Corneal injury: Clinical and molecular aspects

Barrientez, Brayden; Nicholas, Sarah E.; Whelchel, Amy; Sharif, Rabab; Hjortdal, Jesper; Karamichos, Dimitrios

doi:10.1016/j.exer.2019.107709

Cited by 72 publications

(43 citation statements)

References 154 publications

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“…Corneal diseases represent one of the leading causes of vision loss and blindness globally ( 1 ). Inherited corneal dystrophies can compromise the structure and transparency of the cornea.…”

Section: Introductionmentioning

confidence: 99%

Analyzing pre-symptomatic tissue to gain insights into the molecular and mechanistic origins of late-onset degenerative trinucleotide repeat disease

Chu

Liang

et al. 2020

Nucleic Acids Research

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Abstract 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 CTG expansion in an intron within the TCF4 gene. The mutant intronic CUG RNA is present at one–two 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: (i) Affected tissue is routinely removed during surgery; (ii) The expanded CTG 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 (iii) 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 cells. 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 pre-symptomatic 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.

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Section: Introductionmentioning

confidence: 99%

Analyzing pre-symptomatic tissue to gain insights into the molecular and mechanistic origins of late-onset degenerative trinucleotide repeat disease

Chu

Liang

et al. 2020

Nucleic Acids Research

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“…83,84 Several other gene knockdown strategies for ocular scarring are also being tested in animals. 1,[9][10][11]14 In this study, we used the fully modified siRNA conjugate to achieve maximal activity and longevity of the effect in vivo. 48 Regarding the possibility of off-target effects, the asymmetric (20/15) chemically modified siRNA used in this study was designed to avoid any sequence identity with other rabbit genes within the 2-18 region of the anti-sense strand.…”

Section: Discussionmentioning

confidence: 99%

“…Corneal scarring results from mechanical injury, burn, infection, or surgery. 1 Other examples of ocular scarring include glaucoma filtration surgery (the bleb to relieve intraocular pressure can heal fibrotically) 2 and other ocular morbidity such as proliferative vitreoretinopathy (PVR) and retinal detachment. 3,4 Mitomycin C (MMC) to improve healing and avert scarring is a standard of care for some of these indications, but there is a high failure rate with the filtration surgery and cell toxicity concerns in corneal surgeries.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Mitomycin C (MMC) to improve healing and avert scarring is a standard of care for some of these indications, but there is a high failure rate with the filtration surgery and cell toxicity concerns in corneal surgeries. 2,[5][6][7][8] Although there are several other therapeutic modalities being tested for the cornea, including viral delivery of genes, growth factors, and stem cells derived from various sources, 1,[9][10][11][12][13][14][15] currently transplant of non-autologous corneal tissue is the only option available. Furthermore, there is a global shortage of tissue and limited access to this procedure for most of the world.…”

Section: Introductionmentioning

confidence: 99%

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USP10 Targeted Self-Deliverable siRNA to Prevent Scarring in the Cornea

Boumil

Castro

Phillips

et al. 2020

Molecular Therapy - Nucleic Acids

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Ocular scarring after surgery, trauma, or infection leads to vision loss. The transparent cornea is an excellent model system to test anti-scarring therapies. Cholesterol-conjugated fully modified asymmetric small interfering RNAs (siRNAs) (selfdeliverable siRNAs [sdRNAs]) are a novel modality for in vivo gene knockdown, transfecting cells and tissues without any additional formulations. Myofibroblasts are a main contributor to scarring and fibrosis. a v integrins play a central role in myofibroblast pathological adhesion, overcontraction, and transforming growth factor b (TGF-b) activation. Previously, we demonstrated that a v integrins are protected from intracellular degradation after wounding by upregulation of the deubiquitinase (DUB) ubiquitin-specific protease 10 (USP10), leading to integrin cell surface accumulation. In this study, we tested whether knockdown of USP10 with a USP10-targeting sdRNA (termed US09) will reduce scarring after wounding a rabbit cornea in vivo. The wounded corneal stroma was treated once with US09 or non-targeting control (NTC) sdRNA. At 6 weeks US09 treatment resulted in faster wound closure, limited scarring, and suppression of fibrotic markers and immune response. Specifically, fibronectin-extra domain A (EDA), collagen III, and a-smooth muscle actin (p < 0.05), CD45 + cell infiltration (p < 0.01), and apoptosis at 24 (p < 0.01) and 48 h (p < 0.05) were reduced post-wounding. Corneal thickness and cell proliferation were restored to unwounded parameters. Targeting the DUB, USP10 is a novel strategy to reduce scarring. This study indicates that ubiquitin-mediated pathways should be considered in the pathogenesis of fibrotic healing.

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“…Keratoconus (KC) is an asymmetrically bilateral corneal dystrophy characterized by progressive thinning of the cornea, which becomes cone-shaped in a process called ectasia, with a prevalence of approximately 1 in 2000 people [1][2][3][4][5][6][7]. It is currently known that KC is a multifactorial disease, involving genetic, environmental, and behavioral factors and etiology remains poorly understood [3,[7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Absence of the c.169+50delTAAACAG mutation of SOD1 gene in a sample of keratoconus patients in Brazilian population

et al. 2020

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Objective: To determine the presence of the 7-bp deletion c.169+50delTAA ACA G in intron 2 of Superoxide Dismutase-1 gene in keratoconic patients from the State of São Paulo, Brazil, which promotes splicing variations, resulting in non-functional Superoxide Dismutase-1 antioxidant proteins, which may damage the corneal structure. Results: A group of 35 keratoconic patients, from whom 35 peripheral blood samples and 58 samples of corneal fragments were evaluated, and a control group of 89 individuals, from whom 41 blood samples and 149 samples of corneal fragments were collected. After the amplification of DNA fragments by polymerase chain reaction, mutational screening analysis was performed by enzymatic digestion, followed by direct sequencing. The absence of the 7-bp c.169+50delTAA ACA G mutation in intron 2 of Superoxide Dismutase-1 gene was detected in the analyzed subjects of the 2 groups, both in the cornea and peripheral blood samples. Then, according to our results, there is no involvement of c.169+50delTAA ACA G deletion in the pathogenesis of keratoconus in this population, once it was not detected. But we emphasize that studies involving this deletion must be continued in an attempt to elucidate this issue.

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Corneal injury: Clinical and molecular aspects

Cited by 72 publications

References 154 publications

Analyzing pre-symptomatic tissue to gain insights into the molecular and mechanistic origins of late-onset degenerative trinucleotide repeat disease

Analyzing pre-symptomatic tissue to gain insights into the molecular and mechanistic origins of late-onset degenerative trinucleotide repeat disease

USP10 Targeted Self-Deliverable siRNA to Prevent Scarring in the Cornea

Absence of the c.169+50delTAAACAG mutation of SOD1 gene in a sample of keratoconus patients in Brazilian population

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