title: Systemic delivery of a Peptide-linked morpholino oligonucleotide neutralizes mutant RNA toxicity in a mouse model of myotonic dystrophy.
abstract: Expansions of CUG trinucleotide sequences in RNA transcripts provide the basis for toxic RNA gain-of-function that leads to detrimental changes in RNA metabolism. A CTG repeat element normally resides in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, but when expanded it is the genetic lesion of myotonic dystrophy type 1 (DM1), a hereditary neuromuscular disease. The pathogenic DMPK transcript containing the CUG expansion is retained in ribonuclear foci as part of a complex with RNA-binding proteins such as muscleblind-like 1 (MBNL1), resulting in aberrant splicing of numerous RNA transcripts and consequent physiological abnormalities including myotonia. Herein, we demonstrate molecular and physiological amelioration of the toxic effects of mutant RNA in the HSA(LR) mouse model of DM1 by systemic administration of peptide-linked morpholino (PPMO) antisense oligonucleotides bearing a CAG repeat sequence. Intravenous administration of PPMO conjugates to HSA(LR) mice led to redistribution of Mbnl1 protein in myonuclei and corrections in abnormal RNA splicing. Additionally, myotonia was completely eliminated in PPMO-treated HSA(LR) mice. These studies provide proof of concept that neutralization of RNA toxicity by systemic delivery of antisense oligonucleotides that target the CUG repeat is an effective therapeutic approach for treating the skeletal muscle aspects of DM1 pathology.
authors: Genzyme, a Sanofi Company , Framingham, MA 01701, USA. andrew.leger@genzyme.com
authors: Andrew J
authors: AJ
authors: Leger
authors: Leocadia M
authors: LM
authors: Mosquea
authors: Nicholas P
authors: NP
authors: Clayton
authors: I-Huan
authors: IH
authors: Wu
authors: Timothy
authors: T
authors: Weeden
authors: Carol A
authors: CA
authors: Nelson
authors: Lucy
authors: L
authors: Phillips
authors: Errin
authors: E
authors: Roberts
authors: Peter A
authors: PA
authors: Piepenhagen
authors: Seng H
authors: SH
authors: Cheng
authors: Bruce M
authors: BM
authors: Wentworth
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D006801:Humans; D051379:Mice; D060172:Morpholinos / Q000008:administration & dosage* / Q000737:chemistry; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D065636:Myotonin-Protein Kinase; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000633:toxicity; D012326:RNA Splicing / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C585517:DMPK protein, human; C585516:DMPK protein, mouse; C493663:MBNL1 protein, human; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D010455:Peptides; D016601:RNA-Binding Proteins; D012313:RNA; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases