title: Treatment of type 1 myotonic dystrophy by engineering site-specific RNA endonucleases that target (CUG)(n) repeats.
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.
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China; Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Choudhury
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Macro Science Solutions LLP, Chapel Hill, North Carolina, USA. Electronic address: zefeng@med.unc.edu.
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Wang
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D004722:Endoribonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D006868:Hydrolysis; D009223:Myotonic Dystrophy / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D011485:Protein Binding; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D004722:Endoribonucleases