Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects

Matthaei, Mario; Hribek, Agathe; Clahsen, Thomas; Bachmann, Björn; Cursiefen, Claus; Jun, Albert S.

doi:10.1146/annurev-vision-091718-014852

Cited by 92 publications

(113 citation statements)

References 144 publications

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“…Numerous corneal diseases have been linked to abnormal gene expression such as Fuchs' endothelial corneal dystrophy (FECD) [5], corneal fibrosis [6], corneal neovascularization [7], keratoconus [8], and several corneal dystrophies [9]. The advantages of ASOs for treating these diseases include (1) Generality, Watson-Crick base-pairing allows recognition of any gene to modulate its expression; (2) the potential for local delivery; and (3) the potential suggested by experience with Spinraza and other recent drugs, for potent and long-lasting effects accompanied by mild side effects.…”

Section: Introductionmentioning

confidence: 99%

Delivery of Antisense Oligonucleotides to the Cornea

Chau

Gong

et al. 2020

Nucleic Acid Therapeutics

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Antisense oligonucleotides (ASOs) are synthetic nucleic acids that recognize complementary RNA sequences inside cells and modulate gene expression. In this study, we explore the feasibility of ASO delivery to the cornea. We used quantitative polymerase chain reaction to test the efficacy of a benchmark ASO targeting a noncoding nuclear RNA, Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1), in a human corneal endothelial cell line, ex vivo human corneas, and in vivo in mice. In vivo delivery was via intravitreal or intracameral injections as well as topical administration. The anti-MALAT1 ASO significantly reduced expression of MALAT1 in a corneal endothelial cell line. We achieved a dose-dependent reduction of target gene expression in endothelial tissue from ex vivo human donor corneas. In vivo mouse experiments confirmed MALAT1 reduction in whole corneal tissue via intravitreal and intracameral routes, 82% and 71% knockdown, respectively (P < 0.001). Effects persisted up to at least 21 days, 32% (P < 0.05) and 43% (P < 0.05) knockdown, respectively. We developed protocols for the isolation and analysis of mouse corneal endothelium and observed reduction in MALAT1 expression upon both intravitreal and intracameral administrations, 64% (P < 0.05) and 63% (P < 0.05) knockdown, respectively. These data open the possibility of using ASOs to treat corneal disease.

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Section: Introductionmentioning

confidence: 99%

Delivery of Antisense Oligonucleotides to the Cornea

Chau

Gong

et al. 2020

Nucleic Acid Therapeutics

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“…Inherited corneal dystrophies can compromise the structure and transparency of the cornea. Late-onset Fuchs' endothelial corneal dystrophy (FECD) is one of the most common genetic disorders, affecting four percent of the population in the United States over the age of forty (2)(3)(4). The corneal endothelium is the inner hexagonal monolayer responsible for maintenance of stromal dehydration and corneal clarity.…”

Section: Introductionmentioning

confidence: 99%

Analyzing Presymptomatic Tissue to Gain Insights into the Molecular and Mechanistic Origins of Late-Onset Degenerative Trinucleotide Repeat Disease

Mootha

Corey

Chu

et al. 2020

Preprint

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How genetic defects trigger the molecular changes that cause late-onset disease is important for understanding disease progression and therapeutic development. Fuchs' endothelial corneal dystrophy (FECD) is an RNA-mediated disease caused by a trinucleotide CUG expansion in an intron within the TCF4 gene. The mutant intronic CUG RNA is present at 1-2 copies per cell, posing a challenge to understand how a rare RNA can cause disease. Late-onset FECD is a uniquely advantageous model for studying how RNA triggers disease because; 1) Affected tissue is routinely removed during surgery; 2) The expanded CUG mutation is one of the most prevalent disease-causing mutations, making it possible to obtain pre-symptomatic tissue from eye bank donors to probe how gene expression changes precede disease; and 3) The affected tissue is a homogeneous single cell monolayer, facilitating accurate transcriptome analysis. Here we use RNA sequencing (RNAseq) to compare tissue from individuals who are pre-symptomatic (Pre_S) to tissue from patients with late stage FECD (FECD_REP). The abundance of mutant repeat intronic RNA in Pre_S and FECD_REP tissue is elevated due to increased half-life in a corneal cell-specific manner. In Pre_S tissue, changes in splicing and extracellular matrix gene expression foreshadow the changes observed in advanced disease and predict the activation of the fibrosis pathway and immune system seen in late-stage patients. The absolute magnitude of splicing changes is similar in presymptomatic and late stage tissue. Our data identify gene candidates for early drivers of disease and biomarkers that may represent diagnostic and therapeutic targets for FECD. We conclude that changes in alternative splicing and gene expression are observable decades prior to the diagnosis of late-onset trinucleotide repeat disease. 3 3 6 6

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“…FECD is a bilateral, slowly progressive corneal disease. It is characterized by deterioration of endothelial cells and development of guttae excrescences of Descemet's membrane [1][2][3][4] , which may eventually lead to corneal edema and reduced vision [4,5] . The pathophysiology of FECD involves several proposed mechanisms involving channelopathies, oxidative stress, apoptosis, and the epithelial-mesenchymal transition.…”

Section: Introductionmentioning

confidence: 99%

A Family of Fuchs Endothelial Corneal Dystrophy and Anterior Polar Cataract with An Analysis of Whole Exome Sequencing

Jiang

Jin

Zhang

et al. 2020

Preprint

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Background Our aim was to introduce a family affected by this rare phenotype, and perform the whole exome sequencing (WES) to explore the potential candidate genes causing the disorders.Methods A five-generation family including 5 patients affected by FECD with APC, and 9 patients suffered from only FECD was recruited from the First Affiliated Hospital of Harbin Medical University. All participants received ophthalmic examinations. 8 family members were selected to perform WES with a bioinformatics analysis.Results Patients in this family had FECD as the common feature. The proband (a 65-year-old female) was affected by FECD and APC in both eyes, with epithelial bullae in the left eye of the. Slit-lamp, specular and confocal microscope and OCT images showed guttae more serious in the central cornea than the peripheral area, confirming the diagnosis of FECD. In this family, most corneal guttae were bilateral with almost equal degree of progression in Descemet membrane, APC was found around the age of 10, perhaps even earlier. Bioinformatics analysis showed that 83 potential candidate genes in total may cause this condition in this family. No known causative gene of this phenotype or FECD was found by WES.Conclusion We introduced a family of FECD with APC, with no known causative gene found by WES, inferring that there may be a novel gene-locus associated with this condition. Further study will be engaged on candidate gene screening and variants validation with corresponding functional aspects to clarify the relationship between genotype and phenotype.

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Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects

Cited by 92 publications

References 144 publications

Delivery of Antisense Oligonucleotides to the Cornea

Delivery of Antisense Oligonucleotides to the Cornea

Analyzing Presymptomatic Tissue to Gain Insights into the Molecular and Mechanistic Origins of Late-Onset Degenerative Trinucleotide Repeat Disease

A Family of Fuchs Endothelial Corneal Dystrophy and Anterior Polar Cataract with An Analysis of Whole Exome Sequencing

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