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

Manoj K. Mishra, Emanuele Loro, Kasturi Sengupta, Steve D. Wilton, Tejvir S. Khurana

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere0182676
JournalPLoS One
Volume12
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Fingerprint

Utrophin
muscular dystrophy
dystrophin
Muscle
oligonucleotides
Muscles
muscles
Duchenne Muscular Dystrophy
microRNA
Dystrophin
animal models
MicroRNAs
phenotype
Oligonucleotides
Inbred mdx Mouse
injection site
genetic disorders
intraperitoneal injection
fibrosis
histology

Cite this

Mishra, Manoj K. ; Loro, Emanuele ; Sengupta, Kasturi ; Wilton, Steve D. ; Khurana, Tejvir S. / Functional improvement of dystrophic muscle by repression of utrophin : Let-7c interaction. In: PLoS One. 2017 ; Vol. 12, No. 10.
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Functional improvement of dystrophic muscle by repression of utrophin : Let-7c interaction. / Mishra, Manoj K.; Loro, Emanuele; Sengupta, Kasturi; Wilton, Steve D.; Khurana, Tejvir S.

In: PLoS One, Vol. 12, No. 10, e0182676, 01.10.2017.

Research output: Contribution to journalArticle

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