title: Targeting nuclear RNA for in vivo correction of myotonic dystrophy.
abstract: Antisense oligonucleotides (ASOs) hold promise for gene-specific knockdown in diseases that involve RNA or protein gain-of-function effects. In the hereditary degenerative disease myotonic dystrophy type 1 (DM1), transcripts from the mutant allele contain an expanded CUG repeat and are retained in the nucleus. The mutant RNA exerts a toxic gain-of-function effect, making it an appropriate target for therapeutic ASOs. However, despite improvements in ASO chemistry and design, systemic use of ASOs is limited because uptake in many tissues, including skeletal and cardiac muscle, is not sufficient to silence target messenger RNAs. Here we show that nuclear-retained transcripts containing expanded CUG (CUG(exp)) repeats are unusually sensitive to antisense silencing. In a transgenic mouse model of DM1, systemic administration of ASOs caused a rapid knockdown of CUG(exp) RNA in skeletal muscle, correcting the physiological, histopathologic and transcriptomic features of the disease. The effect was sustained for up to 1 year after treatment was discontinued. Systemically administered ASOs were also effective for muscle knockdown of Malat1, a long non-coding RNA (lncRNA) that is retained in the nucleus. These results provide a general strategy to correct RNA gain-of-function effects and to modulate the expression of expanded repeats, lncRNAs and other transcripts with prolonged nuclear residence.
authors.affiliation: Department of Neurology, University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Thurman M
authors.initials: TM
authors.lastname: Wheeler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Leger
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Pandey
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Wentworth
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D065636:Myotonin-Protein Kinase; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012313:RNA / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics; D016914:Ribonuclease H / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C585517:DMPK protein, human; C585516:DMPK protein, mouse; C557040:Malat1 long non-coding RNA, mouse; D016376:Oligonucleotides, Antisense; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D022661:RNA, Untranslated; D012313:RNA; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D016914:Ribonuclease H