Approaches for corneal endothelium regenerative medicine

Progress in Retinal and Eye Research, Journal Year: 2021, Volume and Issue: 87, P. 100987 - 100987

Published: July 6, 2021

The state of the art therapy for treating corneal endothelial disease is transplantation. Advances in reproducibility and accessibility surgical techniques are increasing number transplants, thereby causing a global deficit donor corneas leaving 12.7 million patients with addressable visual impairment. Approaches to regenerate endothelium offer solution current tissue scarcity treatment those need. Methods generating cells into numbers that could address shortage possible strategies used deliver them have now become therapeutic reality clinical trials taking place Japan, Singapore Mexico. Nevertheless, there still long way before such therapies approved by regulatory bodies practice. Moreover, acellular graft equivalents certain drugs provide option specific conditions without need or cells. Finally, emergence gene modulation treat disease, it would be presymptomatic presenting early symptoms, drastically reducing tissue. It necessary understand most recent developments this rapidly evolving field know which treated approach. This article provides an overview developing regenerative medicine guidance understanding towards disease.

Language: Английский

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Advancing genomic technologies and clinical awareness accelerates discovery of disease-associated tandem repeat sequences

Genome Research, Journal Year: 2021, Volume and Issue: 32(1), P. 1 - 27

Published: Dec. 29, 2021

Expansions of gene-specific DNA tandem repeats (TRs), first described in 1991 as a disease-causing mutation humans, are now known to cause >60 phenotypes, not just disease, and only humans. TRs common form genetic variation with biological consequences, observed, so far, dogs, plants, oysters, yeast. Repeat diseases show atypical clinical features, anticipation, multiple partially penetrant phenotypes among family members. Discovery repeat expansion loci accelerated through technological advances sequencing computational analyses. Between 2019 2021, 17 new TR expansions were reported, totaling 63 (>69 diseases), likelihood more discoveries, organisms. Recent historical lessons reveal that properly assessed presentations, coupled awareness, can guide discovery unstable TRs. We highlight critical but underrecognized aspects mutations. motifs may be present current reference genomes will forthcoming gapless long-read references. motif size single nucleotide kilobases/unit. At given locus, sequence purity vary consequence. Pathogenic “insertions” within nonpathogenic Expansions, contractions, somatic length variations have clinical/biological consequences. instabilities occur humans other epigenetically modified and/or chromosomal fragile sites. discuss the expanding field disease-associated instabilities, highlighting prospects, clues, tools, challenges for further discoveries understanding their pathological impacts—a vista is about expand.

Language: Английский

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Fuchs endothelial corneal dystrophy: an updated review

International Ophthalmology, Journal Year: 2024, Volume and Issue: 44(1)

Published: Feb. 12, 2024

Language: Английский

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Squishy matters – Corneal mechanobiology in health and disease

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 99, P. 101234 - 101234

Published: Jan. 2, 2024

The cornea, as a dynamic and responsive tissue, constantly interacts with mechanical forces in order to maintain its structural integrity, barrier function, transparency refractive power. Cells within the cornea sense respond various that fundamentally regulate their morphology fate development, homeostasis pathophysiology. Corneal cells also dynamically extracellular matrix (ECM) ensuing cell-ECM crosstalk serves signaling reservoir providing biophysical biochemical cues corneal cells. Here we provide an overview of mechanotransduction pathways then delve into recent advances mechanobiology, focusing on interplay between responses epithelial, stromal, endothelial We identify species-specific differences biomechanics facilitate identification optimal animal models study wound healing, disease, novel therapeutic interventions. Finally, key knowledge gaps opportunities mechanobiology are pressing for research community address especially pertinent domains limbal stem cell deficiency, keratoconus Fuchs' dystrophy. By furthering our understanding can contextualize discoveries regarding diseases well innovative treatments them.

Language: Английский

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A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: April 6, 2024

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with previous largest GWAS, total 3970 cases and 333,794 controls. confirm four loci, identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, COL18A1. further TCF4 locus GWAS admixed African Hispanic/Latino ancestries show an enrichment European-ancestry haplotypes at cases. Among associations are low frequency missense variants laminin genes LAMA5 LAMB1 which, together previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations may destabilize LM511 altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide scans colocalization analyses suggest CTG18.1 trinucleotide repeat expansion leads to dysregulation ion transport endothelium has pleiotropic effects on renal function.

Language: Английский

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Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(10), P. 5732 - 5755

Published: April 10, 2024

Expansion of a G4C2 repeat in the C9orf72 gene is associated with familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). To investigate underlying mechanisms instability, which occurs both somatically intergenerationally, we created novel mouse model ALS/FTD that harbors 96 copies repeats at humanized locus. In embryonic stem cells, observed two modes expansion. First, noted minor increases length per expansion event, was dependent on mismatch repair pathway protein Msh2. Second, found major event when DNA double- or single-strand break (DSB/SSB) artificially introduced proximal to repeats, homology-directed (HDR) pathway. mice, first mode primarily drove somatic Major changes length, including expansion, were SSB one-cell embryos, intergenerationally without DSB/SSB introduction if exceeded 400 copies, although spontaneous HDR-mediated has yet be identified. These findings provide strategy non-human genome offer insights into mechanism behind instability.

Language: Английский

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Novel insights into gene therapy in the cornea

Experimental Eye Research, Journal Year: 2020, Volume and Issue: 202, P. 108361 - 108361

Published: Nov. 16, 2020

Language: Английский

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RNA-Seq–based transcriptome analysis of corneal endothelial cells derived from patients with Fuchs endothelial corneal dystrophy

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: May 27, 2023

Fuchs endothelial corneal dystrophy (FECD) is the most common inherited disease. Fibrillar focal excrescences called guttae and edema due to cell death result in progressive vision loss. Multiple genetic variants have been reported, but pathogenesis of FECD not fully understood. In this study, we used RNA-Seq analyze differential gene expression endothelium obtained from patients with FECD. Differential analysis transcriptomic profiles revealed that 2366 genes (1092 upregulated 1274 downregulated genes) was significantly altered compared healthy subjects. Gene ontology demonstrated an enrichment involved extracellular matrix (ECM) organization, response oxidative stress, apoptotic signaling. Several pathway analyses consistently indicated dysregulation ECM-associated pathways. Our findings support previously proposed underlying mechanisms, including stress apoptosis cells, as well phenotypic clinical hallmark ECM deposits. Further investigation focusing on differentially expressed related these pathways might be beneficial for elucidating mechanisms developing novel therapies.

Language: Английский

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Deciphering novel TCF4-driven mechanisms underlying a common triplet repeat expansion-mediated disease

PLoS Genetics, Journal Year: 2024, Volume and Issue: 20(5), P. e1011230 - e1011230

Published: May 7, 2024

Fuchs endothelial corneal dystrophy (FECD) is an age-related cause of vision loss, and the most common repeat expansion-mediated disease in humans characterised to date. Up 80% European FECD cases have been attributed expansion a non-coding CTG element (termed CTG18.1) located within ubiquitously expressed transcription factor encoding gene, TCF4. The nature transcriptomic complexity TCF4 made it extremely challenging experimentally decipher molecular mechanisms underlying this disease. Here we comprehensively describe CTG18.1 expansion-driven components primary patient-derived cells (CECs), generated from large cohort individuals with CTG18.1-expanded (Exp+) 18.1-independent (Exp-) FECD. We employ long-read, short-read, spatial techniques interrogate expansion-specific biomarkers. Interrogation long-read sequencing alternative splicing analysis short-read data together reveals global extent altered occurring Exp+ FECD, unique transcripts associated CTG18.1-expansions. Similarly, differential gene expression highlights total consequences CECs. Furthermore, exon usage, pathway enrichment transcriptomics reveal isoform ratio skewing solely potential downstream functional consequences. Lastly, exome 134 Exp- identified rare (minor allele frequency <0.005) potentially deleterious (CADD>15) variants 7/134 cases, suggesting that independent may increase risk. In summary, our study supports hypothesis at least two distinct pathogenic mechanisms, RNA toxicity isoform-specific dysregulation, both underpin pathophysiology anticipate these will inform guide development translational interventions for triplet-repeat mediated

Language: Английский

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Dysregulation of the TCF4 Isoform in Corneal Endothelial Cells of Patients With Fuchs Endothelial Corneal Dystrophy

Investigative Ophthalmology & Visual Science, Journal Year: 2024, Volume and Issue: 65(6), P. 27 - 27

Published: June 17, 2024

This study evaluated the dysregulation of TCF4 isoforms and differential exon usage (DEU) in corneal endothelial cells (CECs) Fuchs dystrophy (FECD) with or without trinucleotide repeat (TNR) expansion intron region gene.

Language: Английский

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