Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy

Jiaxin Hu, Ziye Rong, Xin Gong, Zhengyang Zhou, Vivek K. Sharma, Chao Xing, Jonathan K. Watts, David R. Corey, V. Vinod Mootha

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Abstract

Fuchs' endothelial corneal dystrophy (FECD) is the most common repeat expansion disorder. FECD impacts 4% of U.S. population and is the leading indication for corneal transplantation. Most cases are caused by an expanded intronic CUG tract in the TCF4 gene that forms nuclear foci, sequesters splicing factors and impairs splicing.We investigated the sense and antisense RNA landscape at the FECD gene and find that the sense-expanded repeat transcript is the predominant species in patient corneas. In patient tissue, sense foci number were negatively correlated with age and showed no correlation with sex. Each endothelial cell has 2 sense foci and each foci is single RNA molecule.We designed antisense oligonucleotides (ASOs) to target the mutant-repetitive RNA and demonstrated potent inhibition of foci in patient-derived cells. Ex vivo treatment of FECD human corneas effectively inhibits foci and reverses pathological changes in splicing. FECD has the potential to be a model for treating many trinucleotide repeat diseases and targeting the TCF4 expansion with ASOs represents a promising therapeutic strategy to prevent and treat FECD.

Original languageEnglish
Pages (from-to)1015-1026
Number of pages12
JournalHuman Molecular Genetics
Volume27
Issue number6
DOIs
StatePublished - 15 Mar 2018

Fingerprint

Fuchs' Endothelial Dystrophy
Trinucleotide Repeats
Oligonucleotides
RNA
Antisense Oligonucleotides
Cornea
Antisense RNA
Corneal Transplantation
Genes
Endothelial Cells
Corneal Dystrophy, Fuchs Endothelial, 1
Therapeutics
Population

Cite this

Hu, Jiaxin ; Rong, Ziye ; Gong, Xin ; Zhou, Zhengyang ; Sharma, Vivek K. ; Xing, Chao ; Watts, Jonathan K. ; Corey, David R. ; Vinod Mootha, V. / Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 6. pp. 1015-1026.
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title = "Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy",
abstract = "Fuchs' endothelial corneal dystrophy (FECD) is the most common repeat expansion disorder. FECD impacts 4{\%} of U.S. population and is the leading indication for corneal transplantation. Most cases are caused by an expanded intronic CUG tract in the TCF4 gene that forms nuclear foci, sequesters splicing factors and impairs splicing.We investigated the sense and antisense RNA landscape at the FECD gene and find that the sense-expanded repeat transcript is the predominant species in patient corneas. In patient tissue, sense foci number were negatively correlated with age and showed no correlation with sex. Each endothelial cell has 2 sense foci and each foci is single RNA molecule.We designed antisense oligonucleotides (ASOs) to target the mutant-repetitive RNA and demonstrated potent inhibition of foci in patient-derived cells. Ex vivo treatment of FECD human corneas effectively inhibits foci and reverses pathological changes in splicing. FECD has the potential to be a model for treating many trinucleotide repeat diseases and targeting the TCF4 expansion with ASOs represents a promising therapeutic strategy to prevent and treat FECD.",
author = "Jiaxin Hu and Ziye Rong and Xin Gong and Zhengyang Zhou and Sharma, {Vivek K.} and Chao Xing and Watts, {Jonathan K.} and Corey, {David R.} and {Vinod Mootha}, V.",
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Hu, J, Rong, Z, Gong, X, Zhou, Z, Sharma, VK, Xing, C, Watts, JK, Corey, DR & Vinod Mootha, V 2018, 'Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy', Human Molecular Genetics, vol. 27, no. 6, pp. 1015-1026. https://doi.org/10.1093/hmg/ddy018

Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy. / Hu, Jiaxin; Rong, Ziye; Gong, Xin; Zhou, Zhengyang; Sharma, Vivek K.; Xing, Chao; Watts, Jonathan K.; Corey, David R.; Vinod Mootha, V.

In: Human Molecular Genetics, Vol. 27, No. 6, 15.03.2018, p. 1015-1026.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy

AU - Hu, Jiaxin

AU - Rong, Ziye

AU - Gong, Xin

AU - Zhou, Zhengyang

AU - Sharma, Vivek K.

AU - Xing, Chao

AU - Watts, Jonathan K.

AU - Corey, David R.

AU - Vinod Mootha, V.

PY - 2018/3/15

Y1 - 2018/3/15

N2 - Fuchs' endothelial corneal dystrophy (FECD) is the most common repeat expansion disorder. FECD impacts 4% of U.S. population and is the leading indication for corneal transplantation. Most cases are caused by an expanded intronic CUG tract in the TCF4 gene that forms nuclear foci, sequesters splicing factors and impairs splicing.We investigated the sense and antisense RNA landscape at the FECD gene and find that the sense-expanded repeat transcript is the predominant species in patient corneas. In patient tissue, sense foci number were negatively correlated with age and showed no correlation with sex. Each endothelial cell has 2 sense foci and each foci is single RNA molecule.We designed antisense oligonucleotides (ASOs) to target the mutant-repetitive RNA and demonstrated potent inhibition of foci in patient-derived cells. Ex vivo treatment of FECD human corneas effectively inhibits foci and reverses pathological changes in splicing. FECD has the potential to be a model for treating many trinucleotide repeat diseases and targeting the TCF4 expansion with ASOs represents a promising therapeutic strategy to prevent and treat FECD.

AB - Fuchs' endothelial corneal dystrophy (FECD) is the most common repeat expansion disorder. FECD impacts 4% of U.S. population and is the leading indication for corneal transplantation. Most cases are caused by an expanded intronic CUG tract in the TCF4 gene that forms nuclear foci, sequesters splicing factors and impairs splicing.We investigated the sense and antisense RNA landscape at the FECD gene and find that the sense-expanded repeat transcript is the predominant species in patient corneas. In patient tissue, sense foci number were negatively correlated with age and showed no correlation with sex. Each endothelial cell has 2 sense foci and each foci is single RNA molecule.We designed antisense oligonucleotides (ASOs) to target the mutant-repetitive RNA and demonstrated potent inhibition of foci in patient-derived cells. Ex vivo treatment of FECD human corneas effectively inhibits foci and reverses pathological changes in splicing. FECD has the potential to be a model for treating many trinucleotide repeat diseases and targeting the TCF4 expansion with ASOs represents a promising therapeutic strategy to prevent and treat FECD.

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U2 - 10.1093/hmg/ddy018

DO - 10.1093/hmg/ddy018

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JO - Human Molecular Genetics

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SN - 0964-6906

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