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Decoy gene therapy to reverse RNA toxicity in DM1
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Edité par CCSD -
International audience. "Introduction: Currently, a number of RNA-based therapeutic strategies for DM1 are beingdeveloped, including small molecule and antisense oligonucleotide approches. Here weassessed a gene therapy approach using a modified RNA-binding protein (RBP) with a highaffinity for expanded CUG repeats aimed to act as a decoy to displace sequesteredendogenous MBNL proteins from NA foci and reverse NA toxicity.Methods: We engineered a truncated MBNL1 protein that keeps the ZnF domains requiredfor the binding to CUG repeats but lacks the C-terminal domain. This MBNL1A-decoy hasreduced splicing activity but can still compete with MBNL1 for binding to CUGexp. Effect ofthe MBNL1A-decoy was assessed in both human DM1 muscle cells and HSA-LR mousemodel.Results: The binding of the decoy to CUGexp in DM1 muscle cells allows the releasesequestered endogenous MBNL1 from nuclear RNA foci, restores MBNL1 activity andcorrects the transcriptomic signature of DM1. In addtion, MBNL14-decoy forms less stableribonucleoprotein complexes than MBNL1 resulting in reduce levels of CUGexp-transcripts.In vivo, local or systemic delivery of the AAV-decoy into the skeletal muscle of HSA-LR miceleads to lonq-lasting correction of splicing defects and improvement of muscle physiology.Conclusions: This study supports the development of decov RBPs with high bindingaffinities for CUGexp as a therapeutic strategy for DM1."
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