Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity

• Published in: American journal of human genetics Vol. 102; no. 4; pp. 528 - 539
• Main Authors: Zarouchlioti, Christina, Sanchez-Pintado, Beatriz, Hafford Tear, Nathaniel J., Klein, Pontus, Liskova, Petra, Dulla, Kalyan, Semo, Ma’ayan, Vugler, Anthony A., Muthusamy, Kirithika, Dudakova, Lubica, Levis, Hannah J., Skalicka, Pavlina, Hysi, Pirro, Cheetham, Michael E., Tuft, Stephen J., Adamson, Peter, Hardcastle, Alison J., Davidson, Alice E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.04.2018; Elsevier
• Subjects: Aged; Animals; antisense oligonucleotide; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cohort Studies; corneal dystrophy; Endothelial Cells - metabolism; Endothelium, Corneal - pathology; Female; Fuchs endothelial corneal dystrophy; Fuchs' Endothelial Dystrophy - genetics; Fuchs' Endothelial Dystrophy - pathology; Genetic Predisposition to Disease; Humans; Male; Mice, Inbred C57BL; non-coding mutations; Oligonucleotides, Antisense - pharmacology; Organ Specificity; repeat-expansion; Risk Factors; RNA Precursors - genetics; RNA Processing, Post-Transcriptional; RNA Splicing Factors - metabolism; RNA toxicity; RNA, Messenger - metabolism; transcription factor 4; Transcription Factor 4 - genetics; Trinucleotide Repeat Expansion - genetics; triplet repeat-mediated disease; RNA toxicity; repeat-expansion; antisense oligonucleotide; non-coding mutations; corneal dystrophy; Fuchs endothelial corneal dystrophy; triplet repeat-mediated disease; transcription factor 4
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2018.02.010

Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.