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, Venkateswara Mootha

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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 (US)
Pages (from-to)1015-1026
Number of pages12
JournalHuman molecular genetics
Issue number6
StatePublished - Mar 15 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy'. Together they form a unique fingerprint.

Cite this