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Genes Jun 2024Inherited retinal diseases (IRDs) represent a frequent cause of blindness in children and adults. As a consequence of the phenotype and genotype heterogeneity of the...
Inherited retinal diseases (IRDs) represent a frequent cause of blindness in children and adults. As a consequence of the phenotype and genotype heterogeneity of the disease, it is difficult to have a specific diagnosis without molecular testing. To date, over 340 genes and loci have been associated with IRDs. We present the molecular finding of 191 individuals with IRD, analyzed by targeted next-generation sequencing (NGS). For 67 of them, we performed a family segregation study, considering a total of 126 relatives. A total of 359 variants were identified, 44 of which were novel. Genetic diagnostic yield was 41%. However, after stratifying the patients according to their clinical suspicion, diagnostic yield was higher for well-characterized diseases such as Stargardt disease (STGD), at 65%, and for congenital stationary night blindness 2 (CSNB2), at 64%. Diagnostic yield was higher in the patient group where family segregation analysis was possible (68%) and it was higher in younger (55%) than in older patients (33%). The results of this analysis demonstrated that targeted NGS is an effective method for establishing a molecular genetic diagnosis of IRDs. Furthermore, this study underlines the importance of segregation studies to understand the role of genetic variants with unknow pathogenic role.
Topics: Humans; High-Throughput Nucleotide Sequencing; Male; Female; Retinal Dystrophies; Adult; Stargardt Disease; Pedigree; Child; Middle Aged; Night Blindness; Eye Diseases, Hereditary; Adolescent; Mutation; Macular Degeneration; Myopia; Child, Preschool; Phenotype; Young Adult; Aged; Genetic Diseases, X-Linked
PubMed: 38927702
DOI: 10.3390/genes15060766 -
Genes Jun 2024Gene therapy holds promise as a transformative approach in the treatment landscape of age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic... (Review)
Review
Gene therapy holds promise as a transformative approach in the treatment landscape of age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic macular edema (DME), aiming to address the challenges of frequent intravitreal anti-vascular endothelial growth factor (VEGF) injections. This manuscript reviews ongoing gene therapy clinical trials for these disorders, including ABBV-RGX-314, ixoberogene soroparvovec (ixo-vec), and 4D-150. ABBV-RGX-314 utilizes an adeno-associated virus (AAV) vector to deliver a transgene encoding a ranibizumab-like anti-VEGF antibody fragment, demonstrating promising results in Phase 1/2a and ongoing Phase 2b/3 trials. Ixo-vec employs an AAV2.7m8 capsid for intravitreal delivery of a transgene expressing aflibercept, showing encouraging outcomes in Phase 1 and ongoing Phase 2 trials. 4D-150 utilizes an evolved vector to express both aflibercept and a VEGF-C inhibitory RNAi, exhibiting positive interim results in Phase 1/2 studies. Other therapies reviewed include EXG102-031, FT-003, KH631, OLX10212, JNJ-1887, 4D-175, and OCU410. These therapies offer potential advantages of reduced treatment frequency and enhanced safety profiles, representing a paradigm shift in management towards durable and efficacious cellular-based biofactories. These advancements in gene therapy hold promise for improving outcomes in AMD and addressing the complex challenges of DME and DR, providing new avenues for the treatment of diabetic eye diseases.
Topics: Humans; Diabetic Retinopathy; Genetic Therapy; Macular Degeneration; Genetic Vectors; Dependovirus; Vascular Endothelial Growth Factor A; Animals
PubMed: 38927656
DOI: 10.3390/genes15060720 -
Biomolecules Jun 2024The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further... (Review)
Review
The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further processed before they are sent to the brain to be interpreted as images. The retina is unique in that it is continuously exposed to light and has the highest metabolic rate and demand for energy amongst all the tissues in the body. Consequently, the retina is very susceptible to oxidative stress. VDAC, a pore in the outer membrane of mitochondria, shuttles metabolites between mitochondria and the cytosol and normally protects cells from oxidative damage, but when a cell's integrity is greatly compromised it initiates cell death. There are three isoforms of VDAC, and existing evidence indicates that all three are expressed in the retina. However, their precise localization and function in each cell type is unknown. It appears that most retinal cells express substantial amounts of VDAC2 and VDAC3, presumably to protect them from oxidative stress. Photoreceptors express VDAC2, HK2, and PKM2-key proteins in the Warburg pathway that also protect these cells. Consistent with its role in initiating cell death, VDAC is overexpressed in the retinal degenerative diseases retinitis pigmentosa, age related macular degeneration (AMD), and glaucoma. Treatment with antioxidants or inhibiting VDAC oligomerization reduced its expression and improved cell survival. Thus, VDAC may be a promising therapeutic candidate for the treatment of these diseases.
Topics: Humans; Voltage-Dependent Anion Channels; Retina; Animals; Oxidative Stress; Retinal Diseases; Mitochondria; Retinitis Pigmentosa
PubMed: 38927058
DOI: 10.3390/biom14060654 -
Scientific Reports Jun 2024To compare the efficacy and safety of the proposed aflibercept biosimilar SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration,... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
To compare the efficacy and safety of the proposed aflibercept biosimilar SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration, this randomized, double-masked, parallel-group, multicenter study was conducted in 14 countries from 13 August 2020 to 8 September 2022. Patients with neovascular age-related macular degeneration. With subfoveal, juxtafoveal, or extrafoveal choroidal neovascularization were aged 50 years or older. Intravitreal injection of SCD411 or aflibercept (2.0 mg) were administered every 4 weeks for the first three injections and every 8 weeks until week 48. The primary efficacy endpoint was the change in best-corrected visual acuity from baseline to week 8 with an adjusted equivalence margin of ± 3.0 letters. Patients were randomly assigned to receive either SCD411 (n = 288) or reference aflibercept (n = 288). A total of 566 participants (98.3%) completed week 8 of the study. The least-squares mean difference of change in best-corrected visual acuity from baseline to week 8 (SCD411-aflibercept) was - 0.4 letters (90% confidence interval = - 1.6 to 0.9). The incidence of ocular (69 of 287 [24.0%] vs. 71 of 286 [24.8%]) and serious ocular (5 of 287 [1.7%] vs. 3 of 286 [1.0%]) treatment-emergent adverse effects were similar between the SCD411 and aflibercept groups. Immunogenicity analysis revealed a low incidence of neutralizing antibody formation in both groups. In conclusion, SCD411 has equivalent efficacy compared with reference aflibercept in patients with neovascular age-related macular degeneration and has a comparable safety profile. The results support the potential use of SCD411 for the treatment of neovascular age-related macular degeneration.
Topics: Humans; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Male; Female; Aged; Visual Acuity; Intravitreal Injections; Treatment Outcome; Macular Degeneration; Middle Aged; Double-Blind Method; Aged, 80 and over; Choroidal Neovascularization; Biosimilar Pharmaceuticals; Angiogenesis Inhibitors
PubMed: 38926553
DOI: 10.1038/s41598-024-65815-6 -
Scientific Reports Jun 2024This study aims to assess the association between nicotine replacement therapy (NRT), varenicline, and untreated smoking with the risk of developing eye disorders. We...
This study aims to assess the association between nicotine replacement therapy (NRT), varenicline, and untreated smoking with the risk of developing eye disorders. We employed a new-user design to investigate the association between NRT use and the incidence of eye disorders by the Taiwan National Health Insurance program. This study included 8416 smokers who received NRT and 8416 smokers who did not receive NRT (control group) matched using propensity scores between 2007 and 2018. After adjustment for relevant factors, a multivariable Cox regression analysis revealed that compared with untreated smokers, NRT use was associated with a significantly reduced risk of macular degeneration (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.13-0.87, P = 0.024). When stratified by dose, short-term NRT use (8-28 defined daily doses) was associated with significantly lower risk of glaucoma (HR: 0.35; 95% CI: 0.16-0.80, P = 0.012) and a trend toward reduced risk of cataract (HR: 0.60; 95% CI: 0.36-1.01, P = 0.053) compared to no treatment. However, these associations were not observed with long-term NRT use. The results of this real-world observational study indicate that NRT use, particularly short-term use, was associated with a lower risk of certain eye disorders compared to no treatment for smoking cessation. Long-term NRT use did not demonstrate the same benefits. Thus, short-term NRT may be a beneficial treatment strategy for reducing the risk of eye disorders in smokers attempting to quit. However, further evidence is required to verify these findings and determine the optimal duration of NRT use.
Topics: Humans; Male; Female; Smoking Cessation; Glaucoma; Middle Aged; Macular Degeneration; Retrospective Studies; Cataract; Taiwan; Aged; Adult; Smoking; Tobacco Use Cessation Devices; Incidence; Varenicline
PubMed: 38926484
DOI: 10.1038/s41598-024-65813-8 -
Ceska a Slovenska Oftalmologie :... 2024Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare disease characterized by accumulation of yellowish deposits in the macula. Rarely, it may be complicated...
Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare disease characterized by accumulation of yellowish deposits in the macula. Rarely, it may be complicated by choroidal neovascularization (CNV). Cases with CNV may be confused with occult CNV in age-related macular degeneration. In our case, we will present the visual and anatomical results of a patient with AOVF-related CNV, in which we administered 3 doses of intravitreal ranibizumab (IVR). A 59-year-old female patient, who attended our clinic with the complaint of decreased vision in both eyes, was diagnosed with AOVF-related CNV in both eyes and was treated with 3 doses of IVR for 3 months. Despite the improvement in visual and anatomical functions 1 month after the first dose, vision decreased, and anatomical functions regressed to the pre-injection state in continued injections. IVR therapy is not an appropriate treatment option in the treatment of AOVF-associated CNV.
Topics: Humans; Ranibizumab; Female; Vitelliform Macular Dystrophy; Middle Aged; Intravitreal Injections; Angiogenesis Inhibitors; Choroidal Neovascularization; Antibodies, Monoclonal, Humanized
PubMed: 38925903
DOI: 10.31348/2024/21 -
Ceska a Slovenska Oftalmologie :... 2024This article presents an overview of treatment regimens of drugs containing antivascular endothelial growth factor for the treatment of neovascular form of age-related... (Review)
Review
This article presents an overview of treatment regimens of drugs containing antivascular endothelial growth factor for the treatment of neovascular form of age-related macular degeneration. Currently, drugs containing antivascular endothelial growth factor are the only effective treatment for this chronic and progressive disease. The treatment regimens for this disease in the last two decades have seen a shift from a simple endeavor to stabilize the disease to achieving maximum improvement of visual acuity and its maintenance, with improvement of the patient's quality of life and a minimal treatment burden on patients and their families. Other goals of the alternative dosing regimens that have replaced the original fixed regimens were greater individualization of the dosing regimen, better patient cooperation, saving financial costs and reducing the burden on application centers. Age-related macular degeneration, whether dry form or wet form, represents a serious health and socioeconomic problem, as the disease is one of the most common causes of severe and irreversible central visual acuity disorders up to the degree of practical blindness of one or both eyes in people over 50 years of age in developed industrialized countries. The most important issue is to ensure early diagnosis of this disease, followed by prompt and continuous treatment with an individualized proactive treatment regimen, with the aim of stabilizing and improving anatomical and functional results.
Topics: Humans; Angiogenesis Inhibitors; Macular Degeneration; Vascular Endothelial Growth Factor A; Bevacizumab
PubMed: 38925899
DOI: 10.31348/2024/25 -
Ceska a Slovenska Oftalmologie :... 2024The aim of this study was to evaluate the outcomes of Ozurdex® (DEX) implant in patients with diabetic macular edema (DME) in real-world clinical practice, and to...
OBJECTIVE
The aim of this study was to evaluate the outcomes of Ozurdex® (DEX) implant in patients with diabetic macular edema (DME) in real-world clinical practice, and to determine the correlation between known OCT biomarkers and the effect of treatment.
MATERIAL AND METHODS
This retrospective study included 42 eyes of 33 patients (16 women, 17 men) treated with DEX at the Department of Ophthalmology, Faculty of Medicine and Dentistry of Palacký University and University Hospital Olomouc for DME indication between 2020 and 2023. Follow-up examinations were conducted at 1, 3, and 6 months after the first DEX application. The main assessed parameters were: best-corrected visual acuity (BCVA), intraocular pressure (IOP), central retinal thickness (CRT), OCT biomarkers. The results were subsequently statistically evaluated.
RESULTS
At the first follow-up after DEX application, there was an average decrease in CRT of 186 ±146µm and a gain of 3 ±7 letters. Positive morphological and functional responses were observed in 39 eyes (92.9%) and 23 eyes (54.8%) respectively. The disorganization of retinal inner layers (DRIL) biomarker was initially present in 41 eyes (97.6%), with reduction or disappearance observed in 13 eyes (31%) post-application. Eyes with ellipsoid zone disruption (EZ disruption) had an average initial BCVA of 49.6 letters, compared to 57.8 letters in the group without this biomarker. The mean gain in BCVA was +8.7 letters in treatment-naive eyes and +2.1 letters in previously treated eyes. Chronic DME was less frequent in treatment-naive (n = 1, 14.3%) compared to previously treated eyes (n = 28, 84.8%). All these results were statistically significant (p < 0.05). An increase in IOP post-DEX application occurred in 9 patients (21.4%).
CONCLUSION
Our results confirm DEX as a safe and effective treatment option for DME. Treatment-naive patients achieved better functional outcomes. We confirmed ellipsoid zone disruption (EZ disruption) as a negative biomarker. Additionally, we demonstrated the capacity of DEX to reduce disorganization of the retinal inner layers (DRIL).
Topics: Humans; Macular Edema; Male; Female; Diabetic Retinopathy; Dexamethasone; Retrospective Studies; Middle Aged; Aged; Intravitreal Injections; Drug Implants; Visual Acuity; Glucocorticoids; Tomography, Optical Coherence
PubMed: 38925895
DOI: 10.31348/2024/29 -
Translational Vision Science &... Jun 2024This study investigated the distribution of fundus tessellation density (FTD) in a Chinese pediatric population and its potential in reflecting early myopic maculopathy...
PURPOSE
This study investigated the distribution of fundus tessellation density (FTD) in a Chinese pediatric population and its potential in reflecting early myopic maculopathy (tessellated fundus).
METHODS
Participants were enrolled from kindergartens, primary schools, and middle schools, with cluster sampling in Shanghai, China. A series of ophthalmic examinations was conducted. Based on fundus photograph, FTD was quantitatively assessed using an artificial intelligence algorithm, and tessellated fundus was diagnosed by well-trained ophthalmologists.
RESULTS
A total of 14,234 participants aged four to 18 years were included, with 7421 boys (52.1%). Tessellated fundus was observed in 2200 (15.5%) participants. The median of FTD was 0.86% (range 0.0-42.1%). FTD increased with age and axial length. In the logistics regression, larger FTD was independently associated with tessellated fundus (P < 0.001). The area under curves of receiver operating characteristic curve for categorizing tessellated fundus using FTD was 0.774, and the cutoff point of FTD was 2.22%.
CONCLUSIONS
The density of fundus tessellation was consistent with the severity of myopia. FTD could help diagnose the early stage of myopic maculopathy, tessellated fundus, providing a new pattern for myopia screening and detection of early myopic fundus changes.
TRANSLATIONAL RELEVANCE
Quantification of fundus tessellation with artificial intelligence could help detect early myopic maculopathy.
Topics: Humans; Male; Adolescent; Child; Female; Fundus Oculi; Child, Preschool; China; ROC Curve; Myopia, Degenerative; Macular Degeneration; Artificial Intelligence; Photography
PubMed: 38922627
DOI: 10.1167/tvst.13.6.22 -
Biological Procedures Online Jun 2024Age-related macular degeneration (AMD) is a leading cause of blindness, affecting millions worldwide. Its complex pathogenesis involves a variety of risk factors,...
INTRODUCTION
Age-related macular degeneration (AMD) is a leading cause of blindness, affecting millions worldwide. Its complex pathogenesis involves a variety of risk factors, including lipid metabolism and inflammation. This study aims to elucidate the causal relationships between biomarkers related to these processes and AMD, leveraging Mendelian randomization (MR) and cross-sectional analysis from the National Health and Nutrition Examination Survey (NHANES).
METHOD
We conducted a two-phase study, initially using MR to explore the causality between 35 biomarkers and various AMD subtypes, followed by observational analysis with NHANES data to validate these findings.
RESULTS
MR analysis identified a protective role of TG and a risk factor role of HDL-C and CRP in AMD development. NHANES data corroborated these findings, highlighting a nuanced relationship between these biomarkers and AMD. Notably, lipid metabolism-related biomarkers showed stronger associations with early AMD, whereas CRP's significance was pronounced in late AMD.
CONCLUSION
This comprehensive analysis, combining MR with NHANES data, reinforces the importance of lipid metabolism and inflammation in AMD's etiology. Future research should further investigate these biomarkers' mechanisms and their potential as therapeutic targets for AMD prevention and treatment.
PubMed: 38918699
DOI: 10.1186/s12575-024-00248-z