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

Zarouchlioti, Christina, Sanchez-Pintado, Beatriz, Tear, Nathaniel J Hafford, Klein, Pontus, Liskova, Petra, Dulla, Kalyan, Semo, Ma'ayan, Vugler, Anthony A, Muthusamy, Kirithika, Dudakova, Lubica
et al (show 8 more authors) (2018) Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity. American Journal of Human Genetics, 102 (4). pp. 528-539.

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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 (R50 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.

Item Type: Article
Uncontrolled Keywords: antisense oligonucleotide, Fuchs endothelial corneal dystrophy, repeat-expansion, transcription factor 4, RNA toxicity, triplet repeat-mediated disease, corneal dystrophy, non-coding mutations
Depositing User: Symplectic Admin
Date Deposited: 20 Aug 2018 13:16
Last Modified: 19 Jan 2023 01:26
DOI: 10.1016/j.ajhg.2018.02.010
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