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Functional Improvement of Dystrophic Muscle via let7 Site Blocking Oligonucleotide Mediated Utrophin Upregulation
Author(s) -
Mishra Manoj K,
Loro Emanuele,
Wilton Steve D,
Khurana Tejvir S
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb601
Subject(s) - utrophin , dystrophin , downregulation and upregulation , duchenne muscular dystrophy , phenotype , mdx mouse , skeletal muscle , muscular dystrophy , microbiology and biotechnology , microrna , chemistry , endocrinology , biology , bioinformatics , medicine , genetics , gene
Duchenne's muscular dystrophy (DMD) is a fatal genetic disease caused by the absence of dystrophin. Utrophin is the autosomal homolog of dystrophin and when overexpressed can compensate for dystrophin and rescue the dystrophic phenotype of the mdx mouse model of DMD. Utrophin is subject to miRNA mediated repression in muscle by several miRNAs including the let‐7c miRNA. Blocking the let‐7c‐utrophin interaction would be predicted to ‘repress the repression’ and increase utrophin expression. We developed and tested the ability of 2′‐O‐Methyl phosphorothioate (2OMePS)‐based utrophin 3′UTR let‐7c site blocking oligonucleotides (SBOs) to upregulate utrophin and improve the dystrophic phenotype in vivo . Blockade of the let‐7c‐utrophin interaction using bi‐weekly intraperitoneal injections of let7c SBOs for 1 month in young mdx mice led to increased utrophin expression along with improved muscle morphology, decreased muscle fibrosis and increased muscle specific strength. The functional improvement of dystrophic muscle achieved by using 2OMePS‐let7c SBOs suggests a novel, utrophin upregulation based therapeutic strategy for DMD. Support or Funding Information Acknowledgements: MDA, Shire Plc.