Search Results (93)

Age-related macular degeneration (AMD) is a progressive retinal disorder and a leading cause of irreversible blindness among elderly individuals, impacting millions of people globally. This review synthesizes the current understanding of the cellular and molecular signaling mechanisms driving AMD, with a focus on the distinct pathophysiological features of dry and wet AMD subtypes. Key mechanisms include oxidative stress, inflammation, lipid metabolism dysregulation, and immune dysregulation, all of which converge on the retinal pigment epithelium (RPE) as a central player in disease initiation and progression. In dry AMD, oxidative damage, mitochondrial dysfunction, and lipofuscin accumulation impair RPE function, contributing to drusen formation and geographic atrophy. In wet AMD, vascular endothelial growth factor-mediated angiogenesis, coupled with inflammation and endothelial metabolic reprogramming, drives choroidal neovascularization. This article integrates findings from multiomics approaches and highlights the potential of artificial intelligence in elucidating AMD pathogenesis and advancing personalized therapies. Future research directions emphasize targeting these molecular pathways to develop innovative treatments, offering hope for improved management of this debilitating condition. Full article

Recently, marketing authorizations were granted by the Federal Drug Administration (FDA) for pegcetacoplan and avacincaptad pegol, which inhibit C3 and C5 complement components, respectively. These two drugs were demonstrated to slow down the growth of atrophic areas in the retina. These authorizations represent a huge breakthrough for patients suffering from geographic atrophy (GA), the late stage of the dry form of Age-related Macular Degeneration (AMD). Until then, no treatment was available to treat this blinding disease. However, these two new compounds inhibiting the complement system are still not available for patients outside of the United States, and they are not devoid of drawbacks, including a poor effect on vision improvement, an increased risk of occurrence of the neovascular form of AMD and the burden of patients receiving recurrent intravitreal injections. Thus, the important medical need posed by GA remains incompletely answered, and new therapeutic options with alternative modes of action are still required. Oxidative stress and inflammation are two major potential targets to limit the progression of atrophic retinal lesions. Dimethyl fumarate, dimethyl itaconate and other activators of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) display antioxidants and immunomodulatory properties that have shown evidence of efficacy in in vitro and in vivo models of dry AMD. Tecfidera^®, whose active principle is dimethyl fumarate, is already commercialized for the treatment of autoimmune diseases such as multiple sclerosis and psoriasis. The aim of this review is to present the rationale and the design of the clinical trial we initiated to test the effectiveness and safety of repurposing Tecfidera^®, which could represent a new therapeutic alternative in patients with the dry form of AMD. Full article

Geographic atrophy (GA) is a progressive retinal disease associated with late-stage age-related macular degeneration (AMD), a significant cause of visual impairment in senior adults. GA lesion segmentation is important for disease monitoring in clinical trials and routine ophthalmic practice; however, its manual delineation is time-consuming, laborious, and subject to inter-grader variability. The use of artificial intelligence (AI) is rapidly expanding within the medical field and could potentially improve accuracy while reducing the workload by facilitating this task. This systematic review evaluates the performance of AI algorithms for GA segmentation and highlights their key limitations from the literature. Five databases and two registries were searched from inception until 23 March 2024, following the PRISMA methodology. Twenty-four studies met the prespecified eligibility criteria, and fifteen were included in this meta-analysis. The pooled Dice similarity coefficient (DSC) was 0.91 (95% CI 0.88–0.95), signifying a high agreement between the reference standards and model predictions. The risk of bias and reporting quality were assessed using QUADAS-2 and CLAIM tools. This review provides a comprehensive evaluation of AI applications for GA segmentation and identifies areas for improvement. The findings support the potential of AI to enhance clinical workflows and highlight pathways for improved future models that could bridge the gap between research settings and real-world clinical practice. Full article

Stem cell therapy has emerged as a promising approach for treating various retinal diseases, particularly degenerative retinal diseases such as geographic atrophy in age-related macular degeneration (AMD), retinitis pigmentosa (RP), and Stargardt disease. A wide variety of imaging techniques have been employed in both preclinical and clinical settings to assess the efficacy and safety of stem cell therapy for retinal diseases. These techniques can be classified into two categories: methods for imaging stem cells and those for the overall morphology and function of the retina. The techniques employed for stem cell imaging include optical imaging, magnetic resonance imaging (MRI), and radionuclide imaging. Additional imaging techniques include fundus photography, fluorescein angiography, and fundus autofluorescence. Each technique has its own advantages and disadvantages, and thus, the use of multimodal imaging can help to overcome the shortcomings and achieve a more comprehensive evaluation of stem cell therapy in retinal disease. This review discusses the characteristics of the main techniques and cell-labeling techniques applied in stem cell therapy, with a particular focus on the applications of multimodal imaging. Furthermore, this review discusses the challenges and prospects of multimodal imaging in stem cell therapy for retinal disease. Full article

Background/Objectives: The objective of this study was to analyze the relationships between diet and geographic atrophy (GA) progression, both area-based and proximity-based, for dietary pattern, components, and micronutrients. Methods: In the Age-Related Eye Diseases Study (AREDS) and AREDS2, an Alternative Mediterranean Diet Index (aMedi), its nine components, and individual micronutrient intakes were calculated. Mixed-model regression was performed for square root GA area, GA foveal proximity, and acuity. Results: The study populations comprised 657 (AREDS) and 1179 eyes (AREDS2). For area-based progression, a higher aMedi was associated with slower progression in AREDS2 and (in analyses excluding MUFA:SFA) AREDS. A higher intake was associated with slower progression for seven components (including vegetables and fruit at Bonferroni) and four components (including fruit and less red meat at Bonferroni), and seven and 15 nutrients, in AREDS1/2, respectively. For proximity-based progression, a higher aMedi was associated with slower progression in AREDS. A higher intake was associated with slower progression for three components (including vegetables at Bonferroni) and two components, and 10 and 8 nutrients, in AREDS1/2, respectively. With increasing oral supplementation, associations between proximity-based progression and aMedi/components/nutrients were weaker. In AREDS2 eyes with non-central GA, higher aMedi was associated with a slower acuity decline. Conclusions: A Mediterranean-type diet is associated with slower GA area-based progression and slower progression to the fovea, accompanied by a slower decline in acuity. The most important components and micronutrients for incidence, area-based progression, and foveal progression overlap only partially. For the latter two, they include vegetables, fruit, and less red meat. These findings suggest the benefits of targeted nutritional and supplementation strategies. Full article

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. Due to an aging population, its prevalence is expected to increase, making novel and optimized therapy options imperative. However, both late-stage forms of the disease, neovascular AMD (nAMD) and geographic atrophy (GA), exhibit considerable variability in disease progression and treatment response, complicating the evaluation of therapeutic efficacy and making it difficult to design clinical trials that are both inclusive and statistically robust. Traditional trial designs frequently rely on generalized endpoints that may not fully capture the nuanced benefits of treatment, particularly in diseases like GA, where functional improvements can be gradual or subtle. Artificial intelligence (AI) has the potential to address these issues by identifying novel, condition-specific biomarkers or endpoints, enabling precise patient stratification and improving recruitment strategies. By providing an overview of the advances and application of AI-based optical coherence tomography analysis in the context of AMD clinical trials, this review highlights the transformative potential of AI in optimizing clinical trial outcomes for patients with nAMD or GA secondary to AMD. Full article

Background: Telemedicine represents a growing opportunity to improve access to personalized care for patients with rare diseases, addressing the challenges of specialized healthcare that is often limited by geographical barriers. The aim of this narrative review is to explore how telemedicine can facilitate tailored nutritional interventions for rare diseases, focusing on inherited metabolic diseases, rare neurological disorders, such as leukodystrophies, and neuromuscular disorders, including spinal muscular atrophies. Methods: This narrative review is based on a systematic search of the published literature over the past 20 years, and includes systematic reviews, meta-analysis, retrospective studies, and original articles. References were selected through searches in databases such as PubMed and Scopus, applying predefined inclusion and exclusion criteria. Among the inclusion criteria, studies focusing on pediatric patients aged 0 to 18 years, diagnosed with rare neurological diseases or inherited metabolic disorders, and using telemedicine in addition to in-person visits at their reference center were considered. Among the exclusion criteria, studies involving patients with other pathologies or comorbidities and those involving patients older than 18 years were excluded. Results: A total of 66 documents were analyzed to examine the challenges and specific needs of patients with rare diseases, highlighting the advantages and limitations of telemedicine compared to traditional care. The use of telemedicine has revolutionized the medical approach, facilitating integrated care by multidisciplinary teams. Conclusions: Telemedicine still faces several technical, organizational, and security challenges, as well as disparities in access across different geographical areas. Emerging technologies such as artificial intelligence could positively transform the monitoring and management of patients with rare diseases. Telemedicine has great potential ahead of it in the development of increasingly personalized and effective care, in fact, emerging technologies are important to provide remote care, especially for patients with rare diseases. Full article

Background/Objectives: Age-related macular degeneration (AMD) is a global cause of vision loss, with limited therapeutic options highlighting the need for effective biomarkers. This study aimed to characterize plasma DNA methyltransferase expression (DNMT1, DNMT3A, and DNMT3B) in AMD patients and explore divergent expression patterns across different stages of AMD. Methods: Thirty-eight AMD patients were prospectively enrolled and stratified by disease severity: eAMD, iAMD, nAMD, and aAMD. Comprehensive ophthalmological assessments were performed, including best-corrected visual acuity, digital color fundus photographs, and Spectral Domain Optical Coherence Tomography. Peripheral blood samples were collected for RNA extraction and qRT-PCR to access epigenetic effectors’ transcriptional expression, namely DNMT1, DNMT3A, and DNMT3B genes. The collected data were analyzed using IBM SPSS 29. Results: DNMT1 expression was significantly downregulated in late AMD (−0.186 ± 0.341) compared to early/intermediate AMD (0.026 ± 0.246). Within late AMD, aAMD exhibited a marked downregulation of DNMT1 (−0.375 ± 0.047) compared to nAMD (0.129 ± 0.392). DNMT3A and DNMT3B showed similar divergent expression patterns, correlating with disease stage. Conclusions: This study identified stage-specific transcriptional differences in DNMT expression, emphasizing its potential as a biomarker for AMD progression and a target for future research into personalized therapeutic strategies. Full article

Objective: Lesions characterized as complete retinal pigment epithelium and outer retinal atrophy (cRORA) are linked to the progression of intermediate age-related macular degeneration (iAMD). However, the extent of functional impairment of such precursor lesions remains uncertain. Methods: In this cross-sectional study, 4 participants (mean age ± standard deviation: 71.5 ± 2.1 years) underwent extensive multimodal imaging and psychophysical testing of cRORA lesions secondary to iAMD. Lesion-specific functional testing was performed using patient individualized testing grids with clinical conventional available (Stimulus size: 0.43°, ~125 µm) and experimental adaptive optics scanning light ophthalmoscope (AOSLO, stimulus size 0.07°, ~20 µm) based microperimetry (MP). One cRORA lesion site and one in-eye control region were tested per patient, respectively. Results: AOSLO imaging revealed an overall decrease in photoreceptor reflectivity, areas of hyporeflectivity over drusen, interspersed with hyperreflective foci, and disrupted photoreceptor mosaic in regions of cRORA. Localized retinal sensitivity assessment with clinical conventional MP yielded an average loss of −14.0 ± 3.3 dB at cRORA lesions compared to the in-eye control regions. In contrast, localized visual impairment assessed by high-resolution AOSLO-MP with smaller test stimuli (20 µm) revealed a sensitivity loss of −15.1 ± 5.1 dB at cRORA lesions (p < 0.01). Notably, also the area surrounding cRORA lesions can be impacted. Conclusions: We demonstrated that cRORA lesions are associated with severe localized functional impairment. cRORA precursor lesions may thus be considered as a surrogate outcome measure in future interventional iAMD trials. Full article

Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly, significantly diminishing quality of life. Currently, there is no available treatment to reverse retinal degeneration and neuronal loss, prompting a focus on interventions that slow the progression of intermediate AMD and geographic atrophy. Berries are rich in bioactive compounds, including flavonoids, anthocyanins, carotenoids, and resveratrol, known for their antioxidant, anti-inflammatory, and anti-angiogenic properties. Preclinical studies suggest that extracts from various berries, such as aronia, honeysuckle, black currant, goji, and bilberry, can improve retinal health by reducing oxidative stress and inflammation. Although clinical trials are limited, emerging evidence indicates that dietary intake of these compounds may enhance visual function and slow the progression of AMD. This review summarizes findings from both animal studies and clinical trials to identify specific berries that have been validated to prevent or delay AMD progression, as well as those with potential therapeutic value. Furthermore, we examine the key phytochemicals present in these berries, their mechanisms of action on macular degeneration, and their distinct properties for therapeutic application. A deeper understanding of these characteristics could enable the rational appliance of berries, especially wolfberry, and berry-derived components, such as carotenoids and anthocyanins, to optimize better therapeutic outcomes in AMD management. Full article

Background and Objectives: Age-related macular degeneration (AMD) is the leading cause of low vision and legal blindness in adults in developed countries. Wet AMD can be successfully treated using vascular endothelial growth factor (VEGF) inhibitors; however, dry AMD currently has no effective treatment. The purpose of this study is to analyze the efficacy of intraocular injection of plasma rich in growth factors (PRGF) in an AMD mouse model induced by intraperitoneal administration of sodium iodate. Materials and Methods: Intravitreal application of PRGF (experimental group) and saline (control group) was performed immediately after intraperitoneal injection of sodium iodate. Retinographies were performed at 2 and 7 days after treatment administration. The eyes were retrieved for histological and immunohistological analysis. Statistical analysis was performed to compare the outcomes between the study groups. Results: In comparison to saline solution, PRGF significantly decreased the depigmentation of the RPE, showing a more reddened retina. PRGF intravitreal treatment significantly reduced the glial fibrillary acidic protein (GFAP) stained processes, suggesting a significant reduction in the risk of scar formation. Moreover, the myofibroblast invasion into the RPE cell layer was significantly reduced in the PRGF-treated group of mice. There was a tendency for better preservation of the photoreceptors in the PRGF group. Conclusions: Within the limitations of this study, intravitreal injection of PRGF provided significant protection against the degeneration of the photoreceptors and the RPE induced by the systemic administration of NaIO₃. Full article

The smaller-incision new-generation implantable miniature telescope (SING IMT) represents an advancement over the previous model, WA-IMT, serving as a unilateral prosthetic device for patients with late-stage age-related macular degeneration (AMD). Purpose: This study aims to report changes in multifocal electroretinography (mfERG) 6 months post–SING IMT implantation. Methods: In this case series, we prospectively evaluated a cohort of phakic patients with late-stage AMD who underwent SING IMT implantation at the Ophthalmology Unit, University of Bari Aldo Moro, Italy. We assessed best-corrected distance visual acuity (BCDVA) and best-corrected near visual acuity (BCNVA) preoperatively and at 6 months postoperatively. Additionally, mfERGs were conducted using Retimax (CSO, Florence, Italy). Results: All four treated patients showed an increase in both BCDVA and BCNVA at the 6-month follow-up. Additionally, all eyes demonstrated increased P1 density at this time point, with the greatest augmentation observed at the central fixation point, gradually diminishing across the five concentric rings. While all patients displayed a general increase in P1 amplitude, the third patient exhibited a slight decrease in the foveal region. Conclusions: In this case series with four cases, the new generation implantable miniature telescope, SING IMT, demonstrates promising results in enhancing mfERG parameters in patients with late-stage AMD. Six months post-surgery, we observed an augmentation in both P1 density and amplitude, predominantly at the fixation point and gradually tapering in the surrounding concentric rings. Full article

Docosahexaenoate is a cytoprotective ω-3 polyunsaturated lipid that is abundant in the retina and is essential for its function. Due to its six unsaturated double bonds, docosahexaenoate is highly susceptible to oxidation and the formation of products with photosensitizing properties. This study aimed to test on cultured human retinal pigment epithelial cells ARPE-19 the (photo)cytotoxic potential of partly oxidized docosahexaenoate and its effect on the formation of lipofuscin from phagocytosed photoreceptor outer segments (POSs). The results demonstrate that the cytoprotective effects of docosahexaenoate do not counteract the deleterious effects of its oxidation products, leading to the concentration-dependent loss of cell metabolic activity, which is exacerbated by concomitant exposure to visible light. Partly oxidized docosahexaenoate does not cause permeability of the cell plasma membrane but does cause apoptosis. While vitamin E can provide partial protection from the (photo)toxicity of partly oxidized docosahexaenoate, zeaxanthin undergoes rapid photodegradation and can exacerbate the (photo)toxicity. Feeding cells with POSs enriched in partly oxidized docosahexaenoate results in a greater accumulation of intracellular fluorescent lipofuscin than in cells fed POSs without the addition. In conclusion, partly oxidized docosahexaenoate increases the accumulation of lipofuscin-like intracellular deposits, is cytotoxic, and its toxicity increases during exposure to light. These effects may contribute to the increased progression of geographic atrophy observed after long-term supplementation with docosahexaenoate in age-related macular degeneration patients. Full article

There are currently no effective treatments for retinal pigment epithelial (RPE) cell loss in atrophic AMD (aAMD). However, our research on Prominin-1 (Prom1), a known structural protein in photoreceptors (PRs), has revealed its distinct role in RPE and offers promising insights. While pathogenic Prom1 mutations have been linked to macular diseases with RPE atrophy, the broader physiological impact of dysfunctional Prom1 in RPE loss is unclear. We have shown that Prom1 plays a crucial role in regulating autophagy and cellular homeostasis in human and mouse RPE (mRPE) cells in vitro. Nevertheless, a comprehensive understanding of its in vivo expression and function in mRPE remains to be elucidated. To characterize Prom1 expression in RPE in situ, we used RNAscope assays and immunogold electron microscopy (EM). Our use of chromogenic and fluorescent RNAscope assays in albino and C57BL/6J mouse retinal sections has revealed Prom1 mRNA expression in perinuclear regions in mRPE in situ. Immunogold EM imaging showed Prom1 expression in RPE cytoplasm and mitochondria. To confirm Prom1 expression in RPE, we interrogated human RPE single-cell RNA-sequencing datasets using an online resource, Spectacle. Our analysis showed Prom1 expression in human RPE. To investigate Prom1’s function in RPE homeostasis, we performed RPE-specific Prom1 knockdown (KD) using subretinal injections of AAV2/1.CMV.saCas9.U6.Prom1gRNA in male and female mice. Our data show that RPE-specific Prom1-KD in vivo resulted in abnormal RPE morphology, subretinal fluid accumulation, and secondary PR loss. These changes were associated with patchy RPE cell death and reduced a-wave amplitude, indicating retinal degeneration. Our findings underscore the central role of Prom1 in cell-autonomous mRPE homeostasis. The implications of Prom1-KD causing aAMD-like RPE defects and retinal degeneration in a mouse model are significant and could lead to novel treatments for aAMD. Full article

Background: Monoclonal antibodies (mAbs) have demonstrated substantial potential in the treatment of intraocular diseases. This review aimed to comprehensively evaluate the applications, efficacy, and safety of mAbs in the management of intraocular conditions. Methods: A comprehensive literature search was conducted in major medical databases through July 2024. Relevant studies on monoclonal antibodies for intraocular diseases were included. Two independent researchers screened the literature, extracted data, and assessed study quality. Cost-effectiveness analyses were also reviewed. Results: Anti-vascular endothelial growth factor (VEGF) antibodies, such as bevacizumab, ranibizumab, and aflibercept, showed significant therapeutic effects in neovascular age-related macular degeneration (NVAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). Tumor necrosis factor-alpha (TNF-α) inhibitors demonstrated promising results in treating noninfectious uveitis. Complement system-targeted therapies like pegcetacoplan offered new options for geographic atrophy. Anti-VEGF antibodies showed potential in managing retinopathy of prematurity (ROP). However, challenges persist, including high costs, potential drug resistance, and limited long-term safety data in certain scenarios. Conclusions: Monoclonal antibodies are vital for treating intraocular diseases, but continuous innovation and rigorous clinical evaluation are essential. Future research should focus on developing novel delivery systems, exploring combination therapies, conducting long-term follow-up studies, and investigating personalized treatment strategies to provide safer, more effective, and cost-effective therapeutic solutions. Full article