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Gene Jun 2024Retinitis pigmentosa 1-like 1 (RP1L1) is a component of photoreceptor cilia. Pathogenic variants in RP1L1 cause photoreceptor diseases, suggesting that RP1L1 plays an... (Review)
Review
Retinitis pigmentosa 1-like 1 (RP1L1) is a component of photoreceptor cilia. Pathogenic variants in RP1L1 cause photoreceptor diseases, suggesting that RP1L1 plays an important role in photoreceptor biology, although its exact function is unknown. To date, RP1L1 variants have been associated with occult macular dystrophy (cone degeneration) and retinitis pigmentosa (rod degeneration). Here, we summarize the reported RP1L1-associated photoreceptor pathogenic mutations. The association between RP1L1 and other diseases (mainly several tumors) is also summarized and RP1L1 is included in a wider range of diseases. Finally, it is necessary to further explore the influence mechanism of RP1L1 gene on the health of photoreceptors and how it participates in the occurrence and development of tumors.
Topics: Humans; Eye Proteins; Macular Degeneration; Neoplasms; Retinitis Pigmentosa
PubMed: 38485037
DOI: 10.1016/j.gene.2024.148367 -
International Journal of Molecular... Jun 2024Age-related macular degeneration (AMD) is a chronic disease, which often develops in older people, but this is not the rule. AMD pathogenesis changes include the... (Review)
Review
Age-related macular degeneration (AMD) is a chronic disease, which often develops in older people, but this is not the rule. AMD pathogenesis changes include the anatomical and functional complex. As a result of damage, it occurs, in the retina and macula, among other areas. These changes may lead to partial or total loss of vision. This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form. A coexistence of both forms is possible. AMD etiology is not fully understood. Extensive genetic studies have shown that this disease is multifactorial and that genetic determinants, along with environmental and metabolic-functional factors, are important risk factors. This article reviews the impact of heavy metals, macro- and microelements, and genetic factors on the development of AMD. We present the current state of knowledge about the influence of environmental factors and genetic determinants on the progression of AMD in the confrontation with our own research conducted on the Polish population from Kuyavian-Pomeranian and Lubusz Regions. Our research is concentrated on showing how polluted environments of large agglomerations affects the development of AMD. In addition to confirming heavy metal accumulation, the growth of risk of acute phase factors and polymorphism in the genetic material in AMD development, it will also help in the detection of new markers of this disease. This will lead to a better understanding of the etiology of AMD and will help to establish prevention and early treatment.
Topics: Humans; Macular Degeneration; Risk Factors; Genetic Predisposition to Disease; Metals, Heavy; Environmental Exposure; Immunogenetics
PubMed: 38928273
DOI: 10.3390/ijms25126567 -
Asia-Pacific Journal of Ophthalmology... 2024Decades of studies on age-related macular degeneration (AMD), cardiovascular disease and stroke have not found consistent associations between AMD and systemic vascular... (Review)
Review
Decades of studies on age-related macular degeneration (AMD), cardiovascular disease and stroke have not found consistent associations between AMD and systemic vascular disease. This study suggests that there is in fact no general relationship, but instead a strong, specific association between only the subretinal drusenoid deposit (SDD) phenotype of AMD on retinal imaging and certain co-existent vascular diseases that are high risk for compromised cardiac output or internal carotid artery stenosis. Future screening initiatives for these high -risk vascular diseases (HRVDs) with fast, inexpensive retinal imaging could make a significant contribution to public health and save lives. Likewise, screening patients with known HRVDs for unrecognized AMD of the SDD form could enable needed treatment and save vision.
Topics: Humans; Retinal Drusen; Cardiovascular Diseases; Tomography, Optical Coherence; Macular Degeneration; Vascular Diseases; Fluorescein Angiography
PubMed: 38244930
DOI: 10.1016/j.apjo.2024.100036 -
JAMA Network Open Jan 2024Light pollution's impact on human health is increasingly recognized, but its link to exudative age-related macular degeneration (EAMD) remains unclear.
IMPORTANCE
Light pollution's impact on human health is increasingly recognized, but its link to exudative age-related macular degeneration (EAMD) remains unclear.
OBJECTIVE
To investigate the association between exposure to outdoor artificial light at night (OALAN) and the risk of incident EAMD.
DESIGN, SETTING, AND PARTICIPANTS
In this nationwide population-based case-control study, all individuals 50 years or older with newly diagnosed EAMD between January 1, 2010, and December 31, 2011, were identified with reference to the Korean National Health Insurance Service registration program database for rare and intractable diseases. Birth year- and sex-matched controls (with no EAMD diagnosis until 2020) were selected at a 1:30 ratio. Data were acquired from May 1 to December 31, 2021, and analyzed from June 1 to November 30, 2022.
EXPOSURES
Mean levels of OALAN at participants' residential addresses during 2008 and 2009 were estimated using time-varying satellite data for a composite view of persistent nighttime illumination at an approximate scale of 1 km2.
MAIN OUTCOMES AND MEASURES
The hazard ratios (HRs) and 95% CIs of the association between residential OALAN and risk of incident EAMD were determined based on maximum likelihood estimation after adjusting for sociodemographic characteristics, comorbidities, and area-level risk factors (ie, nighttime traffic noise and particulate matter of aerodynamic diameter ≤10 μm in each participant's administrative district of residence).
RESULTS
A total of 126 418 participants were included in the analysis (mean [SD] age, 66.0 [7.9] years; 78 244 men [61.9%]). Of these, 4078 were patients with newly diagnosed EAMD and 122 340 were EAMD-free matched controls. In fully adjusted models, an IQR (55.8 nW/cm2/sr) increase in OALAN level was associated with an HR of 1.67 (95% CI, 1.56-1.78) for incident EAMD. The exposure-response curve demonstrated a nonlinear, concave upward slope becoming more pronounced at higher levels of light exposure (ie, at approximately 110 nW/cm2/sr). In a subgroup analysis, an IQR increase in OALAN was associated with increased risk of incident EAMD in urban areas (HR, 1.46 [95% CI, 1.33-1.61]) but not in rural areas (HR, 1.01 [95% CI, 0.84-1.22]).
CONCLUSIONS AND RELEVANCE
In this nationwide population-based case-control study, higher levels of residential OALAN were associated with an increased risk of incident EAMD. Future studies with more detailed information on exposure, individual adaptive behaviors, and potential mediators are warranted.
Topics: Aged; Humans; Male; Case-Control Studies; Databases, Factual; Macular Degeneration; Republic of Korea; Lighting
PubMed: 38227312
DOI: 10.1001/jamanetworkopen.2023.51650 -
Translational Vision Science &... Sep 2023The purpose of this study was to determine the impact of prophylactic ranibizumab (PR) injections given every 3 months in eyes with intermediate nonexudative... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The purpose of this study was to determine the impact of prophylactic ranibizumab (PR) injections given every 3 months in eyes with intermediate nonexudative age-related macular degeneration (AMD) on drusen volume, macular layer thicknesses, and progression of geographic atrophy (GA) area over 24 months in the PREVENT trial.
METHODS
This post hoc analysis of the prospective PREVENT trial compared eyes with intermediate AMD randomized to PR versus sham injections to determine rates of conversion to neovascular AMD over 24 months. Drusen area and volume, macular thickness and volume, and retinal layer thicknesses were measured on spectral-domain optical coherence tomography images and analyzed. Masked grading of GA area and subretinal drusenoid deposits (SDDs) using fundus autofluorescence images was performed.
RESULTS
There were no statistical differences in drusen area and volumes between groups, and similar reductions in central subfield thickness, mean cube thickness, cube volume, and retinal sublayer thickness from baseline to 24 months (P = 0.018 to < 0.001), with no statistical differences between groups in any of these anatomic parameters. These findings were not impacted by the presence or absence of SDD. Among the 9 eyes with GA in this study, mean GA growth rate from baseline to 24 months was 1.34 +/- 0.79 mm2/year after PR and 1.95 +/- 1.73 mm2/year in sham-treated eyes (P = 0.49), and similarly showed no statistical difference with square root transformation (P = 0.61).
CONCLUSIONS
Prophylactic ranibizumab given every 3 months did not appear to affect drusen volume, macular thinning, or GA progression in eyes with intermediate AMD.
TRANSLATIONAL RELEVANCE
This work investigates the impact of PR on progressive retinal degeneration in a clinical trial.
Topics: Humans; Child, Preschool; Ranibizumab; Angiogenesis Inhibitors; Prospective Studies; Vascular Endothelial Growth Factor A; Visual Acuity; Wet Macular Degeneration; Retina; Geographic Atrophy
PubMed: 37656449
DOI: 10.1167/tvst.12.9.1 -
Journal of Perinatal Medicine Jul 2023The mammalian retina lacks regenerative potency to replace damaged or degenerated cells. Therefore, traumatic or genetic insults that lead to the degeneration of retinal...
The mammalian retina lacks regenerative potency to replace damaged or degenerated cells. Therefore, traumatic or genetic insults that lead to the degeneration of retinal neurons or retinal pigment epithelium (RPE) cells alter visual perception and ultimately can lead to blindness. The advent of human stem cells and their exploitation for vision restoration approaches has boosted the field. Traditionally, animal models - mostly rodents - have been generated and used to mimic certain monogenetic hereditary diseases. Of note, some models were extremely useful to develop specific gene therapies, for example for Retinitis Pigmentosa, Leber congenital amaurosis and achromatopsia. However, complex multifactorial diseases are not well recapitulated in rodent models such as age-related macular degeneration (AMD) as rodents lack a macula. Here, human stem cells are extremely valuable to advance the development of therapies. Particularly, cell replacement therapy is of enormous importance to treat retinal degenerative diseases. Moreover, different retinal degenerative disorders require the transplantation of unique cell types. The most advanced one is to substitute the RPE cells, which stabilize the light-sensitive photoreceptors. Some diseases require also the transplantation of photoreceptors. Depending on the disease pattern, both approaches can also be combined. Within this article, I briefly feature the underlying principle of cell replacement therapies, demonstrate some successes and discuss certain shortcomings of these approaches for clinical application.
Topics: Animals; Humans; Retinal Degeneration; Retinal Pigment Epithelium; Retina; Macular Degeneration; Stem Cells; Mammals
PubMed: 36474335
DOI: 10.1515/jpm-2022-0510 -
Pharmacological Research Nov 2023Ocular neovascular disease (OND), characterized by the aberrant formation of immature blood vessels, is the leading cause of vision impairment and blindness. It is... (Review)
Review
Ocular neovascular disease (OND), characterized by the aberrant formation of immature blood vessels, is the leading cause of vision impairment and blindness. It is important to find effective ways to diagnose and treat these diseases. Circular RNA (circRNA) is a group of endogenous non-coding RNA that play a crucial role in regulating different biological processes. Due to their close association with ocular disease and angiogenesis, circRNAs have become a hotspot in OND research. In this review, we intensively investigate the possibility of using circRNAs in the management of ONDs. In general, angiogenesis is divided into five phases. On the basis of these five steps, we describe the potential of using circRNAs by introducing how they regulate angiogenesis. Subsequently, the interactions between circRNAs and ONDs, including pterygium, corneal neovascularization, age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, are analyzed in detail. We also introduce the potential use of circRNAs as OND diagnostic biomarkers. Finally, we summarize the prospects of using circRNAs as a potential strategy in OND management. The gaps in recent research are also pointed out with the purpose of promoting the introduction of circRNAs into clinical applications.
Topics: Humans; Infant, Newborn; RNA, Circular; Eye; Retinal Diseases; Macular Degeneration; Diabetic Retinopathy
PubMed: 37797661
DOI: 10.1016/j.phrs.2023.106946 -
Preclinical investigations on broccoli-derived sulforaphane for the treatment of ophthalmic disease.Drug Discovery Today Sep 2023Vision loss causes a significant burden on individuals and communities on a financial, emotional and social level. Common causes include age-related macular degeneration... (Review)
Review
Vision loss causes a significant burden on individuals and communities on a financial, emotional and social level. Common causes include age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and retinitis pigmentosa (RP; also known as 'rod-cone dystrophy'). As the population continues to grow and age globally, an increasing number of people will experience vision loss. Hence, there is an urgent need to develop therapies that can curb early pathological events. The broccoli-derived compound, sulforaphane (SFN), is reported to have multiple health benefits and modes of action. In this review, we outline the preclinical findings on SFN in ocular diseases and discuss the future clinical testing of this compound.
Topics: Humans; Brassica; Retinitis Pigmentosa; Macular Degeneration; Isothiocyanates; Vision Disorders
PubMed: 37467881
DOI: 10.1016/j.drudis.2023.103718 -
Cells Nov 2023Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate...
Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60-94 years) using a standardized published protocol. Significant findings were then validated in an independent set of well-characterized donor eyes ( = 85). There was limited overlap between DEGs and DSGs, suggesting distinct mechanisms at play in AMD pathophysiology. A greater number of previously reported AMD loci overlapped with DSGs compared to DEGs between disease states, and no DEG overlap with previously reported loci was found in the macular retina between disease states. Additionally, we explored allele-specific expression (ASE) in coding regions of previously reported AMD risk loci, uncovering a significant imbalance in rs2230199 and rs1061170 in the macular RPE/choroid for normal eyes and intermediate AMD (iAMD), and for rs1061147 in the macular RPE/choroid for normal eyes and iAMD, and separately neovascular AMD (NEO). Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. , validated between the iAMD vs. normal comparison, and , , , , , , and , validated between the NEO vs. normal comparison, revealed an intricate regulatory network with transcription factors and miRNAs identifying potential upstream and downstream regulators. Findings regarding the complement genes and suggest that coding variants at these loci may influence AMD development via an imbalance of gene expression in a tissue-specific manner. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes, potential splice variation, and allelic imbalance), which may open new avenues for AMD diagnostics and therapies specific to iAMD and NEO.
Topics: Humans; Alleles; Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A; Visual Acuity; Wet Macular Degeneration; Gene Expression; Cytoskeletal Proteins; Phosphate-Binding Proteins; Carrier Proteins; Nerve Tissue Proteins; GTP-Binding Proteins; Serine-Type D-Ala-D-Ala Carboxypeptidase
PubMed: 38067097
DOI: 10.3390/cells12232668 -
Clinical and Translational Medicine Aug 2023Age-related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The...
BACKGROUND
Age-related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to CNV pathogenesis. Previous gene editing research indicated that disrupting these genes in retinal pigment epithelial cells could have a preventive effect on CNV progression. However, no studies have yet been conducted using gene editing to disrupt VEGF signalling after CNV induction for therapeutic validation, which is critical to the clinical application of wet AMD gene editing therapies.
METHOD
Here, we employed the single-adeno-associated virus-mediated Nme Cas9 to disrupt key molecules in VEGF signalling, Hif1α, Vegfa and Vegfr2 after inducing CNV and estimated their therapeutic effects.
RESULTS
We found that Nme Cas9 made efficient editing in target genes up to 71.8% post 11 days in vivo. And only Nme Cas9-Vegfa treatment during the early stage of CNV development reduced the CNV lesion area by 49.5%, compared to the negative control, while Nme Cas9-Hif1α or Nme Cas9-Vegfr2 treatment did not show therapeutic effect. Besides, no off-target effects were observed in Nme Cas9-mediated gene editing in vivo.
CONCLUSIONS
This study provides proof-of-concept possibility of employing Nme Cas9 for potential anti-angiogenesis therapy in wet AMD.
Topics: Aged; Humans; Vascular Endothelial Growth Factor A; CRISPR-Cas Systems; Macular Degeneration; Immunotherapy; Gene Editing
PubMed: 37598400
DOI: 10.1002/ctm2.1383