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- Title
Treatment of Type 1 Myotonic Dystrophy by Engineering Site-specific RNA Endonucleases that Target (CUG)<sub>n</sub> Repeats.
- Authors
Zhang, Wenjing; Wang, Yang; Dong, Shuyun; Choudhury, Rajarshi; Jin, Yongfeng; Wang, Zefeng
- Abstract
Myotonic dystrophy type 1 (DM1) is caused by the expansion of (CTG)n in the 3′ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, which is transcribed as (CUG)n repeats that accumulate in the nucleus. The RNA repeats specifically sequester or change the expression levels of several RNA-binding proteins, leading to aberrant splicing of many target genes. In this study, we developed artificial site-specific RNA endonucleases (ASREs) that specifically bind and cleave (CUG)n repeats RNA. We have generated one ASRE that can target the expanded RNA repeats in DM1 patient cells and specifically degrade the pathogenic DMPK messenger RNAs with minimal effect on wild-type alleles. Such ASRE treatment significantly decreased the number of nuclear foci in DM1 patient cells and can reverse the missplicing of many genes affected in DM1 patients. Taken together, the application of ASRE provides a new route of gene therapy for DM1 treatment.
- Subjects
MYOTONIA atrophica; ENDONUCLEASES; RNA; PROTEIN kinases; GENETIC engineering; GENE therapy; THERAPEUTICS
- Publication
Molecular Therapy, 2014, Vol 22, Issue 2, p312
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1038/mt.2013.251