Proof of concept of peptide-linked blockmiR-induced MBNL functional rescue in myotonic dystrophy type 1 mouse model

Myotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase (DMPK) gene. DM1 patients exhibit a pathogenic number of rep...

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Published in:Molecular therapy. Nucleic acids 2022-03, Vol.27, p.1146-1155
Main Authors: Overby, Sarah J., Cerro-Herreros, Estefanía, González-Martínez, Irene, Varela, Miguel A., Seoane-Miraz, David, Jad, Yahya, Raz, Richard, Møller, Thorleif, Pérez-Alonso, Manuel, Wood, Matthew J., Llamusí, Beatriz, Artero, Rubén
Format: Article
Language:English
Subjects:
antisense oligonucleotides
blockmiRs
CPPs
miR-23b
muscleblind
myotonic dystrophy
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Summary:Myotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase (DMPK) gene. DM1 patients exhibit a pathogenic number of repetitions in DMPK, which leads to downstream symptoms. Another disease characteristic is altered microRNA (miRNA) expression. It was previously shown that miR-23b regulates the translation of MBNL1 into protein. Antisense oligonucleotide (AON) treatment targeting this miRNA can improve disease symptoms. Here, we present a refinement of this strategy targeting a miR-23b binding site on the MBNL1 3ʹ UTR in DM1 model cells and mice by using AONs called blockmiRs. BlockmiRs linked to novel cell-penetrating peptide chemistry showed an increase in MBNL1 protein in DM1 model cells and HSALR mice. They also showed an increase in muscle strength and significant rescue of downstream splicing and histological phenotypes in mice without disturbing the endogenous levels of other miR-23b target transcripts. [Display omitted] Targeting of the miR-23b binding site on the MBNL1 3ʹ UTR through the use of a peptide-conjugated blockmiR AON increases MBNL1 protein production in DM1 cells and HSALR mice. The blockmiR treatment also rescued hallmark splicing patterns and histological phenotypes and increased grip strength in mice.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2022.02.003