Format

Send to

Choose Destination
Cell Rep. 2015 Dec 22;13(11):2386-2394. doi: 10.1016/j.celrep.2015.11.028. Epub 2015 Dec 10.

Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models.

Author information

1
Institute of Molecular Biology and Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA.
2
Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
3
Department of Chemistry, Reed College, Portland, OR 97202, USA.
4
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.

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.

PMID:
26686629
PMCID:
PMC4691565
DOI:
10.1016/j.celrep.2015.11.028
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center