title: Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models.
abstract: Myotonic dystrophy type 1 (DM1) is an inherited disease characterized by the inability to relax contracted muscles. Affected individuals carry large CTG expansions that are toxic when transcribed. One possible treatment approach is to reduce or eliminate transcription of CTG repeats. Actinomycin D (ActD) is a potent transcription inhibitor and FDA-approved chemotherapeutic that binds GC-rich DNA with high affinity. Here, we report that ActD decreased CUG transcript levels in a dose-dependent manner in DM1 cell and mouse models at significantly lower concentrations (nanomolar) compared to its use as a general transcription inhibitor or chemotherapeutic. ActD also significantly reversed DM1-associated splicing defects in a DM1 mouse model, and did so within the currently approved human treatment range. RNA-seq analyses showed that low concentrations of ActD did not globally inhibit transcription in a DM1 mouse model. These results indicate that transcription inhibition of CTG expansions is a promising treatment approach for DM1.
authors.affiliation: Institute of Molecular Biology and Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Siboni
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.affiliation: Institute of Molecular Biology and Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Wagner
authors.affiliation: Institute of Molecular Biology and Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Struck
authors.affiliation: Institute of Molecular Biology and Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Coonrod
authors.affiliation: Department of Chemistry, Reed College, Portland, OR 97202, USA.
authors.forename: Shanee A
authors.initials: SA
authors.lastname: Harriott
authors.affiliation: Department of Chemistry, Reed College, Portland, OR 97202, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Cass
authors.affiliation: Institute of Molecular Biology and Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Tanner
authors.affiliation: Institute of Molecular Biology and Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA; Department of Biochemistry & Molecular Biology, Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610, USA. Electronic address: aberglund@ufl.edu.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Berglund
mesh_terms: D000818:Animals; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D002151:Calorimetry; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology*; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D009223:Myotonic Dystrophy / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D012326:RNA Splicing / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic / Q000187:drug effects; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects* / Q000235:genetics; D033921:Vesicular Transport Proteins
chemical_list: C506944:Atp2a1 protein, mouse; D000071183:Autophagy-Related Proteins; C086321:CLC-1 channel; D018118:Chloride Channels; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C479922:Mbnl1 protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C550074:VPS39 protein, mouse; D033921:Vesicular Transport Proteins; D003609:Dactinomycin; D012313:RNA; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases