A decoy-based gene therapy targeting CUGexp-DMPK transcripts in DM1

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Matloka, Magdalena | Arandel, Ludovic | Klein, Arnaud | Ney, Michel | Sureau, Alain | Rau, Frédérique | Marie, Joelle | Polay-Espinoza, Micaela | Naouar, Naira | Sergeant, Nicolas | Furling, Denis

Edité par CCSD -

International audience. Deleterious interactions of RNA binding factors with expanded CUG repeats leads to functional loss of MBNL1 resulting in alternative splicing misregulations and ultimately, to DM1 symptoms. Correction of disease-associated phenotypes such as splicing defects and myotonia by antisense oligonucleotides that either degrade mutant transcripts or interfere with CUGexp repeats act through the release of sequestered MBNL1 from CUGexp-RNA.Here we assessed a decoy-based gene therapy to restore a functional level of MBNL1 in DM1 cells and inhibit CUGexp-RNA toxicity using a truncated MBNL∆ polypeptide that lacks C-terminal part of the MBNL1 protein. The splicing activity of MBNL∆ is abolished but its RNA binding property is maintained.

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