010034 (optical coherence tomography).
• Fundus autofluorescence (FAF): Intense hyperautofluorescence corresponding to vitelliform deposits; useful for disease monitoring (bianco2024multimodalimagingin pages 1-2, padhy2026reviewofthe pages 2-4, amato2023genetherapyin pages 2-3).
• Near-infrared fundus autofluorescence (NIR-AF): Helps identify pre-vitelliform stage changes (padhy2026reviewofthe pages 2-4).
• Color fundus photography: Classic "egg-yolk" yellow macular lesion appearance (bianco2024multimodalimagingin pages 1-2, yang2023best1novelmutation pages 4-5).
• OCT angiography (OCTA): Emerging role in detecting macular neovascularization, with a higher prevalence of non-exudative CNV in late stages (bianco2024multimodalimagingin pages 1-2).

Genetic Testing

• Recommended approach: Molecular genetic confirmation is considered the gold standard for Best disease diagnosis due to variable clinical presentation (beryozkin2024bestdiseaseglobal pages 1-2).
• Gene panels: IRD panels including BEST1 variant testing are routinely used (NCT07185256 chunk 1).
• Single gene testing: Sanger sequencing of BEST1 coding exons (nowomiejska2022diseaseexpressioncaused pages 1-2, shi2023comprehensivegeneticanalysis pages 5-8).
• Whole exome sequencing (WES): Used for comprehensive diagnostic screening (beryozkin2024bestdiseaseglobal pages 1-2).
• Whole genome sequencing (WGS): Can detect deep intronic variants missed by standard approaches; three deep intronic variants (c.1101-491A>G, c.867+97G>A, c.867+97G>T) were identified through WGS in a Chinese cohort (shi2023comprehensivegeneticanalysis pages 5-8).

Differential Diagnosis

Conditions to distinguish from BEST1-related dominant retinopathy include: - Age-related macular degeneration (AMD) - Adult-onset foveomacular vitelliform dystrophy (pattern dystrophy without BEST1 mutation) - Central serous chorioretinopathy - Stargardt disease (ABCA4-related) - PRPH2-related vitelliform macular dystrophy - IMPG1/IMPG2-related vitelliform macular dystrophy (OpenTargets Search: -BEST1)

11. Outcome/Prognosis

Visual Prognosis

• Most patients experience slow visual decline over decades (amato2023genetherapyin pages 2-3, amato2023genetherapyin pages 6-7).
• Approximately 75% of patients under age 40 maintain best-corrected visual acuity of 6/12 (20/40) or better in at least one eye (haldrup2025genetherapystrategies pages 3-5).
• Visual acuity can range from near-normal to severe impairment depending on disease stage (haldrup2025genetherapystrategies pages 3-5).
• Central photoreceptors usually remain viable for decades despite subretinal material accumulation, providing a wide therapeutic window (amato2023genetherapyin pages 2-3, amato2023genetherapyin pages 6-7).

Complications

• Choroidal neovascularization (CNV) may develop in late-stage disease, with OCTA studies showing a greater prevalence of non-exudative CNV than previously recognized (bianco2024multimodalimagingin pages 1-2).
• Macular atrophy and fibrosis represent end-stage disease (padhy2026reviewofthe pages 2-4, haldrup2025genetherapystrategies pages 3-5).
• Angle-closure glaucoma is primarily associated with recessive BEST1 disease rather than dominant forms (yang2023best1novelmutation pages 1-2).

Life Expectancy

BEST1-related dominant retinopathy is not associated with reduced life expectancy; morbidity is limited to progressive visual impairment.

12. Treatment

Current Treatments

Currently, no approved curative or disease-modifying treatments exist for any bestrophinopathy (haldrup2025genetherapystrategies pages 7-8, haldrup2025genetherapystrategies pages 1-3). Management is limited to: - Supportive care: Low-vision aids, adaptive technologies, and occupational therapy. - Anti-VEGF therapy: For secondary choroidal neovascularization (CNV) when present. - Monitoring: Regular multimodal imaging follow-up.

Experimental/Investigational Treatments

Gene Therapy

The following clinical trials are currently investigating or characterizing BEST1-related retinopathy for therapeutic development:

Table: This table summarizes the main clinical studies currently identified for BEST1-related retinopathy, including the ongoing OPGx-BEST1 interventional gene therapy trial and key observational natural history/modeling studies. It is useful for quickly comparing trial purpose, status, intervention type, and outcome focus.

OPGx-BEST1 (BIRD-1 trial, NCT07185256): This is the first interventional gene therapy trial for bestrophinopathies, sponsored by Opus Genetics. OPGx-BEST1 is a codon-optimized full-length human BEST1 transgene under an RPE-specific VMD2 promoter, delivered via subretinal injection. Two dose levels (1.5E9 vg/eye and 4.5E9 vg/eye) are being explored in adults with BVMD or ARB. The trial began enrolling in September 2025 with 5-year follow-up planned (NCT07185256 chunk 1, NCT07185256 chunk 2). MAXO: MAXO:0001001 (gene therapy).

Preclinical gene augmentation: AAV-mediated gene augmentation therapy has demonstrated reversal of retinal microdetachments in canine bestrophinopathy models within 4–12 weeks post-injection, with sustained effects up to 245 weeks without inflammatory responses (amato2023genetherapyin pages 6-7, padhy2026reviewofthe pages 6-9). In iPSC-RPE cells, baculovirus and AAV2 vector-delivered wildtype BEST1 rescues calcium-dependent chloride channel function (grewal2021bestrophinopathiesperspectiveson pages 9-11).

CRISPR/Cas9 Gene Editing

• Allele-specific CRISPR/Cas9 genome editing has shown proof-of-concept for silencing mutant BEST1 transcripts in hiPSC-RPE cells, with one study demonstrating 96% frameshift efficiency via NHEJ (grewal2021bestrophinopathiesperspectiveson pages 9-11).
• Allele-specific silencing combined with gene augmentation has been proposed as a universal strategy, particularly for gain-of-function variants where gene augmentation alone is insufficient (amato2023genetherapyin pages 4-6).
• Recent work (Milenkovic & Weber 2026) demonstrated that eliminating the mutant BEST1 transcript via allele-specific CRISPR editing led to enhanced BEST1 localization, improved protein stability, and restoration of anion transport function in clonal hiPSC-RPE lines (from milenkovic2026 abstract).

Small Molecule Approaches

Small molecule drugs showing promise in preclinical models include: bafilomycin-A1 (slowing POS degradation), valproic acid (accelerating POS degradation), curcumin (enhancing ZO-1 and bestrophin-1 expression and improving phagocytosis), and sodium phenylbutyrate (4PBA) (xu2024ionchannelsresearch pages 4-5).

Treatment Strategy by Mutation Type

• LOF and DN mutations: Amenable to gene augmentation alone, potentially requiring higher doses for stronger dominant negative effects (amato2023genetherapyin pages 1-2, haldrup2025genetherapystrategies pages 8-10).
• GOF mutations: Require combination approach: gene silencing (CRISPR or ASO) plus gene augmentation (amato2023genetherapyin pages 4-6).

13. Prevention

Primary Prevention

No primary prevention is available, as the disease is caused by germline genetic variants.

Secondary Prevention (Early Detection)

• Genetic screening: Cascade genetic testing of family members of affected individuals is recommended to identify asymptomatic carriers (beryozkin2024bestdiseaseglobal pages 1-2).
• Carrier screening/preimplantation genetic diagnosis (PGD): Available for families with known BEST1 mutations for family planning purposes.
• Genetic counseling: Essential for affected families given the autosomal dominant inheritance, variable expressivity, and incomplete penetrance (grewal2021bestrophinopathiesperspectiveson pages 1-2). MAXO: MAXO:0000127 (genetic counseling).

Tertiary Prevention

• Regular ophthalmological monitoring with multimodal imaging (OCT, FAF, EOG) to detect disease progression and complications such as CNV (bianco2024multimodalimagingin pages 1-2, amato2023genetherapyin pages 2-3).
• Prompt anti-VEGF treatment for secondary choroidal neovascularization.

Natural History Studies

The NCT05809635 natural history study (Columbia University, PI: Stephen Tsang) is currently recruiting to establish the natural course of BEST1 vitelliform macular dystrophy and identify sensitive structural and functional outcome measures for future clinical trials (NCT05809635 chunk 1).

14. Other Species / Natural Disease

Canine Bestrophinopathy

Canine multifocal retinopathy (CMR) is a naturally occurring bestrophinopathy identified in multiple dog breeds, representing the most important large animal model for BEST1-related disease (dufour2025caninemodelsof pages 4-5, winkler2020largeanimalmodels pages 11-12):

• cmr1: p.Arg25Ter mutation in Great Pyrenees and mastiff breeds (winkler2020largeanimalmodels pages 11-12).
• cmr2: p.Gly161Asp mutation in Coton de Tulear (dufour2025caninemodelsof pages 4-5, winkler2020largeanimalmodels pages 11-12).
• cmr3: Two mutations in Swedish Lapponian Herder (dufour2025caninemodelsof pages 4-5, winkler2020largeanimalmodels pages 11-12).

Species: Canis lupus familiaris (NCBI Taxon: 9615).

Key differences from human disease: Canine CMR follows autosomal recessive inheritance (unlike the dominant human BVMD), but recapitulates clinical, histological, and molecular features of human bestrophinopathy including multifocal retinal detachments, lipofuscin accumulation, and RPE apical microvilli loss (dufour2025caninemodelsof pages 4-5, winkler2020largeanimalmodels pages 11-12). The retina-wide microdetachment is light-modulated, making it useful as an outcome measure for gene therapy studies (dufour2025caninemodelsof pages 4-5).

Translational value: Gene therapy using rAAV2 vectors delivering wildtype BEST1 successfully resolved detachments and restored RPE microvilli for over 207 weeks (approximately 4 years) post-injection in dogs, independent of age or mutation type (winkler2020largeanimalmodels pages 11-12).

15. Model Organisms

Mouse Models

• Best1 knockout mice: Do not exhibit bestrophinopathy phenotypes or significant chloride current abnormalities, limiting their utility (amato2023genetherapyin pages 6-7, xu2024ionchannelsresearch pages 4-5).
• Best1 p.W93C knock-in mice: Display disease features with dominant inheritance, including reduced EOG light-rise and serous retinal detachments, but unexpectedly maintain normal chloride currents (padhy2026reviewofthe pages 6-9, xu2024ionchannelsresearch pages 4-5).
• Best1 p.Y227N knock-in mice: Show no ocular abnormalities up to 2 years of age (xu2024ionchannelsresearch pages 4-5).

iPSC-RPE Models

Patient-derived induced pluripotent stem cell (iPSC)-RPE models represent the most flexible and disease-relevant in vitro system for studying BEST1-related dominant retinopathy (amato2023genetherapyin pages 6-7, xu2024ionchannelsresearch pages 4-5, xu2024ionchannelsresearch pages 14-14): - Successfully reproduce disease features including BEST1 protein mislocalization, defective chloride conductance, impaired phagocytosis, lipofuscin accumulation, and reduced transepithelial fluid transport (xu2024ionchannelsresearch pages 4-5). - Particularly valuable for studying dominant BEST1 mutations, since canine models lack dominant genotypes and mouse knockouts show no phenotype (amato2023genetherapyin pages 6-7). - Used for gene therapy preclinical testing and CRISPR/Cas9 proof-of-concept studies (grewal2021bestrophinopathiesperspectiveson pages 9-11, xu2024ionchannelsresearch pages 14-14).

Model Limitations

• Canine models: Recessive inheritance limits applicability to dominant human disease (xu2024ionchannelsresearch pages 4-5).
• Mouse models: Generally poor recapitulation of human phenotype; species-specific differences in RPE physiology limit translational value (amato2023genetherapyin pages 6-7, xu2024ionchannelsresearch pages 4-5).
• iPSC-RPE: Two-dimensional cell culture lacks the complex retinal architecture and three-dimensional tissue interactions present in vivo (xu2024ionchannelsresearch pages 4-5).

Summary

BEST1-related dominant retinopathy, most commonly manifesting as Best vitelliform macular dystrophy, is a Mendelian inherited retinal dystrophy caused by heterozygous mutations in BEST1 encoding the bestrophin-1 calcium-activated chloride channel in the RPE. The disease is characterized by progressive vitelliform macular lesions, reduced EOG light rise, and variable visual impairment. With over 250 known pathogenic variants and three distinct molecular mechanisms (loss-of-function, dominant negative, and gain-of-function), the condition shows remarkable genetic and phenotypic heterogeneity. While no approved treatments currently exist, the first gene therapy clinical trial (BIRD-1/NCT07185256) began recruiting in 2025, and multiple preclinical gene therapy and gene editing strategies show considerable promise. The slow disease progression and prolonged photoreceptor viability provide a wide therapeutic window, positioning bestrophinopathies as a particularly attractive target for emerging genetic therapies.

References

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Artifacts

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