Featured
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Article
| Open Access
Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression
Complement factor H-related 4 protein (FHR-4) has been implicated in the pathophysiology of age-related macular degeneration (AMD). Here, in contrast, the authors find that levels of FHR-4 in plasma or ocular tissue do not appear to influence susceptibility to AMD or its course of progression, questioning whether modulation of FHR-4 is likely to be an effective therapeutic strategy.
- M. A. Zouache
- , B. T. Richards
- & G. S. Hageman
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Article
| Open Access
Improving model fairness in image-based computer-aided diagnosis
Deep learning models can reflect and amplify human bias, potentially resulting inaccurate missed diagnoses. Here, the authors show that by leveraging the marginal pairwise equal opportunity, their model reduces bias in medical image classification by over 35% compared to baseline models, with minimal impact on AUC values.
- Mingquan Lin
- , Tianhao Li
- & Yifan Peng
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Article
| Open Access
Contribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes
A deep understanding of the genetic signatures of neovascular age-related macular degeneration subtypes in Asian patients remains a significant gap. Here the authors pinpoint contributing common and rare variants using GWAS and exome sequencing approaches.
- Qiao Fan
- , Hengtong Li
- & Ching-Yu Cheng
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Article
| Open Access
Antibody blockade of Jagged1 attenuates choroidal neovascularization
Current treatment for neovascular age-related macular degeneration (nAMD) does not help all patients. Here, the authors show that using antibodies to block Jagged1 reduces disease burden in a model of nAMD, which could enable new treatment options.
- Torleif Tollefsrud Gjølberg
- , Jonas Aakre Wik
- & Eirik Sundlisæter
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Article
| Open Access
Single-cell analysis reveals inflammatory interactions driving macular degeneration
Single-nucleus RNA-seq was used to profile 11 retinas with varying stages of age-related macular degeneration and 6 control retinas. The authors identified shared glial states across neurodegeneration, indicating that the retina provides a human system for investigating therapeutic approaches in neurodegeneration.
- Manik Kuchroo
- , Marcello DiStasio
- & Brian P. Hafler
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Article
| Open Access
Electronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats
Retinal prosthetics has shown its promise in restoring vision, despite limited acuity. Here, the authors demonstrate a high-resolution prosthetic vision that enables grating acuity matching the natural visual resolution in rats, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.
- Bing-Yi Wang
- , Zhijie Charles Chen
- & Daniel Palanker
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Article
| Open Access
Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration
The protease HTRA1 is a genetic risk factor for geographic atrophy. Here, Gerhardy et al. describe its inhibition by a clinical Fab, whose binding locks it in an inactive state. The mechanism identifies an essential function of LoopA with this protease family.
- Stefan Gerhardy
- , Mark Ultsch
- & Daniel Kirchhofer
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Article
| Open Access
Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of vision loss, and there is no approved treatment for AMD with geographic atrophy. Here, the authors used transcriptomic and proteomic analyses of patient induced pluripotent stem cell-derived retinal pigment epithelium to better understand disease mechanisms.
- Anne Senabouth
- , Maciej Daniszewski
- & Alice Pébay
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Article
| Open Access
Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice
Treatments to rescue vision are currently limited. Here, the authors identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in humans. They also show that activating laterally projecting cells results improved vision in two mouse models of retinal degeneration.
- M. Rizzi
- , K. Powell
- & R. R. Ali
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Article
| Open Access
Simultaneous perception of prosthetic and natural vision in AMD patients
Atrophic age-related macular degeneration (AMD) results in visual impairment. Here the authors report interim analysis of open-label single group feasibility trial using a wireless photovoltaic subretinal implant in patients with atrophic AMD, and report that the patients exhibited prosthetic visual perception with acuity closely matching the pixel size during the 18-24 month follow-up period.
- D. Palanker
- , Y. Le Mer
- & J. A. Sahel
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Article
| Open Access
Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of blindness and is characterised by the accumulation of lipid deposits, called drusen. Here, the authors show that mice lacking chloride intracellular channel 4 in retinal pigment epithelium have defective lipid processing in the eye and pathological features mirroring human AMD, including drusen formation.
- Jen-Zen Chuang
- , Nan Yang
- & Ching-Hwa Sung
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Article
| Open Access
DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously
Bispecific antibodies can bind to two distinct targets though the fusion of two different Fv regions. In this study, the authors develop DutaFabs that present two separated and independent antigen binding sites within the same Fv region, giving rise to bispecific Fab fragments.
- Roland Beckmann
- , Kristian Jensen
- & Hubert Kettenberger
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Article
| Open Access
The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Here, the authors show that microglia-specific deletion of TSPO and chemical inhibition of TSPO prevent neuroinflammation and vascular damage in a mouse model of AMD.
- Anne Wolf
- , Marc Herb
- & Thomas Langmann
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Article
| Open Access
Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration
“Genome-wide association studies have identified variants associated with age-related macular degeneration (AMD); however, other than identifying this as a complement mediated inflammatory disease, little biology has emerged. Here, authors used novel computational tools from the Broad Institute to examine the relationship of single-cell transcriptomics and genome-wide association studies (GWAS) in the human retina and demonstrate that GWAS-associated risk alleles associated with AMD are enriched in glia and vascular cells and that human retinal glia are more diverse than previously thought
- Madhvi Menon
- , Shahin Mohammadi
- & Brian P. Hafler
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Perspective
| Open Access
A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration
No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.
- James T. Handa
- , Cathy Bowes Rickman
- & Lindsay A. Farrer
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Article
| Open Access
Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration
Current treatments for age-related neovascular macular degeneration (nAMD) suffer from limited efficacy. Here, Zhao et al. show that pharmacological inhibition or genetic deletion of the mineralocorticoid receptor (MR) limits choroidal neovascularisation in rodents, and show in a pilot clinical study that targeting the MR pathway may provide clinical benefits in nAMD patiens.
- Min Zhao
- , Irmela Mantel
- & Francine Behar-Cohen
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Article
| Open Access
CRISPR-LbCpf1 prevents choroidal neovascularization in a mouse model of age-related macular degeneration
The CRISPR endonuclease LbCpf1 is reported to have greater efficiency and specificity than Cas9. Here, the authors use LbCpf1 to target the angiogenesis-related genes VEGF and HIF1a, and show that delivery of the nuclease using AAV9 is effective in mouse models of macular degeneration.
- Taeyoung Koo
- , Sung Wook Park
- & Jin-Soo Kim
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Article
| Open Access
ATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration
Age-related macular degeneration (AMD) leads to dysfunctional retinal pigment epithelium (RPE) and vision loss. Here, the authors perform ATAC-seq to study chromatin accessibility and find that differentially accessible regions are enriched for photoreceptor and RPE-specific transcription factors in AMD
- Jie Wang
- , Cristina Zibetti
- & Jiang Qian
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Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations
Age-related macular degeneration is a prominent cause of irreversible blindness among the elderly. Here Huang et al.identify a novel missense variant in UBE3D that sheds new light on the pathogenesis of the disease.
- Lv-Zhen Huang
- , Ying-Jie Li
- & Xiao-Xin Li
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Article
| Open Access
New loci and coding variants confer risk for age-related macular degeneration in East Asians
Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Here, the authors carry out a two-stage genome-wide association study for AMD and identify three new AMD risk loci, highlighting the shared and distinct genetic basis of the disease in East Asians and Europeans.
- Ching-Yu Cheng
- , Kenji Yamashiro
- & Chiea Chuen Khor
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Article
| Open Access
A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration
Semaphorin 4A is implicated in photoreceptor survival. Nojima and colleagues generate transgenic mice with different mutations in the Sema4A gene and find that point mutation of F350 causes severe degeneration in photoreceptor cells, which can be rescued by virus-mediated gene therapy.
- Satoshi Nojima
- , Toshihiko Toyofuku
- & Atsushi Kumanogoh
QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration