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Investigative Ophthalmology & Visual... Nov 2023To identify associations of common, low-frequency, and rare variants with advanced age-related macular degeneration (AMD) using whole genome sequencing (WGS).
PURPOSE
To identify associations of common, low-frequency, and rare variants with advanced age-related macular degeneration (AMD) using whole genome sequencing (WGS).
METHODS
WGS data were obtained for 2123 advanced AMD patients (participants of clinical trials for advanced AMD) and 2704 controls (participants of clinical trials for asthma [N = 2518] and Alzheimer's disease [N = 186]), and joint genotype calling was performed, followed by quality control of the dataset. Single variant association analyses were performed for all identified common, low-frequency, and rare variants. Gene-based tests were executed for rare and low-frequency variants using SKAT-O and three groups of variants based on putative impact information: (1) all variants, (2) modifier impact variants, and (3) high- and moderate-impact variants. To ascertain independence of the identified associations from previously reported AMD and asthma loci, conditional analyses were performed.
RESULTS
Previously identified AMD variants at the CFH, ARMS2/HTRA1, APOE, and C3 loci were associated with AMD at a genome-wide significance level. We identified new single variant associations for common variants near the PARK7 gene and in the long non-coding RNA AC103876.1, and for a rare variant near the TENM3 gene. In addition, gene-based association analyses identified a burden of modifier variants in eight intergenic and gene-spanning regions and of high- and moderate-impact variants in the C3, CFHR5, SLC16A8, and CFI genes.
CONCLUSIONS
We describe the largest WGS study in AMD to date. We confirmed previously identified associations and identified several novel associations that are worth exploring in further follow-up studies.
Topics: Humans; Genotype; Macular Degeneration; Genetic Testing; Whole Genome Sequencing; Asthma; Polymorphism, Single Nucleotide; Complement Factor H; Genetic Predisposition to Disease; Membrane Proteins; Nerve Tissue Proteins
PubMed: 37975850
DOI: 10.1167/iovs.64.14.24 -
Indian Journal of Ophthalmology Jul 2024
Topics: Humans; Tomography, Optical Coherence; Macular Degeneration; Fluorescein Angiography; Fundus Oculi; Macula Lutea; Male; Visual Acuity; Diagnosis, Differential; Female
PubMed: 38905458
DOI: 10.4103/IJO.IJO_3168_23 -
Acta Biomaterialia Aug 2023Choroidal neovascularization (CNV) is the main cause of vision loss in patients with wet age-related macular degeneration (AMD). Currently, treatment of these conditions...
Choroidal neovascularization (CNV) is the main cause of vision loss in patients with wet age-related macular degeneration (AMD). Currently, treatment of these conditions requires repeated intravitreal injections, which may lead to complications such as infection and hemorrhage. So, we have developed a noninvasive method for treating CNV with nanoparticles, namely, Angiopoietin1-anti CD105-PLGA nanoparticles (AAP NPs), which targets the CNV to enhance drug accumulation at the site. These nanoparticles, with PLGA as a carrier, can slowly release encapsulated Angiopoietin 1 (Ang 1) and target the choroidal neovascularization marker CD105 to enhance drug accumulation, increases vascular endothelial cadherin (VE-cadherin) expression between vascular endothelial cells, effectively reduce neovascularization leakage and inhibit Angiopoietin 2(Ang 2) secretion by endothelial cells. In a rat model of laser-induced CNV, intravenous injection of AAP NPs exerted a good therapeutic effect in reducing CNV leakage and area. In short, these synthetic AAP NPs provide an effective alternative treatment for AMD and meet the urgent need for noninvasive treatment in neovascular ophthalmopathy. STATEMENT OF SIGNIFICANCE: This work describes the synthesis, injection-mediated delivery, in vitro and in vivo efficacy of targeted nanoparticles with encapsulated Ang1; via these nanoparticles, the drug can be targeted to choroidal neovascularization lesions for continuous treatment. The release of Ang1 can effectively reduce neovascularization leakage, maintain vascular stability, and inhibit Ang2 secretion and inflammation. This study provides a new approach for the treatment of wet age-related macular degeneration.
Topics: Rats; Animals; Endothelial Cells; Choroidal Neovascularization; Wet Macular Degeneration; Inflammation; Nanoparticles; Disease Models, Animal
PubMed: 37196903
DOI: 10.1016/j.actbio.2023.05.021 -
The Canadian Journal of Urology Dec 2023Interstitial cystitis (IC) is a chronic disease with urinary tract symptoms and pain. Pentosan polysulfate (PPS) is the only U.S. Food and Drug Administration approved... (Review)
Review
INTRODUCTION
Interstitial cystitis (IC) is a chronic disease with urinary tract symptoms and pain. Pentosan polysulfate (PPS) is the only U.S. Food and Drug Administration approved oral medication for the treatment of IC pain and symptoms. Recently, articles described a pigmentary maculopathy in IC patients on long term PPS therapy. Currently, there is no definitive study directly linking PPS as the cause of the pigmentary maculopathy. The aim of this review is to evaluate if PPS is the causative factor of the pigmentary maculopathy or if PPS use is only associated with the pigmentary maculopathy.
MATERIALS AND METHODS
A comprehensive review of peer reviewed journals using the search terms IC, maculopathy, mast cells, immune inflammatory components, Tamm-Horsfall protein, cations and tight junctions was performed to examine the pathophysiology and role of chronic inflammation in IC and known retinal maculopathies.
RESULTS
Chronic inflammatory cells have been reported in age-related macular degeneration choroid blood vessels and in bladder submucosal and detrusor layers in IC patients. Studies in IC and maculopathies demonstrate a significant milieu of activated chronic inflammatory and immunologic responses that cause a more "leaky" epithelium and a subsequent cascade of inflammatory events that results in the pathological changes seen in these two conditions.
CONCLUSIONS
After an analysis of the literature describing a pigmentary maculopathy in IC patients on long term PPS, a causal relationship does not appear to be present. An alternate model is proposed postulating that the causative factor for the pigmentary maculopathy is the underlying inflammatory state associated with IC and not PPS use.
Topics: Humans; Pentosan Sulfuric Polyester; Macular Degeneration; Cystitis, Interstitial; Pain; Inflammation
PubMed: 38104330
DOI: No ID Found -
Nutrients Jul 2023Age-related macular degeneration (AMD) is a largely incurable disease and an emerging problem in aging societies. It occurs in two forms, dry and wet (exudative,... (Review)
Review
Age-related macular degeneration (AMD) is a largely incurable disease and an emerging problem in aging societies. It occurs in two forms, dry and wet (exudative, neovascular), which may cause legal blindness and sight loss. Currently, there is not any effective treatment for dry AMD. Meanwhile, repeated intravitreal injections with antibodies effective against vascular endothelial growth factor A (VEGFA) slow down wet AMD progression but are not free from complications. (-)-Epigallocatechin-3-gallate (EGCG) is an active compound of green tea, which exerts many beneficial effects in the retinal pigment epithelium and the neural retina. It has been reported to downregulate the gene by suppressing its activators. The inhibition of mitogen-activated protein kinases 1 and 3 (MAPK1 and MAPK3) may lie behind the antiangiogenic action of EGCG mediated by VEGFA. EGCG exerts protective effects against UV-induced damage to retinal cells and improves dysfunctional autophagy. EGCG may also interact with the mechanistic target rapamycin (MTOR) and unc-51-like autophagy activating kinase (ULK1) to modulate the interplay between autophagy and apoptosis. Several other studies report beneficial effects of EGCG on the retina that may be related to wet AMD. Therefore, controlled clinical trials are needed to verify whether diet supplementation with EGCG or green tea consumption may improve the results of anti-VEGFA therapy in wet AMD.
Topics: Humans; Vascular Endothelial Growth Factor A; Tea; Retina; Macular Degeneration
PubMed: 37571296
DOI: 10.3390/nu15153358 -
Cell Reports. Medicine Oct 2023Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD...
Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is a need for the development of less invasive treatments. Here, we designed an allosteric inhibitor of end binding-3 (EB3) protein, termed EBIN, which reduces the effects of environmental stresses on endothelial cells by limiting pathological calcium signaling. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of wet AMD prevents both neovascular leakage and choroidal neovascularization. EBIN reverses the epigenetic changes induced by environmental stresses, allowing an activation of a regenerative program within metabolic-active endothelial cells comprising choroidal neovascularization (CNV) lesions. These results suggest the therapeutic potential of EBIN in preventing the degenerative processes underlying wet AMD.
Topics: Mice; Animals; Endothelial Cells; Choroidal Neovascularization; Wet Macular Degeneration
PubMed: 37794584
DOI: 10.1016/j.xcrm.2023.101223 -
Eye (London, England) Aug 2023The aim of this systematic literature review is twofold, (1) detail the impact of retinal biomarkers identifiable via optical coherence tomography (OCT) on disease... (Review)
Review
UNLABELLED
The aim of this systematic literature review is twofold, (1) detail the impact of retinal biomarkers identifiable via optical coherence tomography (OCT) on disease progression and response to treatment in neovascular age-related macular degeneration (nAMD) and (2) establish which biomarkers are currently identifiable by artificial intelligence (AI) models and the utilisation of this technology. Following the PRISMA guidelines, PubMed was searched for peer-reviewed publications dated between January 2016 and January 2022.
POPULATION
Patients diagnosed with nAMD with OCT imaging.
SETTINGS
Comparable settings to NHS hospitals.
STUDY DESIGNS
Randomised controlled trials, prospective/retrospective cohort studies and review articles. From 228 articles, 130 were full-text reviewed, 50 were removed for falling outside the scope of this review with 10 added from the author's inventory, resulting in the inclusion of 90 articles. From 9 biomarkers identified; intraretinal fluid (IRF), subretinal fluid, pigment epithelial detachment, subretinal hyperreflective material (SHRM), retinal pigmental epithelial (RPE) atrophy, drusen, outer retinal tabulation (ORT), hyperreflective foci (HF) and retinal thickness, 5 are considered pertinent to nAMD disease progression; IRF, SHRM, drusen, ORT and HF. A number of these biomarkers can be classified using current AI models. Significant retinal biomarkers pertinent to disease activity and progression in nAMD are identifiable via OCT; IRF being the most important in terms of the significant impact on visual outcome. Incorporating AI into ophthalmology practice is a promising advancement towards automated and reproducible analyses of OCT data with the ability to diagnose disease and predict future disease conversion.
SYSTEMATIC REVIEW REGISTRATION
This review has been registered with PROSPERO (registration ID: CRD42021233200).
Topics: Humans; Tomography, Optical Coherence; Artificial Intelligence; Retrospective Studies; Prospective Studies; Fluorescein Angiography; Biomarkers; Macular Degeneration; Disease Progression; Wet Macular Degeneration; Angiogenesis Inhibitors
PubMed: 36526863
DOI: 10.1038/s41433-022-02360-4 -
Journal of Controlled Release :... Nov 2023Several chronic eye diseases affect the posterior segment of the eye. Among them age-related macular degeneration can cause vision loss if left untreated and is one of... (Review)
Review
Several chronic eye diseases affect the posterior segment of the eye. Among them age-related macular degeneration can cause vision loss if left untreated and is one of the leading causes of visual impairment in the world. Most treatments are based on intravitreally injected therapeutics that inhibit the action of vascular endothelial growth factor. However, due to the need for monthly injections, this method is associated with poor patient compliance. To address this problem, numerous drug delivery systems (DDSs) have been developed. This review covers a selection of particulate systems, non-stimuli responsive hydrogels, implants, and composite systems that have been developed in the last few decades. Depending on the type of DDS, polymer material, and preparation method, different mechanical properties and drug release profiles can be achieved. Furthermore, DDS development can be optimized by implementing mathematical modeling of both drug release and pharmacokinetic aspects. Several existing mathematical models for diffusion-controlled, swelling-controlled, and erosion-controlled drug delivery from polymeric systems are summarized. Compartmental and physiologically based models for ocular drug transport and pharmacokinetics that have studied drug concentration profiles after intravitreal delivery or release from a DDS are also reviewed. The coupling of drug release models with ocular pharmacokinetic models can lead to obtaining much more efficient DDSs for the treatment of age-related macular degeneration and other diseases of the posterior segment of the eye.
Topics: Humans; Vascular Endothelial Growth Factor A; Drug Delivery Systems; Wet Macular Degeneration; Hydrogels; Polymers; Intravitreal Injections
PubMed: 37774953
DOI: 10.1016/j.jconrel.2023.09.021 -
Stem Cells Translational Medicine Apr 2024Age-related macular degeneration and retinitis pigmentosa are degenerative retinal diseases that cause severe vision loss. Early clinical trials involving... (Review)
Review
Age-related macular degeneration and retinitis pigmentosa are degenerative retinal diseases that cause severe vision loss. Early clinical trials involving transplantation of photoreceptors as treatment for these conditions are underway. In this review, we summarize recent progress in the field of photoreceptor transplantation, including some pertinent results regarding photoreceptor manufacture, photoreceptor transplantation, mechanisms of donor-host cell integration such as material transfer and photoreceptor transplant immunology. We conclude by proposing several approaches that may provide a rational basis for selecting a vision restoration strategy (eg, donor-host synapse formation vs donor-host nanotube formation) and improved transplant efficiency.
Topics: Humans; Retinal Degeneration; Retina; Macular Degeneration; Photoreceptor Cells; Cell- and Tissue-Based Therapy; Stem Cell Transplantation
PubMed: 38417110
DOI: 10.1093/stcltm/szae005 -
International Journal of Molecular... Aug 2023Neovascular age-related macular degeneration (nAMD) is the primary disastrous retinal disease that leads to blindness in the elderly population. In the early 2000s, nAMD... (Review)
Review
Neovascular age-related macular degeneration (nAMD) is the primary disastrous retinal disease that leads to blindness in the elderly population. In the early 2000s, nAMD resulted in irreversible vision loss and blindness with no available treatment options. However, there have been breakthrough advances in the drug development of anti-angiogenic biological agents over the last two decades. The primary target molecule for treating nAMD is the vascular endothelial growth factor (VEGF), and there are currently several anti-VEGF drugs such as bevacizumab, ranibizumab, and aflibercept, which have made nAMD more manageable than before, thus preventing vision loss. Nevertheless, it should be noted that these anti-VEGF drugs for nAMD treatment are not effective in more than half of the patients, and even those who initially gain visual improvements lose their vision over time, along with potential deterioration in the geography of atrophy. As a result, there have been continuous endeavors to improve anti-VEGF agents through better efficacy, fewer doses, expanded intervals, and additional targets. This review describes past and current anti-VEGF therapeutics used to treat nAMD and outlines future directions to improve the effectiveness and safety of anti-VEGF agents.
Topics: Humans; Aged; Vascular Endothelial Growth Factors; Bevacizumab; Blindness; Angiogenesis Inhibitors; Macular Degeneration
PubMed: 37629185
DOI: 10.3390/ijms241613004