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Experimental Eye Research Jun 2024Over the past twenty years, ocular gene therapy has primarily focused on addressing diseases linked to various genetic factors. The eye is an ideal candidate for gene... (Review)
Review
Over the past twenty years, ocular gene therapy has primarily focused on addressing diseases linked to various genetic factors. The eye is an ideal candidate for gene therapy due to its unique characteristics, such as easy accessibility and the ability to target both corneal and retinal conditions, including retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), age-related macular degeneration (AMD), and Stargardt disease. Currently, literature documents 33 clinical trials in this field, with the most promising results emerging from trials focused on LCA. These successes have catalyzed further research into other ocular conditions such as glaucoma, AMD, RP, and choroideremia. The effectiveness of gene therapy relies on the efficient delivery of genetic material to specific cells, ensuring sustained and optimal gene expression over time. Viral vectors have been widely used for this purpose, although concerns about potential risks such as immune reactions and genetic mutations have led to the development of non-viral vector systems. Preliminary laboratory research and clinical investigations have shown a connection between vector dosage and the intensity of immune response and inflammation in the eye. The method of administration significantly influences these reactions, with subretinal delivery resulting in a milder humoral response compared to the intravitreal route. This review discusses various ophthalmic diseases, including both corneal and retinal conditions, and their underlying mechanisms, highlighting recent advances and applications in ocular gene therapies.
PubMed: 38942133
DOI: 10.1016/j.exer.2024.109983 -
JAMA Ophthalmology Jun 2024
PubMed: 38935351
DOI: 10.1001/jamaophthalmol.2024.2209 -
Investigative Ophthalmology & Visual... Jun 2024The purpose of this study was to develop and validate prediction model for myopic macular degeneration (MMD) progression in patients with high myopia.
PURPOSE
The purpose of this study was to develop and validate prediction model for myopic macular degeneration (MMD) progression in patients with high myopia.
METHODS
The Zhongshan High Myopia Cohort for model development included 660 patients aged 7 to 70 years with a bilateral sphere of ≤-6.00 diopters (D). Two hundred twelve participants with an axial length (AL) ≥25.5 mm from the Chinese Ocular Imaging Project were used for external validation. Thirty-four clinical variables, including demographics, lifestyle, myopia history, and swept source optical coherence tomography data, were analyzed. Sequential forward selection was used for predictor selection, and binary classification models were created using five machine learning algorithms to forecast the risk of MMD progression over 10 years.
RESULTS
Over a median follow-up of 10.9 years, 133 patients (20.2%) showed MMD progression in the development cohort. Among them, 69 (51.9%) developed newly-onset MMD, 11 (8.3%) developed patchy atrophy from diffuse atrophy, 54 (40.6%) showed an enlargement of lesions, and 9 (6.8%) developed plus signs. Top six predictors for MMD progression included thinner subfoveal choroidal thickness, longer AL, worse best-corrected visual acuity, older age, female gender, and shallower anterior chamber depth. The eXtreme Gradient Boosting algorithm yielded the best discriminative performance (area under the receiver operating characteristic curve [AUROC] = 0.87 ± 0.02) with good calibration in the training cohort. In a less myopic external validation group (median -5.38 D), 48 patients (22.6%) developed MMD progression over 4 years, with the model's AUROC validated at 0.80 ± 0.008.
CONCLUSIONS
Machine learning model effectively predicts MMD progression a decade ahead using clinical and imaging indicators. This tool shows promise for identifying "at-risk" high myopes for timely intervention and vision protection.
Topics: Humans; Male; Female; Middle Aged; Adult; Machine Learning; Tomography, Optical Coherence; Aged; Disease Progression; Algorithms; Adolescent; Child; Young Adult; Macular Degeneration; Myopia, Degenerative; Follow-Up Studies; Risk Factors; Forecasting; Risk Assessment; Visual Acuity
PubMed: 38935031
DOI: 10.1167/iovs.65.6.40 -
Investigative Ophthalmology & Visual... Jun 2024To assess the association of age-related macular degeneration (AMD) progression and statins, connected with AMD genetic risk, and if there is an interplay between...
PURPOSE
To assess the association of age-related macular degeneration (AMD) progression and statins, connected with AMD genetic risk, and if there is an interplay between statins and genetics.
METHODS
In this analysis, 682 subjects made two visits (6.5-year follow-up) of the Coimbra Eye Study. Subjects who started taking statins at any time point between the two visits were considered. Progressors were defined as not having AMD at baseline and having any AMD at follow-up. Genetic risk scores (GRSs) were calculated individually with 52 independent variants associated with AMD. Time to progression was estimated using unadjusted Kaplan-Meier curves. An extended Cox model was used for the association between statins and GRS with the risk for AMD progression. Multiplicative and additive interactions were assessed.
RESULTS
Median survival time was 7.50 years for subjects not taking statins and 7.62 for subjects taking statins (P < 0.001). Statin intake reduced the risk for progression to AMD in 48%, adjusting for age, sex, body mass index, smoking, and diabetes (model 1) and GRS (model 2). The combined effects of not taking statins and having high GRS increased the progression risk fourfold compared to taking statins and having low GRS (hazard ratio [HR] = 4.25; 95% confidence interval [CI], 1.62-11.16; P = 0.003). For subjects not taking statins, an increased risk of progression was found for those subjects with high GRS compared to subjects with low GRS (HR = 1.80; 95% CI, 1.13-2.85; P = 0.013). No statistically significant multiplicative or additive interactions were found.
CONCLUSIONS
Statins seem to be protective against AMD progression, and genetics may play a role in treatment response.
Topics: Humans; Male; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Aged; Disease Progression; Macular Degeneration; Follow-Up Studies; Risk Factors; Middle Aged; Aged, 80 and over; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 38935028
DOI: 10.1167/iovs.65.6.38 -
Journal of Clinical Medicine Jun 2024The aim of this study is to report short-term outcomes after the shortening of the treatment interval to 4 weeks with a treat-and-extend (TAE) regimen (Si4w) of...
The aim of this study is to report short-term outcomes after the shortening of the treatment interval to 4 weeks with a treat-and-extend (TAE) regimen (Si4w) of aflibercept in patients with refractory neovascular age-related macular degeneration (nAMD). This retrospective study included 34 patients given aflibercept with a TAE regimen of a minimum of a 4-week interval when they had a limited response to bimonthly aflibercept. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) were compared before and after Si4w. The resolution of subretinal and intraretinal fluid before and after Si4w was also examined. The risk factors associated with persistent fluid were analyzed. The average treatment duration until initiation of Si4w was 57.82 ± 28.59 months, with an average of 23.64 ± 12.40 injections administered. The BCVA was not significantly improved after Si4w. The CMT decreased significantly from 427.91 ± 125.74 μm to 336.38 ± 121.67 μm at the third visit ( < 0.001). Eighteen eyes (52.9%) showed complete resolution, and twenty-three eyes (67.6%) experienced complete resolution at least once during the three visits. The duration of fluid before Si4w was significantly associated with complete resolution ( = 0.011). Si4w of aflibercept showed satisfactory anatomical outcomes with complete resolution of fluid in patients with a limited response to bimonthly aflibercept injections, and should be considered as a useful treatment option.
PubMed: 38930032
DOI: 10.3390/jcm13123503 -
Journal of Clinical Medicine Jun 2024: This study aimed to assess the effectiveness of bi-monthly brolucimumab treatment in patients with neovascular age-related macular degeneration (nAMD) refractory to...
: This study aimed to assess the effectiveness of bi-monthly brolucimumab treatment in patients with neovascular age-related macular degeneration (nAMD) refractory to monthly aflibercept treatment. : A retrospective chart review included 32 eyes of patients with refractory nAMD who switched from monthly intravitreal aflibercept treatment to bi-monthly intravitreal brolucizumab treatment. This study evaluated changes in visual acuity (VA), intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED), and central macular thickness (CMT), at specific times as follows: baseline before switching (T0), 2 months after switching (T1), 4 months after switching (T2), and 6 months after switching (T3). : The mean best-corrected visual acuity (BCVA) did not significantly change across all time points (0.52 ± 0.12, 0.48 ± 0.27, 0.48 ± 0.28, and 0.50 ± 0.27 logarithms of the minimum angle of resolution in T0, T1, T2, and T3, respectively). CMT significantly decreased after additional brolucizumab injections compared to the baseline (218.2 ± 48.6 and 207.9 ± 49.8 μm, respectively; = 0.001). The PED height also significantly decreased from 251.0 ± 165.4 to 154.4 ± 115.65 μm ( < 0.001), with complete resolution in nine patients (28%). The mean subfoveal choroidal thickness (SFCT) before brolucizumab treatment was 262.8 ± 79.7 μm, which decreased to 233.0 ± 71.2 μm ( = 0.001) after the first injection. The final SFCT also significantly decreased after additional brolucizumab injections compared to the baseline SFCT ( = 0.012). : Bi-monthly brolucizumab treatment proves effective for patients refractory to monthly fixed aflibercept, resulting in positive anatomical changes without significant deterioration in visual acuity. This approach provides a promising prognosis while reducing the treatment burden on refractory patients.
PubMed: 38929964
DOI: 10.3390/jcm13123434 -
Journal of Personalized Medicine Jun 2024The majority of neurodegenerative eye disorders occur with aging and significantly impair quality of life. Age-related macular degeneration (AMD) is the third most... (Review)
Review
The majority of neurodegenerative eye disorders occur with aging and significantly impair quality of life. Age-related macular degeneration (AMD) is the third most common cause of visual impairment and blindness worldwide. One of the most important elements in the pathophysiology of neurodegenerative eye disease is certainly oxidative stress, with neuroinflammation and ocular ischemia which may also be significant factors. Antioxidants, either by food or oral supplementation, may be able to mitigate the deleterious effects of reactive oxygen species that build as a result of oxidative stress, ischemia, and inflammation. Over the past few decades, a number of research works examining the potential adjuvant impact of antioxidants in AMD have been published. In fact, there is not only more and more interest in already known molecules but also in new molecules that can help clinicians in the management of this complex multifactorial disease, such as astaxanthin and melatonin. However, while some studies showed encouraging outcomes, others were conflicting. In addition, more and more attention is also being paid to nutrition, considered a pivotal key point, especially to prevent AMD. For this reason, the purpose of this review is to analyze the main antioxidant molecules currently used as oral supplements for AMD treatment, as well as the role of diet and food intake in this ocular disease, to better understand how all these factors can improve the clinical management of AMD patients.
PubMed: 38929874
DOI: 10.3390/jpm14060653 -
Life (Basel, Switzerland) May 2024The escalating prevalence of retinal diseases-notably, age-related macular degeneration and hereditary retinal disorders-poses an intimidating challenge to ophthalmic... (Review)
Review
The escalating prevalence of retinal diseases-notably, age-related macular degeneration and hereditary retinal disorders-poses an intimidating challenge to ophthalmic medicine, often culminating in irreversible vision loss. Current treatments are limited and often fail to address the underlying loss of retinal cells. This paper explores the potential of stem-cell-based therapies as a promising avenue for retinal regeneration. We review the latest advancements in stem cell technology, focusing on embryonic stem cells (ESCs), pluripotent stem cells (PSCs), and mesenchymal stem cells (MSCs), and their ability to differentiate into retinal cell types. We discuss the challenges in stem cell transplantation, such as immune rejection, integration into the host retina, and functional recovery. Previous and ongoing clinical trials are examined to highlight the therapeutic efficacy and safety of these novel treatments. Additionally, we address the ethical considerations and regulatory frameworks governing stem cell research. Our analysis suggests that while stem-cell-based therapies offer a groundbreaking approach to treating retinal diseases, further research is needed to ensure long-term safety and to optimize therapeutic outcomes. This review summarizes the clinical evidence of stem cell therapy and current limitations in utilizing stem cells for retinal degeneration, such as age-related macular degeneration, retinitis pigmentosa, and Stargardt's disease.
PubMed: 38929652
DOI: 10.3390/life14060668 -
Medicina (Kaunas, Lithuania) Jun 2024: Age-related macular degeneration (AMD) is a complex and multifactorial condition that can lead to permanent vision loss once it progresses to the neovascular exudative... (Review)
Review
: Age-related macular degeneration (AMD) is a complex and multifactorial condition that can lead to permanent vision loss once it progresses to the neovascular exudative stage. This review aims to summarize the use of deep learning in neovascular AMD. : Pubmed search. : Deep learning has demonstrated effectiveness in analyzing structural OCT images in patients with neovascular AMD. This review outlines the role of deep learning in identifying and measuring biomarkers linked to an elevated risk of transitioning to the neovascular form of AMD. Additionally, deep learning techniques can quantify critical OCT features associated with neovascular AMD, which have prognostic implications for these patients. Incorporating deep learning into the assessment of neovascular AMD eyes holds promise for enhancing clinical management strategies for affected individuals. : Several studies have demonstrated effectiveness of deep learning in assessing neovascular AMD patients and this has a promising role in the assessment of these patients.
Topics: Humans; Deep Learning; Macular Degeneration; Tomography, Optical Coherence
PubMed: 38929607
DOI: 10.3390/medicina60060990 -
Medicina (Kaunas, Lithuania) Jun 2024The complement cascade is a vital system in the human body's defense against pathogens. During the natural aging process, it has been observed that this system is... (Review)
Review
The complement cascade is a vital system in the human body's defense against pathogens. During the natural aging process, it has been observed that this system is imperative for ensuring the integrity and homeostasis of the retina. While this system is critical for proper host defense and retinal integrity, it has also been found that dysregulation of this system may lead to certain retinal pathologies, including geographic atrophy and diabetic retinopathy. Targeting components of the complement system for retinal diseases has been an area of interest, and in vivo, ex vivo, and clinical trials have been conducted in this area. Following clinical trials, medications targeting the complement system for retinal disease have also become available. In this manuscript, we discuss the pathophysiology of complement dysfunction in the retina and specific pathologies. We then describe the results of cellular, animal, and clinical studies targeting the complement system for retinal diseases. We then provide an overview of complement inhibitors that have been approved by the Food and Drug Administration (FDA) for geographic atrophy. The complement system in retinal diseases continues to serve as an emerging therapeutic target, and further research in this field will provide additional insights into the mechanisms and considerations for treatment of retinal pathologies.
Topics: Humans; Retinal Diseases; Complement System Proteins; Animals; Complement Inactivating Agents; Diabetic Retinopathy; Retina
PubMed: 38929562
DOI: 10.3390/medicina60060945