RARE DISEASE
Bietti crystalline dystrophy
Bietti crystalline dystrophy
Bietti crystalline dystrophy
Synonyms: BCD, Bietti crystalline corneoretinal dystrophy, Bietti crystalline retinopathy
Synonyms: BCD, Bietti crystalline corneoretinal dystrophy, Bietti crystalline retinopathy
Synonyms: BCD, Bietti crystalline corneoretinal dystrophy, Bietti crystalline retinopathy
Drug discovery
4
drugs
With orphan designations
Overview
Bietti Crystalline Dystrophy (BCD) is an autosomal recessive chorioretinal dystrophy caused by CYP4V2 gene mutations. Characterized by intraretinal crystalline deposits and progressive RPE-choriocapillaris atrophy, it manifests with nyctalopia, peripheral vision loss, and reduced visual acuity starting in adolescence. Most patients develop legal blindness by their 40s–50s. Diagnosis combines clinical findings, retinal imaging (OCT/FAF), and genetic testing. No cure exists, but emerging gene therapies show promise [1][6][13][19].
Categories: rare genetic diseases, rare ophthalmic disorders
Research Papers
39 drug discovery papers about Bietti crystalline dystrophy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
39 drug discovery papers about Bietti crystalline dystrophy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-06-05 | IRE1α-mediated endoplasmic reticulum stress response regulates oxidative damage in CYP4V2 deficient human retinal pigment epithelial cells.
Given the role of polyunsaturated fatty acid (PUFA) overload and mitochondrial dysfunction in retinal pigment epithelium (RPE) cells in causing retinal degeneration in Bietti crystalline dystrophy (BCD), we aimed to identify the pathways responsible for intracellular oxidative stress and mitochondrial damage in CYP4V2-deficient RPE cells. Proteomic analysis of control and CYP4V2-knockdown (KD) ARPE-19 cells revealed that endoplasmic reticulum (ER) stress was the most enriched pathway. The effects of CYP4V2 deficiency on intracellular reactive oxygen species, mitochondrial integrity, and ATP production were assessed. Inositol-requiring enzyme 1 α (IRE1α) inhibitors suppressed upregulation of endoplasmic reticulum oxidoreductase 1 alpha (ERO1-Lα) protein expression, which contributed to ER-associated oxidative stress. Loss of mitochondrial transmembrane potential and reduced ATP production were mitigated with IRE1α inhibitor in CYP4V2-KD ARPE-19 cells. Our findings reveal a novel regulatory mechanism involving potential reduction in PUFA utilization, IRE1α signaling mediated ER oxidative stress, and mitochondrial dysfunction in BCD, potentially offering future therapeutic avenues.
2024-07-12 | Uncovering the role of ferroptosis in Bietti crystalline dystrophy and potential therapeutic strategies.
Bietti crystalline dystrophy (BCD) is an inherited retinal degeneration disease caused by mutations in the CYP4V2 gene. Currently, there is no clinical therapy approach available for BCD patients. Previous research has suggested that polyunsaturated fatty acids (PUFAs) may play a significant role in the development of BCD, implicating the involvement of ferroptosis in disease pathogenesis. In this work, we aimed to investigate the interplay between ferroptosis and BCD and to detect potential therapeutic strategies for the disease. Genetic-edited RPE cell line was first established in this study by CRISPR-Cas9 technology. Cyp4v3 (the homologous gene of human CYP4V2) knock out (KO) mice have also been used. Lipid profiling and transcriptome analysis of retinal pigment epithelium (RPE) cells from Cyp4v3 KO mice have been conducted. Ferroptosis phenotypes have been first investigated in BCD models in vitro and in vivo, including lipid peroxidation, mitochondrial changes, elevated levels of reactive oxygen species (ROS), and altered gene expression. Additionally, an iron chelator, deferiprone (DFP), has been tested in vitro and in vivo to determine its efficacy in suppressing ferroptosis and restoring the BCD phenotype. Cyp4v3 KO mice exhibited progressive retinal degeneration and lipid accumulation, similar to the BCD phenotype, which was exacerbated by a high-fat diet (HFD). Increased levels of PUFAs, such as EPA (C22:5) and AA (C20:4), were observed in the RPE of Cyp4v3 KO mice. Transcriptome analysis of RPE in Cyp4v3 KO mice revealed changes in genes involved in iron homeostasis, particularly an upregulation of NCOA4, which was confirmed by immunofluorescence. Ferroptosis-related characteristics, including mitochondrial defects, lipid peroxidation, ROS accumulation, and upregulation of related genes, were detected in the RPE both in vitro and in vivo. Abnormal accumulation of ferrous iron was also detected. DFP, an iron chelator administration suppressed ferroptosis phenotype in CYP4V2 mutated RPE. Oral administration of DFP also restored the retinal function and morphology in Cyp4v3 KO mice. This study represented the first evidence of the substantial role of ferroptosis in the development of BCD. PUFAs resulting from CYP4V2 mutation may serve as substrates for ferroptosis, potentially working in conjunction with NCOA4-regulated iron accumulation, ultimately leading to RPE degeneration. DFP administration, which chelates iron, has demonstrated its ability to reverse BCD phenotype both in vitro and in vivo, suggesting a promising therapeutic approach in the future.
2024-07-04 | Targeted lipidomics uncovers oxylipin perturbations and potential circulation biomarkers in Bietti's crystalline dystrophy.
Abnormalities in lipid metabolism have been proposed in Bietti's crystalline dystrophy (BCD). We aim to characterize the lipid profiles in a case-control study. All participants were genetically confirmed by CYP4V2 gene sequencing and underwent chorioretinopathy evaluation by calculating the percentages of AF atrophy (PAFA). Fasting blood samples of BCD patients and controls were collected, and plasma was analyzed for routine lipid profiles. Targeted lipidomic evaluation includes long chain polyunsaturated fatty acids (LCPUFA) and associated eicosanoid metabolites. Routine lipids profiles showed elevated plasma levels of triglyceride (P = 0.043) and low-density lipoprotein cholesterol (P = 0.024) in BCD patients. Lipidomic analysis showed significantly decreased levels of ω-3 LCPUFA including docosahexaenoic acid (DHA, 22:6, P = 0.00068) and eicosapentaenoic acid (EPA, 20:5, P = 0.0016), as well as ω-6 LCPUFA arachidonic acid (ARA, 20:4, P < 0.0001) in BCD patients. Eicosanoid metabolites, either derived from ω-3 and/ or ω-6 LCPUFAs via cyclooxygenase (COX) or lipoxygenase (LOX) pathways, including 5-HEPE, 12-HEPE, 13-HDHA, 15-HETE, 12-HETE, 5-HETE, 6k-PGF1a, PGE2, PGJ2, and TXB2, exhibited significant differences (P < 0.0001) between BCD patients and controls. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites including 5-HETE, 5-HEPE, 12-HEPE and LTB4. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA), as well as their downstream metabolites via the COX and LOX pathways, suggesting that these might be implicated in BCD pathogenesis and could serve as biomarkers and therapeutic targets of the disease. What is known BCD is a vision-threatening hereditary disease the causative gene of which is CYP4V2. Abnormalities in lipid metabolism have been proposed and demonstrated previously in BCD studies. The detailed pathogenesis remains unclear and controversial. What is new We observed prominent lipidomic alterations in the circulation when compared with age, gender, and bodymass index (BMI)-matched healthy controls. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA). Remarkable changes were observed in the downstream metabolites of the LCPUFA via the COX and LOX pathways. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites.
2024-04-16 | Sustained Release Formulation of Hydroxypropyl-β-cyclodextrin Eye Drops Using Xanthan Gum.
Bietti's crystalline dystrophy (BCD) is an autosomal recessive chorioretinal degeneration caused by mutations in the CYP4V2 gene. It is characterized by cholesterol accumulation and crystal-like deposits in the retinas. Hydroxypropyl-β-cyclodextrin (HP-β-CyD) exerts therapeutic effects against BCD by reducing lysosomal dysfunction and inhibiting cytotoxicity in induced pluripotent stem cell (iPSC)-RPE cells established from patient-derived iPS cells. However, the ocular retention of HP-β-CyD is low and needs to be improved. Therefore, this study used a viscous agent to develop a sustained-release ophthalmic formulation containing HP-β-CyD. Our results suggest that HP-β-CyD-containing xanthan gum has a considerably higher sustained release capacity than other viscous agents, such as methylcellulose and sodium alginate. In addition, the HP-β-CyD-containing xanthan gum exhibited pseudoplastic behavior. It was less cytotoxic to human retinal pigment epithelial cells compared with HP-β-CyD alone. Furthermore, the slow release of HP-β-CyD from xanthan gum caused a sustained decrease in free intracellular cholesterol. These results suggest that xanthan gum is a useful substrate for the sustained release formulation of HP-β-CyD, and that HP-β-CyD-containing xanthan gum has potential as an eye drop for BCD treatment.
2022-05-30 | Accumulation of Lipid Droplets in a Novel Bietti Crystalline Dystrophy Zebrafish Model With Impaired PPARα Pathway.
Bietti crystalline dystrophy (BCD) is a progressive retinal degenerative disease primarily characterized by numerous crystal-like deposits and degeneration of retinal pigment epithelium (RPE) and photoreceptor cells. CYP4V2 (cytochrome P450 family 4 subfamily V member 2) is currently the only disease-causing gene for BCD. We aimed to generate a zebrafish model to explore the functional role of CYP4V2 in the development of BCD and identify potential therapeutic targets for future studies. The cyp4v7 and cyp4v8 (homologous genes of CYP4V2) knockout zebrafish lines were generated by CRISPR/Cas9 technology. The morphology of photoreceptor and RPE cells and the accumulation of lipid droplets in RPE cells were investigated at a series of different developmental stages through histological analysis, immunofluorescence, and lipid staining. Transcriptome analysis was performed to investigate the changes in gene expression of RPE cells during the progression of BCD. Progressive retinal degeneration including RPE atrophy and photoreceptor loss was observed in the mutant zebrafish as early as seven months after fertilization. We also observed the excessive accumulation of lipid droplets in RPE cells from three months after fertilization, which preceded the retinal degeneration by several months. Transcriptome analysis suggested that multiple metabolism pathways, especially the lipid metabolism pathways, were significantly changed in RPE cells. The down-regulation of the peroxisome proliferator-activated receptor α (PPARα) pathway was further confirmed in the mutant zebrafish and CYP4V2-knockdown human RPE-1 cells. Our work established an animal model that recapitulates the symptoms of BCD patients and revealed that abnormal lipid metabolism in RPE cells, probably caused by dysregulation of the PPARα pathway, might be the main and direct consequence of CYP4V2 deficiency. These findings will deepen our understanding of the pathogenesis of BCD and provide potential therapeutic approaches.
gene therapies
2025-07-30 | Inborn Errors of Metabolism: Bietti Crystalline Dystrophy.
Bietti crystalline dystrophy (BCD) is an autosomal recessive dystrophy which has been estimated to occur in 1 in 67,000 people; it is more common in people of East Asian descent and presents with night blindness and paracentral scotomas.
2025-07-10 | Comprehensive genotypic and phenotypic analysis of Bietti crystalline dystrophy: insights from a large cohort study.
In this cross-sectional observational study, we conducted comprehensive ophthalmic evaluations, including fundus imaging, fundus autofluorescence (FAF), swept-source optical coherence tomography (SS-OCT), microperimetry, and electroretinography, in 164 patients with Bietti crystalline dystrophy (BCD) from 159 families. The mean age of onset was (29.9±8.9) years, with night blindness being the most common onset symptom (54.3%). FAF revealed diffuse hypoautofluorescence in 86.7% of eyes, and SS-OCT identified outer retinal tabulations (ORTs) in 69.9% of eyes, indicative of severe retinal pigment epithelium (RPE) dysfunction. Microperimetry demonstrated a gradual decline in retinal sensitivity and fixation stability with disease progression, particularly in advanced stages. We identified 34 distinct CYP4V2 variants, three of which were novel. Patients with biallelic truncating mutations experienced earlier disease onset and progressed to legal blindness at a younger age. These findings provide a comprehensive overview of structural and functional deterioration in BCD and underscore the significant impact of truncating mutations on disease progression.
2024-05-06 | In vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment.
Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drugs. It is caused by mutations in CYP4V2 gene, and about 80% of BCD patients carry mutations in exon 7 to 11. Here, we apply CRISPR/Cas9 mediated homology-independent targeted integration (HITI)-based gene editing therapy in HEK293T cells, BCD patient derived iPSCs, and humanized Cyp4v3 mouse model (h-Cyp4v3mut/mut) using two rAAV2/8 vectors via sub-retinal administration. We find that sgRNA-guided Cas9 generates double-strand cleavage on intron 6 of the CYP4V2 gene, and the HITI donor inserts the carried sequence, part of intron 6, exon 7-11, and a stop codon into the DNA break, achieving precise integration, effective transcription and translation both in vitro and in vivo. HITI-based editing restores the viability of iPSC-RPE cells from BCD patient, improves the morphology, number and metabolism of RPE and photoreceptors in h-Cyp4v3mut/mut mice. These results suggest that HITI-based editing could be a promising therapeutic strategy for those BCD patients carrying mutations in exon 7 to 11, and one injection will achieve lifelong effectiveness.
2019-03-02 | CYP4V2 mutation screening in an Iranian Bietti crystalline dystrophy pedigree and evidence for clustering of CYP4V2 mutations
To report the genetic analysis of an Iranian Bietti crystalline dystrophy (BCD)-affected family, and to review previously reported mutations in the gene and assess the distribution of affected amino acids in the encoded protein.The eleven exons of CYP4V2 were sequenced in the DNA of the proband of the Iranian BCD family. The putative disease-causing variation was screened in all affected and non-affected members. BCD causing CYP4V2 mutations previously reported in the literature were compiled, and positions of amino acids affected by nonsense and missense mutations were mapped onto the primary structure of the CYP4V2 protein.C.1219G > T in CYP4V2 that causes p.Glu407* was identified as cause of BCD in the Iranian family. The mutation segregated with disease status. Clinical presentations were similar among affected members, except that one patient presented with retinal macular hole. Twelve nonsense and 47 missense mutations in CYP4V2 were compiled. Inspection of distribution of amino acids affected by the mutations suggested non-random distribution and clustering of affected amino acids in nine regions of the protein, including regions that contain the heme binding site, the metal binding site, and a region between these binding sites. The most C-terminus proximal nonsense mutation affected position 482.This study presents results of the genetic analysis of an Iranian BCD family. Protein regions affected by mutations within the nine mutation clusters include regions well conserved among orthologous proteins and human CYP4 proteins, some of which are associated with known functions. The findings may serve to identify reasonable candidate gene region targets for gene editing therapy approaches.
2014-08-13 | Generation and Characterization of a Murine Model of Bietti Crystalline Dystrophy
Bietti crystalline dystrophy (BCD) is a rare, autosomal recessive, progressive, degenerative eye disease caused by mutations in the CYP4V2 gene, for which no treatments are currently available. Cyp4v3 is the murine ortholog to CYP4V2, and to better understand the molecular pathogenesis of this disease we have established a Cyp4v3-null mouse line.Cyp4v3(-/-) mice were generated by homologous recombination in embryonic stem cells. Ocular morphologic characteristics were evaluated via fundus imaging, plasma lipid profiling, and histologic analysis via Oil Red O reactivity, hematoxylin and eosin staining, and transmission electron microscopy.The Cyp4v3(-/-) mouse recapitulates the characteristic features of corneoretinal crystal accumulation and systemic dyslipidemia seen in BCD. The Cyp4v3(-/-) mice behave normally and are viable and fertile when maintained under specific pathogen-free (SPF) housing conditions.Cyp4v3(-/-) mice represent a promising preclinical model that may be used to better understand the disease etiology and to evaluate pharmacotherapies for this devastating condition.
cell therapies
2024-07-25 | DISCREPANCY BETWEEN FUNDUS AUTOFLUORESCENCE ABNORMALITY AND VISUAL FIELD LOSS IN BIETTI CRYSTALLINE DYSTROPHY.
The aim of this study was to explore the potential benefits of retinal pigment epithelium replacement therapy in patients with Bietti crystalline dystrophy (BCD) by assessing the disease pathology with the distinctive relationship between fundus autofluorescence (FAF) abnormality and visual field defect. Sixteen eyes from 16 patients with BCD and 16 eyes from 16 patients with RHO-associated retinitis pigmentosa were included. Fundus autofluorescence, optical coherence tomography, and Goldmann perimetry results were retrospectively reviewed and assessed using image analyses. In patients with BCD, the FAF abnormality area was not correlated with the overall visual field defect area and median overall visual field defect area (57.5%) was smaller than FAF abnormality area (98.5%). By contrast, the ellipsoid zone width was significantly correlated with the central visual field area (r = 0.806, P < 0.001). In patients with RHO-associated retinitis pigmentosa, the FAF abnormality area and ellipsoid zone width were significantly correlated with the overall visual field defect area (r = 0.833, P < 0.001) and central visual field area (r = 0.887, P < 0.001), respectively. The FAF abnormality shown in patients with BCD involves retinal pigment epithelium degeneration without complete loss of photoreceptors or visual function. These results suggest that patients with BCD are good candidates for retinal pigment epithelium replacement therapy for preservation of residual visual function.
small molecules
2025-06-05 | IRE1α-mediated endoplasmic reticulum stress response regulates oxidative damage in CYP4V2 deficient human retinal pigment epithelial cells.
Given the role of polyunsaturated fatty acid (PUFA) overload and mitochondrial dysfunction in retinal pigment epithelium (RPE) cells in causing retinal degeneration in Bietti crystalline dystrophy (BCD), we aimed to identify the pathways responsible for intracellular oxidative stress and mitochondrial damage in CYP4V2-deficient RPE cells. Proteomic analysis of control and CYP4V2-knockdown (KD) ARPE-19 cells revealed that endoplasmic reticulum (ER) stress was the most enriched pathway. The effects of CYP4V2 deficiency on intracellular reactive oxygen species, mitochondrial integrity, and ATP production were assessed. Inositol-requiring enzyme 1 α (IRE1α) inhibitors suppressed upregulation of endoplasmic reticulum oxidoreductase 1 alpha (ERO1-Lα) protein expression, which contributed to ER-associated oxidative stress. Loss of mitochondrial transmembrane potential and reduced ATP production were mitigated with IRE1α inhibitor in CYP4V2-KD ARPE-19 cells. Our findings reveal a novel regulatory mechanism involving potential reduction in PUFA utilization, IRE1α signaling mediated ER oxidative stress, and mitochondrial dysfunction in BCD, potentially offering future therapeutic avenues.
2024-07-12 | Uncovering the role of ferroptosis in Bietti crystalline dystrophy and potential therapeutic strategies.
Bietti crystalline dystrophy (BCD) is an inherited retinal degeneration disease caused by mutations in the CYP4V2 gene. Currently, there is no clinical therapy approach available for BCD patients. Previous research has suggested that polyunsaturated fatty acids (PUFAs) may play a significant role in the development of BCD, implicating the involvement of ferroptosis in disease pathogenesis. In this work, we aimed to investigate the interplay between ferroptosis and BCD and to detect potential therapeutic strategies for the disease. Genetic-edited RPE cell line was first established in this study by CRISPR-Cas9 technology. Cyp4v3 (the homologous gene of human CYP4V2) knock out (KO) mice have also been used. Lipid profiling and transcriptome analysis of retinal pigment epithelium (RPE) cells from Cyp4v3 KO mice have been conducted. Ferroptosis phenotypes have been first investigated in BCD models in vitro and in vivo, including lipid peroxidation, mitochondrial changes, elevated levels of reactive oxygen species (ROS), and altered gene expression. Additionally, an iron chelator, deferiprone (DFP), has been tested in vitro and in vivo to determine its efficacy in suppressing ferroptosis and restoring the BCD phenotype. Cyp4v3 KO mice exhibited progressive retinal degeneration and lipid accumulation, similar to the BCD phenotype, which was exacerbated by a high-fat diet (HFD). Increased levels of PUFAs, such as EPA (C22:5) and AA (C20:4), were observed in the RPE of Cyp4v3 KO mice. Transcriptome analysis of RPE in Cyp4v3 KO mice revealed changes in genes involved in iron homeostasis, particularly an upregulation of NCOA4, which was confirmed by immunofluorescence. Ferroptosis-related characteristics, including mitochondrial defects, lipid peroxidation, ROS accumulation, and upregulation of related genes, were detected in the RPE both in vitro and in vivo. Abnormal accumulation of ferrous iron was also detected. DFP, an iron chelator administration suppressed ferroptosis phenotype in CYP4V2 mutated RPE. Oral administration of DFP also restored the retinal function and morphology in Cyp4v3 KO mice. This study represented the first evidence of the substantial role of ferroptosis in the development of BCD. PUFAs resulting from CYP4V2 mutation may serve as substrates for ferroptosis, potentially working in conjunction with NCOA4-regulated iron accumulation, ultimately leading to RPE degeneration. DFP administration, which chelates iron, has demonstrated its ability to reverse BCD phenotype both in vitro and in vivo, suggesting a promising therapeutic approach in the future.
2024-07-04 | Targeted lipidomics uncovers oxylipin perturbations and potential circulation biomarkers in Bietti's crystalline dystrophy.
Abnormalities in lipid metabolism have been proposed in Bietti's crystalline dystrophy (BCD). We aim to characterize the lipid profiles in a case-control study. All participants were genetically confirmed by CYP4V2 gene sequencing and underwent chorioretinopathy evaluation by calculating the percentages of AF atrophy (PAFA). Fasting blood samples of BCD patients and controls were collected, and plasma was analyzed for routine lipid profiles. Targeted lipidomic evaluation includes long chain polyunsaturated fatty acids (LCPUFA) and associated eicosanoid metabolites. Routine lipids profiles showed elevated plasma levels of triglyceride (P = 0.043) and low-density lipoprotein cholesterol (P = 0.024) in BCD patients. Lipidomic analysis showed significantly decreased levels of ω-3 LCPUFA including docosahexaenoic acid (DHA, 22:6, P = 0.00068) and eicosapentaenoic acid (EPA, 20:5, P = 0.0016), as well as ω-6 LCPUFA arachidonic acid (ARA, 20:4, P < 0.0001) in BCD patients. Eicosanoid metabolites, either derived from ω-3 and/ or ω-6 LCPUFAs via cyclooxygenase (COX) or lipoxygenase (LOX) pathways, including 5-HEPE, 12-HEPE, 13-HDHA, 15-HETE, 12-HETE, 5-HETE, 6k-PGF1a, PGE2, PGJ2, and TXB2, exhibited significant differences (P < 0.0001) between BCD patients and controls. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites including 5-HETE, 5-HEPE, 12-HEPE and LTB4. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA), as well as their downstream metabolites via the COX and LOX pathways, suggesting that these might be implicated in BCD pathogenesis and could serve as biomarkers and therapeutic targets of the disease. What is known BCD is a vision-threatening hereditary disease the causative gene of which is CYP4V2. Abnormalities in lipid metabolism have been proposed and demonstrated previously in BCD studies. The detailed pathogenesis remains unclear and controversial. What is new We observed prominent lipidomic alterations in the circulation when compared with age, gender, and bodymass index (BMI)-matched healthy controls. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA). Remarkable changes were observed in the downstream metabolites of the LCPUFA via the COX and LOX pathways. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites.
2024-04-16 | Sustained Release Formulation of Hydroxypropyl-β-cyclodextrin Eye Drops Using Xanthan Gum.
Bietti's crystalline dystrophy (BCD) is an autosomal recessive chorioretinal degeneration caused by mutations in the CYP4V2 gene. It is characterized by cholesterol accumulation and crystal-like deposits in the retinas. Hydroxypropyl-β-cyclodextrin (HP-β-CyD) exerts therapeutic effects against BCD by reducing lysosomal dysfunction and inhibiting cytotoxicity in induced pluripotent stem cell (iPSC)-RPE cells established from patient-derived iPS cells. However, the ocular retention of HP-β-CyD is low and needs to be improved. Therefore, this study used a viscous agent to develop a sustained-release ophthalmic formulation containing HP-β-CyD. Our results suggest that HP-β-CyD-containing xanthan gum has a considerably higher sustained release capacity than other viscous agents, such as methylcellulose and sodium alginate. In addition, the HP-β-CyD-containing xanthan gum exhibited pseudoplastic behavior. It was less cytotoxic to human retinal pigment epithelial cells compared with HP-β-CyD alone. Furthermore, the slow release of HP-β-CyD from xanthan gum caused a sustained decrease in free intracellular cholesterol. These results suggest that xanthan gum is a useful substrate for the sustained release formulation of HP-β-CyD, and that HP-β-CyD-containing xanthan gum has potential as an eye drop for BCD treatment.
2022-05-30 | Accumulation of Lipid Droplets in a Novel Bietti Crystalline Dystrophy Zebrafish Model With Impaired PPARα Pathway.
Bietti crystalline dystrophy (BCD) is a progressive retinal degenerative disease primarily characterized by numerous crystal-like deposits and degeneration of retinal pigment epithelium (RPE) and photoreceptor cells. CYP4V2 (cytochrome P450 family 4 subfamily V member 2) is currently the only disease-causing gene for BCD. We aimed to generate a zebrafish model to explore the functional role of CYP4V2 in the development of BCD and identify potential therapeutic targets for future studies. The cyp4v7 and cyp4v8 (homologous genes of CYP4V2) knockout zebrafish lines were generated by CRISPR/Cas9 technology. The morphology of photoreceptor and RPE cells and the accumulation of lipid droplets in RPE cells were investigated at a series of different developmental stages through histological analysis, immunofluorescence, and lipid staining. Transcriptome analysis was performed to investigate the changes in gene expression of RPE cells during the progression of BCD. Progressive retinal degeneration including RPE atrophy and photoreceptor loss was observed in the mutant zebrafish as early as seven months after fertilization. We also observed the excessive accumulation of lipid droplets in RPE cells from three months after fertilization, which preceded the retinal degeneration by several months. Transcriptome analysis suggested that multiple metabolism pathways, especially the lipid metabolism pathways, were significantly changed in RPE cells. The down-regulation of the peroxisome proliferator-activated receptor α (PPARα) pathway was further confirmed in the mutant zebrafish and CYP4V2-knockdown human RPE-1 cells. Our work established an animal model that recapitulates the symptoms of BCD patients and revealed that abnormal lipid metabolism in RPE cells, probably caused by dysregulation of the PPARα pathway, might be the main and direct consequence of CYP4V2 deficiency. These findings will deepen our understanding of the pathogenesis of BCD and provide potential therapeutic approaches.
gene therapies
2025-07-30 | Inborn Errors of Metabolism: Bietti Crystalline Dystrophy.
Bietti crystalline dystrophy (BCD) is an autosomal recessive dystrophy which has been estimated to occur in 1 in 67,000 people; it is more common in people of East Asian descent and presents with night blindness and paracentral scotomas.
2025-07-10 | Comprehensive genotypic and phenotypic analysis of Bietti crystalline dystrophy: insights from a large cohort study.
In this cross-sectional observational study, we conducted comprehensive ophthalmic evaluations, including fundus imaging, fundus autofluorescence (FAF), swept-source optical coherence tomography (SS-OCT), microperimetry, and electroretinography, in 164 patients with Bietti crystalline dystrophy (BCD) from 159 families. The mean age of onset was (29.9±8.9) years, with night blindness being the most common onset symptom (54.3%). FAF revealed diffuse hypoautofluorescence in 86.7% of eyes, and SS-OCT identified outer retinal tabulations (ORTs) in 69.9% of eyes, indicative of severe retinal pigment epithelium (RPE) dysfunction. Microperimetry demonstrated a gradual decline in retinal sensitivity and fixation stability with disease progression, particularly in advanced stages. We identified 34 distinct CYP4V2 variants, three of which were novel. Patients with biallelic truncating mutations experienced earlier disease onset and progressed to legal blindness at a younger age. These findings provide a comprehensive overview of structural and functional deterioration in BCD and underscore the significant impact of truncating mutations on disease progression.
2024-05-06 | In vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment.
Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drugs. It is caused by mutations in CYP4V2 gene, and about 80% of BCD patients carry mutations in exon 7 to 11. Here, we apply CRISPR/Cas9 mediated homology-independent targeted integration (HITI)-based gene editing therapy in HEK293T cells, BCD patient derived iPSCs, and humanized Cyp4v3 mouse model (h-Cyp4v3mut/mut) using two rAAV2/8 vectors via sub-retinal administration. We find that sgRNA-guided Cas9 generates double-strand cleavage on intron 6 of the CYP4V2 gene, and the HITI donor inserts the carried sequence, part of intron 6, exon 7-11, and a stop codon into the DNA break, achieving precise integration, effective transcription and translation both in vitro and in vivo. HITI-based editing restores the viability of iPSC-RPE cells from BCD patient, improves the morphology, number and metabolism of RPE and photoreceptors in h-Cyp4v3mut/mut mice. These results suggest that HITI-based editing could be a promising therapeutic strategy for those BCD patients carrying mutations in exon 7 to 11, and one injection will achieve lifelong effectiveness.
2019-03-02 | CYP4V2 mutation screening in an Iranian Bietti crystalline dystrophy pedigree and evidence for clustering of CYP4V2 mutations
To report the genetic analysis of an Iranian Bietti crystalline dystrophy (BCD)-affected family, and to review previously reported mutations in the gene and assess the distribution of affected amino acids in the encoded protein.The eleven exons of CYP4V2 were sequenced in the DNA of the proband of the Iranian BCD family. The putative disease-causing variation was screened in all affected and non-affected members. BCD causing CYP4V2 mutations previously reported in the literature were compiled, and positions of amino acids affected by nonsense and missense mutations were mapped onto the primary structure of the CYP4V2 protein.C.1219G > T in CYP4V2 that causes p.Glu407* was identified as cause of BCD in the Iranian family. The mutation segregated with disease status. Clinical presentations were similar among affected members, except that one patient presented with retinal macular hole. Twelve nonsense and 47 missense mutations in CYP4V2 were compiled. Inspection of distribution of amino acids affected by the mutations suggested non-random distribution and clustering of affected amino acids in nine regions of the protein, including regions that contain the heme binding site, the metal binding site, and a region between these binding sites. The most C-terminus proximal nonsense mutation affected position 482.This study presents results of the genetic analysis of an Iranian BCD family. Protein regions affected by mutations within the nine mutation clusters include regions well conserved among orthologous proteins and human CYP4 proteins, some of which are associated with known functions. The findings may serve to identify reasonable candidate gene region targets for gene editing therapy approaches.
2014-08-13 | Generation and Characterization of a Murine Model of Bietti Crystalline Dystrophy
Bietti crystalline dystrophy (BCD) is a rare, autosomal recessive, progressive, degenerative eye disease caused by mutations in the CYP4V2 gene, for which no treatments are currently available. Cyp4v3 is the murine ortholog to CYP4V2, and to better understand the molecular pathogenesis of this disease we have established a Cyp4v3-null mouse line.Cyp4v3(-/-) mice were generated by homologous recombination in embryonic stem cells. Ocular morphologic characteristics were evaluated via fundus imaging, plasma lipid profiling, and histologic analysis via Oil Red O reactivity, hematoxylin and eosin staining, and transmission electron microscopy.The Cyp4v3(-/-) mouse recapitulates the characteristic features of corneoretinal crystal accumulation and systemic dyslipidemia seen in BCD. The Cyp4v3(-/-) mice behave normally and are viable and fertile when maintained under specific pathogen-free (SPF) housing conditions.Cyp4v3(-/-) mice represent a promising preclinical model that may be used to better understand the disease etiology and to evaluate pharmacotherapies for this devastating condition.
cell therapies
2024-07-25 | DISCREPANCY BETWEEN FUNDUS AUTOFLUORESCENCE ABNORMALITY AND VISUAL FIELD LOSS IN BIETTI CRYSTALLINE DYSTROPHY.
The aim of this study was to explore the potential benefits of retinal pigment epithelium replacement therapy in patients with Bietti crystalline dystrophy (BCD) by assessing the disease pathology with the distinctive relationship between fundus autofluorescence (FAF) abnormality and visual field defect. Sixteen eyes from 16 patients with BCD and 16 eyes from 16 patients with RHO-associated retinitis pigmentosa were included. Fundus autofluorescence, optical coherence tomography, and Goldmann perimetry results were retrospectively reviewed and assessed using image analyses. In patients with BCD, the FAF abnormality area was not correlated with the overall visual field defect area and median overall visual field defect area (57.5%) was smaller than FAF abnormality area (98.5%). By contrast, the ellipsoid zone width was significantly correlated with the central visual field area (r = 0.806, P < 0.001). In patients with RHO-associated retinitis pigmentosa, the FAF abnormality area and ellipsoid zone width were significantly correlated with the overall visual field defect area (r = 0.833, P < 0.001) and central visual field area (r = 0.887, P < 0.001), respectively. The FAF abnormality shown in patients with BCD involves retinal pigment epithelium degeneration without complete loss of photoreceptors or visual function. These results suggest that patients with BCD are good candidates for retinal pigment epithelium replacement therapy for preservation of residual visual function.
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Drug Discovery Landscape
4 orphan drug designations for Bietti crystalline dystrophy.
4 orphan drug designations for Bietti crystalline dystrophy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
a non-replicating recombinant adeno-associated virus vector serotype 8 delivering CYP4V2 gene | gene therapies | FDA | 2024-10-29 | — | Shanghai Vitalgen BioPharma Co., Ltd. |
recombinant adeno-associated virus serotype 2 vector encoding human cytochrome P450 family 4 subfamily V member 2 (CYP4V2) | gene therapies | FDA | 2024-04-24 | — | NGGT (Suzhou) Biotechnology Co., Ltd. |
Recombinant adeno-associated virus vector carrying human CYP4V2 gene | gene therapies | FDA | 2021-08-09 | — | Chigenovo Co., Ltd. |
recombinant adeno-associated virus vector encoding human CYP4V2 protein | gene therapies | FDA | 2018-06-21 | — | Reflection Biotechnologies Limited |
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