Functional improvement of dystrophic muscle by repression of utrophin: let-7c interaction

Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by an absence of the 427kD muscle-specific dystrophin isoform. Utrophin is the autosomal homolog of dystrophin and when overexpressed, can compensate for the absence of dystrophin and rescue the dystrophic phenotype of the mdx mouse...

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Bibliographic Details
Published inPloS one Vol. 12; no. 10; p. e0182676
Main Authors Mishra, Manoj K., Loro, Emanuele, Sengupta, Kasturi, Wilton, Steve D., Khurana, Tejvir S.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 18.10.2017
Public Library of Science (PLoS)
Subjects
3' Untranslated regions
Analysis
Animals
Biology and Life Sciences
Cancer
Care and treatment
Diagnosis
Duchenne muscular dystrophy
Duchenne's muscular dystrophy
Dystrophin
Dystrophy
Fibrosis
Genes
Health aspects
HEK293 Cells
Histology
Homology
Humans
Injections, Intraperitoneal
Male
Medicine
Medicine and Health Sciences
Mice, Inbred mdx
MicroRNA
MicroRNAs - metabolism
miRNA
Muscle, Skeletal - drug effects
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Muscular dystrophy
Muscular Dystrophy, Duchenne - metabolism
Muscular Dystrophy, Duchenne - pathology
Oligonucleotides
Oligonucleotides - administration & dosage
Oligonucleotides - pharmacology
Phosphorothioate
Physiology
Protein Binding - drug effects
Proteins
Reproducibility of Results
Research and Analysis Methods
Rodents
Studies
Up-Regulation - drug effects
Utrophin
Utrophin - metabolism
United States > US
Pennsylvania
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Summary:Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by an absence of the 427kD muscle-specific dystrophin isoform. Utrophin is the autosomal homolog of dystrophin and when overexpressed, can compensate for the absence of dystrophin and rescue the dystrophic phenotype of the mdx mouse model of DMD. Utrophin is subject to miRNA mediated repression by several miRNAs including let-7c. Inhibition of utrophin: let-7c interaction is predicted to 'repress the repression' and increase utrophin expression. We developed and tested the ability of an oligonucleotide, composed of 2'-O-methyl modified bases on a phosphorothioate backbone, to anneal to the utrophin 3'UTR and prevent let-7c miRNA binding, thereby upregulating utrophin expression and improving the dystrophic phenotype in vivo. Suppression of utrophin: let-7c interaction using bi-weekly intraperitoneal injections of let7 site blocking oligonucleotides (SBOs) for 1 month in the mdx mouse model for DMD, led to increased utrophin expression along with improved muscle histology, decreased fibrosis and increased specific force. The functional improvement of dystrophic muscle achieved using let7-SBOs suggests a novel utrophin upregulation-based therapeutic strategy for DMD.
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Competing Interests: The study was supported in part, by sponsored research agreements from Muscular Dystrophy Association, USA and Shire plc (a commercial entity), which included milestones, patent, royalties and licensing options. Funding sources had no role in design, data collection and analysis, preparation of the manuscript and/or decision to publish. The sponsored research agreements are no longer in effect. TSK and SDW are inventors on patent application "Methods for enhancing utrophin production via inhibition of microrna" related to this strategy (US8916532 B2, 62/193,470). The patent and intellectual property rights are assigned and managed by the Center for Technology Transfer, University of Pennsylvania. The funding and patent does not alter our adherence to PLOS ONE policies on sharing data and materials.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0182676