Pub Date : 2023-11-01DOI: 10.1016/j.preteyeres.2022.101160
Leopold Schmetterer , Hendrik Scholl , Gerhard Garhöfer , Lucas Janeschitz-Kriegl , Federico Corvi , SriniVas R. Sadda , Felipe A. Medeiros
With the identification of novel targets, the number of interventional clinical trials in ophthalmology has increased. Visual acuity has for a long time been considered the gold standard endpoint for clinical trials, but in the recent years it became evident that other endpoints are required for many indications including geographic atrophy and inherited retinal disease. In glaucoma the currently available drugs were approved based on their IOP lowering capacity. Some recent findings do, however, indicate that at the same level of IOP reduction, not all drugs have the same effect on visual field progression. For neuroprotection trials in glaucoma, novel surrogate endpoints are required, which may either include functional or structural parameters or a combination of both. A number of potential surrogate endpoints for ophthalmology clinical trials have been identified, but their validation is complicated and requires solid scientific evidence. In this article we summarize candidates for clinical endpoints in ophthalmology with a focus on retinal disease and glaucoma. Functional and structural biomarkers, as well as quality of life measures are discussed, and their potential to serve as endpoints in pivotal trials is critically evaluated.
{"title":"Endpoints for clinical trials in ophthalmology","authors":"Leopold Schmetterer , Hendrik Scholl , Gerhard Garhöfer , Lucas Janeschitz-Kriegl , Federico Corvi , SriniVas R. Sadda , Felipe A. Medeiros","doi":"10.1016/j.preteyeres.2022.101160","DOIUrl":"10.1016/j.preteyeres.2022.101160","url":null,"abstract":"<div><p>With the identification of novel targets, the number of interventional clinical trials in ophthalmology has increased. Visual acuity has for a long time been considered the gold standard endpoint for clinical trials, but in the recent years it became evident that other endpoints are required for many indications including geographic atrophy and inherited retinal disease. In glaucoma the currently available drugs were approved based on their IOP lowering capacity. Some recent findings do, however, indicate that at the same level of IOP reduction, not all drugs have the same effect on visual field progression. For neuroprotection trials in glaucoma, novel surrogate endpoints are required, which may either include functional or structural parameters or a combination of both. A number of potential surrogate endpoints for ophthalmology clinical trials have been identified, but their validation is complicated and requires solid scientific evidence. In this article we summarize candidates for clinical endpoints in ophthalmology with a focus on retinal disease and glaucoma. Functional and structural biomarkers, as well as quality of life measures are discussed, and their potential to serve as endpoints in pivotal trials is critically evaluated.</p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1350946222001203/pdfft?md5=8e7f3f55817357e608bc5c11daea7ccc&pid=1-s2.0-S1350946222001203-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10472562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-01DOI: 10.1016/j.preteyeres.2023.101219
Pierre-Henry Gabrielle , Hemal Mehta , Daniel Barthelmes , Vincent Daien , Vuong Nguyen , Mark C. Gillies , Catherine P. Creuzot-Garcher
Randomised clinical trials (RCTs) are generally considered the gold-standard for providing scientific evidence for treatments' effectiveness and safety but their findings may not always be generalisable to the broader population treated in routine clinical practice. RCTs include highly selected patient populations that fit specific inclusion and exclusion criteria. Although they may have a lower level of certainty than RCTs on the evidence hierarchy, real-world data (RWD), such as observational studies, registries and databases, provide real-world evidence (RWE) that can complement RCTs. For example, RWE may help satisfy requirements for a new indication of an already approved drug and help us better understand long-term treatment effectiveness, safety and patterns of use in clinical practice. Many countries have set up registries, observational studies and databases containing information on patients with retinal diseases, such as diabetic macular oedema (DMO). These DMO RWD have produced significant clinical evidence in the past decade that has changed the management of DMO. RWD and medico-administrative databases are a useful resource to identify low frequency safety signals. They often have long-term follow-up with a large number of patients and minimal exclusion criteria. We will discuss improvements in healthcare information exchange technologies, such as blockchain technology and FHIR (Fast Healthcare Interoperability Resources), which will connect and extend databases already available. These registries can be linked with existing or emerging retinal imaging modalities using artificial intelligence to aid diagnosis, treatment decisions and provide prognostic information. The results of RCTs and RWE are combined to provide evidence-based guidelines.
{"title":"From randomised controlled trials to real-world data: Clinical evidence to guide management of diabetic macular oedema","authors":"Pierre-Henry Gabrielle , Hemal Mehta , Daniel Barthelmes , Vincent Daien , Vuong Nguyen , Mark C. Gillies , Catherine P. Creuzot-Garcher","doi":"10.1016/j.preteyeres.2023.101219","DOIUrl":"10.1016/j.preteyeres.2023.101219","url":null,"abstract":"<div><p>Randomised clinical trials (RCTs) are generally considered the gold-standard for providing scientific evidence for treatments' effectiveness and safety but their findings may not always be generalisable to the broader population treated in routine clinical practice. RCTs include highly selected patient populations that fit specific inclusion and exclusion criteria. Although they may have a lower level of certainty than RCTs on the evidence hierarchy, real-world data (RWD), such as observational studies, registries and databases, provide real-world evidence (RWE) that can complement RCTs. For example, RWE may help satisfy requirements for a new indication of an already approved drug and help us better understand long-term treatment effectiveness, safety and patterns of use in clinical practice. Many countries have set up registries, observational studies and databases containing information on patients with retinal diseases, such as diabetic macular oedema (DMO). These DMO RWD have produced significant clinical evidence in the past decade that has changed the management of DMO. RWD and medico-administrative databases are a useful resource to identify low frequency safety signals. They often have long-term follow-up with a large number of patients and minimal exclusion criteria. We will discuss improvements in healthcare information exchange technologies, such as blockchain technology and FHIR (Fast Healthcare Interoperability Resources), which will connect and extend databases already available. These registries can be linked with existing or emerging retinal imaging modalities using artificial intelligence to aid diagnosis, treatment decisions and provide prognostic information. The results of RCTs and RWE are combined to provide evidence-based guidelines.</p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1350946223000587/pdfft?md5=917c14928a76d6684eaa6820451c6d59&pid=1-s2.0-S1350946223000587-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66784259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-01DOI: 10.1016/j.preteyeres.2022.101161
Harminder S. Dua , Rui Freitas , Imran Mohammed , Darren S.J. Ting , Dalia G. Said
The pre-Descemet's layer/Dua's layer, also termed the Dua-Fine layer and the pre-posterior limiting lamina layer, lies anterior to the Descemet's membrane in the cornea, is 10 μm (range 6–16) thick, made predominantly of type I and some type VI collagen with abundant elastin, more than any other layer of the cornea. It has high tensile strength (bursting pressure up to 700 mm of Hg), is impervious to air and almost acellular. At the periphery it demonstrates fenestrations and ramifies to become the core of the trabecular meshwork, with implications for intraocular pressure and glaucoma. It has been demonstrated in some species of animals.
The layer has assumed considerable importance in anterior and posterior lamellar corneal transplant surgery by improving our understanding of the behaviour of corneal tissue during these procedures, improved techniques and made the surgery safer with better outcomes. It has led to the innovation of new surgical procedures namely, pre-Descemet's endothelial keratoplasty, suture management of acute hydrops, DALK-triple and Fogla's mini DALK.
The discovery and knowledge of the layer has introduced paradigm shifts in our age old concepts of Descemet's membrane detachment, acute corneal hydrops in keratoconus and Descemetoceles, with impact on management approaches. It has been shown to contribute to the pathology and clinical signs observed in corneal infections and some corneal dystrophies. Early evidence suggests that it may have a role in the pathogenesis of keratoconus in relation to its elastin content. Its contribution to corneal biomechanics and glaucoma are subjects of current investigations.
{"title":"The pre-Descemet's layer (Dua's layer, also known as the Dua-Fine layer and the pre-posterior limiting lamina layer): Discovery, characterisation, clinical and surgical applications, and the controversy","authors":"Harminder S. Dua , Rui Freitas , Imran Mohammed , Darren S.J. Ting , Dalia G. Said","doi":"10.1016/j.preteyeres.2022.101161","DOIUrl":"10.1016/j.preteyeres.2022.101161","url":null,"abstract":"<div><p>The pre-Descemet's layer/Dua's layer, also termed the Dua-Fine layer and the pre-posterior limiting lamina layer, lies anterior to the Descemet's membrane in the cornea, is 10 μm (range 6–16) thick, made predominantly of type I and some type VI collagen with abundant elastin, more than any other layer of the cornea. It has high tensile strength (bursting pressure up to 700 mm of Hg), is impervious to air and almost acellular. At the periphery it demonstrates fenestrations and ramifies to become the core of the trabecular meshwork, with implications for intraocular pressure and glaucoma. It has been demonstrated in some species of animals.</p><p>The layer has assumed considerable importance in anterior and posterior lamellar corneal transplant surgery by improving our understanding of the behaviour of corneal tissue during these procedures, improved techniques and made the surgery safer with better outcomes. It has led to the innovation of new surgical procedures namely, pre-Descemet's endothelial keratoplasty, suture management of acute hydrops, DALK-triple and Fogla's mini DALK.</p><p>The discovery and knowledge of the layer has introduced paradigm shifts in our age old concepts of Descemet's membrane detachment, acute corneal hydrops in keratoconus and Descemetoceles, with impact on management approaches. It has been shown to contribute to the pathology and clinical signs observed in corneal infections and some corneal dystrophies. Early evidence suggests that it may have a role in the pathogenesis of keratoconus in relation to its elastin content. Its contribution to corneal biomechanics and glaucoma are subjects of current investigations.</p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1350946222001215/pdfft?md5=a70dbcd5811aec9179e2fef22e02ebb3&pid=1-s2.0-S1350946222001215-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9080188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-01DOI: 10.1016/j.preteyeres.2022.101158
Birgit M. Govers , Ramon A.C. van Huet , Susanne Roosing , Sander Keijser , Leonoor I. Los , Anneke I. den Hollander , B. Jeroen Klevering
Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.
{"title":"The genetics and disease mechanisms of rhegmatogenous retinal detachment","authors":"Birgit M. Govers , Ramon A.C. van Huet , Susanne Roosing , Sander Keijser , Leonoor I. Los , Anneke I. den Hollander , B. Jeroen Klevering","doi":"10.1016/j.preteyeres.2022.101158","DOIUrl":"10.1016/j.preteyeres.2022.101158","url":null,"abstract":"<div><p>Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1350946222001185/pdfft?md5=3c19118a48af3c4fda7c893f2d972f86&pid=1-s2.0-S1350946222001185-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10847257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-01DOI: 10.1016/j.preteyeres.2022.101159
Yang Pan , Yingbin Fu , Paul N. Baird , Robyn H. Guymer , Taraprasad Das , Takeshi Iwata
Age-related macular degeneration (AMD) is the leading cause of severe irreversible central vision loss in individuals over 65 years old. Genome-wide association studies (GWASs) have shown that the region at chromosome 10q26, where the age-related maculopathy susceptibility (ARMS2/LOC387715) and HtrA serine peptidase 1 (HTRA1) genes are located, represents one of the strongest associated loci for AMD. However, the underlying biological mechanism of this genetic association has remained elusive. In this article, we extensively review the literature by us and others regarding the ARMS2/HTRA1 risk alleles and their functional significance. We also review the literature regarding the presumed function of the ARMS2 protein and the molecular processes of the HTRA1 protein in AMD pathogenesis in vitro and in vivo, including those of transgenic mice overexpressing HtrA1/HTRA1 which developed Bruch's membrane (BM) damage, choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV), similar to human AMD patients. The elucidation of the molecular mechanisms of the ARMS2 and HTRA1 susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.
{"title":"Exploring the contribution of ARMS2 and HTRA1 genetic risk factors in age-related macular degeneration","authors":"Yang Pan , Yingbin Fu , Paul N. Baird , Robyn H. Guymer , Taraprasad Das , Takeshi Iwata","doi":"10.1016/j.preteyeres.2022.101159","DOIUrl":"10.1016/j.preteyeres.2022.101159","url":null,"abstract":"<div><p><span><span>Age-related macular degeneration (AMD) is the leading cause of severe irreversible central vision loss in individuals over 65 years old. Genome-wide association studies (GWASs) have shown that the region at chromosome 10q26, where the age-related </span>maculopathy susceptibility (</span><em>ARMS2/LOC387715</em><span>) and HtrA serine peptidase 1 (</span><em>HTRA1</em>) genes are located, represents one of the strongest associated loci for AMD. However, the underlying biological mechanism of this genetic association has remained elusive. In this article, we extensively review the literature by us and others regarding the <em>ARMS2/HTRA1</em><span><span><span> risk alleles and their functional significance. We also review the literature regarding the presumed function of the ARMS2 protein and the molecular processes<span> of the HTRA1 protein in AMD pathogenesis in vitro and in vivo, including those of transgenic mice overexpressing HtrA1/HTRA1 which developed </span></span>Bruch's membrane (BM) damage, </span>choroidal neovascularization<span> (CNV), and polypoidal choroidal vasculopathy (PCV), similar to human AMD patients. The elucidation of the molecular mechanisms of the </span></span><em>ARMS2</em> and <em>HTRA1</em><span><span> susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for </span>treatment.</span></p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10454125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-01DOI: 10.1016/j.preteyeres.2023.101218
Taraprasad Das , Joveeta Joseph , Matthew P. Simunovic , Andrzej Grzybowski , Kuan-Jen Chen , Vivek Pravin Dave , Savitri Sharma , Patrick Staropoli , Harry Flynn Jr.
Infectious endophthalmitis is a severe intraocular infection caused by bacteria, or less commonly by fungi. It can occur after penetrating eye procedures, trauma, or the spread of infection from contiguous structures or via emboli from distant organs. Because of the time-critical nature of the treatment, endophthalmitis is treated with the clinical diagnosis and modified by the microbiological report of the intraocular contents. The current strategy for managing endophthalmitis relies on pre-clinical literature, case series, and one large multi-center randomized clinical trial on post-cataract surgery endophthalmitis. Culture-susceptibility of the microorganisms from undiluted vitreous guides the definitive treatment in non-responsive cases. Strategies to reduce the incidence of endophthalmitis after penetrating eye procedures have been developed concurrently with refined means of treatment.
Despite these advances, outcomes remain poor for many patients. Although consensus articles have been published on managing endophthalmitis, treatment patterns vary, and controversies remain. These include (1) the use of newer methods for early and precise microbiological diagnosis; (2) the choice of intravitreal antibiotics; (3) the need for systemic therapy; (4) early and complete vitrectomy. Here, we review the current consensus and address controversies in diagnosing and managing endophthalmitis. This review is intended to familiarize physicians and ophthalmologists with different aspects of endophthalmitis management to make informed decisions.
{"title":"Consensus and controversies in the science of endophthalmitis management: Basic research and clinical perspectives","authors":"Taraprasad Das , Joveeta Joseph , Matthew P. Simunovic , Andrzej Grzybowski , Kuan-Jen Chen , Vivek Pravin Dave , Savitri Sharma , Patrick Staropoli , Harry Flynn Jr.","doi":"10.1016/j.preteyeres.2023.101218","DOIUrl":"10.1016/j.preteyeres.2023.101218","url":null,"abstract":"<div><p>Infectious endophthalmitis<span><span> is a severe intraocular infection caused by bacteria, or less commonly by fungi. It can occur after penetrating eye procedures, trauma, or the spread of infection from contiguous structures or via emboli from distant organs. Because of the time-critical nature of the treatment, </span>endophthalmitis<span> is treated with the clinical diagnosis and modified by the microbiological report of the intraocular contents. The current strategy for managing endophthalmitis relies on pre-clinical literature, case series, and one large multi-center randomized clinical trial on post-cataract surgery endophthalmitis. Culture-susceptibility of the microorganisms from undiluted vitreous guides the definitive treatment in non-responsive cases. Strategies to reduce the incidence of endophthalmitis after penetrating eye procedures have been developed concurrently with refined means of treatment.</span></span></p><p>Despite these advances, outcomes remain poor for many patients. Although consensus articles have been published on managing endophthalmitis, treatment patterns vary, and controversies remain. These include (1) the use of newer methods for early and precise microbiological diagnosis; (2) the choice of intravitreal antibiotics; (3) the need for systemic therapy; (4) early and complete vitrectomy. Here, we review the current consensus and address controversies in diagnosing and managing endophthalmitis. This review is intended to familiarize physicians and ophthalmologists with different aspects of endophthalmitis management to make informed decisions.</p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41211034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-30DOI: 10.1016/j.preteyeres.2023.101217
Luis Alarcon-Martinez , Yukihiro Shiga , Deborah Villafranca-Baughman , Jorge L. Cueva Vargas , Isaac A. Vidal Paredes , Heberto Quintero , Brad Fortune , Helen Danesh-Meyer , Adriana Di Polo
Retinal ganglion cells, the neurons that die in glaucoma, are endowed with a high metabolism requiring optimal provision of oxygen and nutrients to sustain their activity. The timely regulation of blood flow is, therefore, essential to supply firing neurons in active areas with the oxygen and glucose they need for energy. Many glaucoma patients suffer from vascular deficits including reduced blood flow, impaired autoregulation, neurovascular coupling dysfunction, and blood-retina/brain-barrier breakdown. These processes are tightly regulated by a community of cells known as the neurovascular unit comprising neurons, endothelial cells, pericytes, Müller cells, astrocytes, and microglia. In this review, the neurovascular unit takes center stage as we examine the ability of its members to regulate neurovascular interactions and how their function might be altered during glaucomatous stress. Pericytes receive special attention based on recent data demonstrating their key role in the regulation of neurovascular coupling in physiological and pathological conditions. Of particular interest is the discovery and characterization of tunneling nanotubes, thin actin-based conduits that connect distal pericytes, which play essential roles in the complex spatial and temporal distribution of blood within the retinal capillary network. We discuss cellular and molecular mechanisms of neurovascular interactions and their pathophysiological implications, while highlighting opportunities to develop strategies for vascular protection and regeneration to improve functional outcomes in glaucoma.
{"title":"Neurovascular dysfunction in glaucoma","authors":"Luis Alarcon-Martinez , Yukihiro Shiga , Deborah Villafranca-Baughman , Jorge L. Cueva Vargas , Isaac A. Vidal Paredes , Heberto Quintero , Brad Fortune , Helen Danesh-Meyer , Adriana Di Polo","doi":"10.1016/j.preteyeres.2023.101217","DOIUrl":"10.1016/j.preteyeres.2023.101217","url":null,"abstract":"<div><p>Retinal ganglion cells, the neurons that die in glaucoma, are endowed with a high metabolism requiring optimal provision of oxygen and nutrients to sustain their activity. The timely regulation of blood flow is, therefore, essential to supply firing neurons in active areas with the oxygen and glucose they need for energy. Many glaucoma patients suffer from vascular deficits including reduced blood flow, impaired autoregulation, neurovascular coupling dysfunction, and blood-retina/brain-barrier breakdown. These processes are tightly regulated by a community of cells known as the neurovascular unit comprising neurons, endothelial cells, pericytes, Müller cells, astrocytes, and microglia. In this review, the neurovascular unit takes center stage as we examine the ability of its members to regulate neurovascular interactions and how their function might be altered during glaucomatous stress. Pericytes receive special attention based on recent data demonstrating their key role in the regulation of neurovascular coupling in physiological and pathological conditions. Of particular interest is the discovery and characterization of tunneling nanotubes, thin actin-based conduits that connect distal pericytes, which play essential roles in the complex spatial and temporal distribution of blood within the retinal capillary network. We discuss cellular and molecular mechanisms of neurovascular interactions and their pathophysiological implications, while highlighting opportunities to develop strategies for vascular protection and regeneration to improve functional outcomes in glaucoma.</p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41146037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-19DOI: 10.1016/j.preteyeres.2023.101216
Zhenyu Zhong, Guannan Su, Peizeng Yang
Behçet's disease is a systemic vasculitis frequently associated with intraocular inflammation. Recent findings identified independent clinical clusters in Behçet's disease, each involving distinct combinations of affected organs. Ocular Behçet's disease, mainly manifested as uveitis, is characterized as an independent cluster with a low likelihood of association with other system involvements, such as intestinal, cardiovascular, or central nervous system. A prevailing theory suggests that the pathogenesis of the disease is multifactorial, where a variety of genetic and infectious agents may interact with each other to cause the disease. Among sporadic cases, the human leukocyte antigen (HLA) genes, including HLA-B51, HLA-A26, HLA-B15, and HLA-B5701, have been found to be a key component conferring genetic susceptibility. Outside the HLA region, a set of susceptibility variants are identified, closely related to interleukin (IL)-23/IL-17 pathway, tumor necrosis factor (TNF) signaling, and pattern recognition receptor systems. Microbial infections, such as Streptococcus sanguinis, Mycobacterium tuberculosis, and Herpes simplex virus (HSV), are linked to play the triggering of disease in immunogenetically predisposed individuals. Clinically, due to the notable relapsing-remitting course of ocular Behçet's disease, the prevention of recurrent attack would be the primary treatment goal. Combination of corticosteroids and immunomodulatory drugs, such as anti-TNF agents, interferon, and conventional immunosuppressants (e.g. cyclosporine, azathioprine), have been the mainstream regimen for the disease. Future research may focus on comparing the effectiveness of immunomodulatory drugs and identifying the most suitable subgroups for a specific drug on the basis of the knowledge of the molecular heterogeneity of the disease.
{"title":"Risk factors, clinical features and treatment of Behçet's disease uveitis","authors":"Zhenyu Zhong, Guannan Su, Peizeng Yang","doi":"10.1016/j.preteyeres.2023.101216","DOIUrl":"10.1016/j.preteyeres.2023.101216","url":null,"abstract":"<div><p><span><span><span>Behçet's disease is a </span>systemic vasculitis<span><span><span> frequently associated with intraocular inflammation. Recent findings identified independent clinical clusters in Behçet's disease, each involving distinct combinations of affected organs. Ocular Behçet's disease, mainly manifested as uveitis, is characterized as an independent cluster with a low likelihood of association with other system involvements, such as intestinal, cardiovascular, or </span>central nervous system. A prevailing theory suggests that the pathogenesis of the disease is multifactorial, where a variety of genetic and infectious agents may interact with each other to cause the disease. Among sporadic cases, the </span>human leukocyte antigen (HLA) genes, including HLA-B51, HLA-A26, HLA-B15, and HLA-B5701, have been found to be a key component conferring </span></span>genetic susceptibility<span>. Outside the HLA region, a set of susceptibility variants are identified, closely related to interleukin (IL)-23/IL-17 pathway, tumor necrosis factor<span> (TNF) signaling, and pattern recognition receptor systems. Microbial infections, such as </span></span></span><span><em>Streptococcus sanguinis</em></span>, <span><em>Mycobacterium tuberculosis</em></span><span><span><span><span>, and Herpes simplex virus (HSV), are linked to play the triggering of disease in immunogenetically predisposed individuals. Clinically, due to the notable relapsing-remitting course of ocular Behçet's disease, the prevention of recurrent attack would be the primary </span>treatment goal. Combination of corticosteroids and </span>immunomodulatory drugs, such as anti-TNF agents, </span>interferon<span><span>, and conventional immunosuppressants (e.g. </span>cyclosporine<span>, azathioprine), have been the mainstream regimen for the disease. Future research may focus on comparing the effectiveness of immunomodulatory drugs and identifying the most suitable subgroups for a specific drug on the basis of the knowledge of the molecular heterogeneity of the disease.</span></span></span></p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41169708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-01DOI: 10.1016/j.preteyeres.2022.101154
David A. Merle , Merve Sen , Angela Armento , Chloe M. Stanton , Eric F. Thee , Magda A. Meester-Smoor , Markus Kaiser , Simon J. Clark , Caroline C.W. Klaver , Pearse A. Keane , Alan F. Wright , Michael Ehrmann , Marius Ueffing
Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distinct regions on chromosome 1 and 10. While the chromosome 1 locus comprises factors of the complement system with well-known functions, the role of the 10q26-locus in AMD-pathophysiology remains enigmatic. 10q26 harbors a cluster of three functional genes, namely PLEKHA1, ARMS2 and HTRA1, with most of the AMD-associated genetic variants mapping to the latter two genes. High linkage disequilibrium between ARMS2 and HTRA1 has kept association studies from reliably defining the risk-causing gene for long and only very recently the genetic risk region has been narrowed to ARMS2, suggesting that this is the true AMD gene at this locus. However, genetic associations alone do not suffice to prove causality and one or more of the 14 SNPs on this haplotype may be involved in long-range control of gene expression, leaving HTRA1 and PLEKHA1 still suspects in the pathogenic pathway. Both, ARMS2 and HTRA1 have been linked to extracellular matrix homeostasis, yet their exact molecular function as well as their role in AMD pathogenesis remains to be uncovered. The transcriptional regulation of the 10q26 locus adds an additional level of complexity, given, that gene-regulatory as well as epigenetic alterations may influence expression levels from 10q26 in diseased individuals. Here, we provide a comprehensive overview on the 10q26 locus and its three gene products on various levels of biological complexity and discuss current and future research strategies to shed light on one of the remaining enigmatic spots in the AMD landscape.
{"title":"10q26 – The enigma in age-related macular degeneration","authors":"David A. Merle , Merve Sen , Angela Armento , Chloe M. Stanton , Eric F. Thee , Magda A. Meester-Smoor , Markus Kaiser , Simon J. Clark , Caroline C.W. Klaver , Pearse A. Keane , Alan F. Wright , Michael Ehrmann , Marius Ueffing","doi":"10.1016/j.preteyeres.2022.101154","DOIUrl":"10.1016/j.preteyeres.2022.101154","url":null,"abstract":"<div><p>Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distinct regions on chromosome 1 and 10. While the chromosome 1 locus comprises factors of the complement system with well-known functions, the role of the 10q26-locus in AMD-pathophysiology remains enigmatic. 10q26 harbors a cluster of three functional genes, namely <em>PLEKHA1</em>, <em>ARMS2</em> and <em>HTRA1</em>, with most of the AMD-associated genetic variants mapping to the latter two genes. High linkage disequilibrium between <em>ARMS2</em> and <em>HTRA1</em> has kept association studies from reliably defining the risk-causing gene for long and only very recently the genetic risk region has been narrowed to <em>ARMS2</em>, suggesting that this is the true AMD gene at this locus. However, genetic associations alone do not suffice to prove causality and one or more of the 14 SNPs on this haplotype may be involved in long-range control of gene expression, leaving <em>HTRA1</em> and <em>PLEKHA1</em> still suspects in the pathogenic pathway. Both, <em>ARMS2</em> and <em>HTRA1</em> have been linked to extracellular matrix homeostasis, yet their exact molecular function as well as their role in AMD pathogenesis remains to be uncovered. The transcriptional regulation of the 10q26 locus adds an additional level of complexity, given, that gene-regulatory as well as epigenetic alterations may influence expression levels from 10q26 in diseased individuals. Here, we provide a comprehensive overview on the 10q26 locus and its three gene products on various levels of biological complexity and discuss current and future research strategies to shed light on one of the remaining enigmatic spots in the AMD landscape.</p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10280074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-01DOI: 10.1016/j.preteyeres.2023.101194
Leopold Schmetterer, Gülgün Tezel, Joel Schuman
{"title":"Neville Osborne - Editor-in-Chief of Progress in Retinal and Eye Research for 40 years","authors":"Leopold Schmetterer, Gülgün Tezel, Joel Schuman","doi":"10.1016/j.preteyeres.2023.101194","DOIUrl":"10.1016/j.preteyeres.2023.101194","url":null,"abstract":"","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":null,"pages":null},"PeriodicalIF":17.8,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10301420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}