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Communication Dans Un Congrès Année : 2022

Decoy gene therapy to reverse RNA toxicity in DM1

Résumé

"Introduction: Currently, a number of RNA-based therapeutic strategies for DM1 are being developed, including small molecule and antisense oligonucleotide approches. Here we assessed a gene therapy approach using a modified RNA-binding protein (RBP) with a high affinity for expanded CUG repeats aimed to act as a decoy to displace sequestered endogenous MBNL proteins from NA foci and reverse NA toxicity. Methods: We engineered a truncated MBNL1 protein that keeps the ZnF domains required for the binding to CUG repeats but lacks the C-terminal domain. This MBNL1A-decoy has reduced splicing activity but can still compete with MBNL1 for binding to CUGexp. Effect of the MBNL1A-decoy was assessed in both human DM1 muscle cells and HSA-LR mouse model. Results: The binding of the decoy to CUGexp in DM1 muscle cells allows the release sequestered endogenous MBNL1 from nuclear RNA foci, restores MBNL1 activity and corrects the transcriptomic signature of DM1. In addtion, MBNL14-decoy forms less stable ribonucleoprotein 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 mice leads to lonq-lasting correction of splicing defects and improvement of muscle physiology. Conclusions: This study supports the development of decov RBPs with high binding affinities for CUGexp as a therapeutic strategy for DM1."
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Dates et versions

hal-03999213 , version 1 (21-02-2023)

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  • HAL Id : hal-03999213 , version 1

Citer

Ludovic Arandel, Arnaud F Klein, Frédérique Rau, Alain Sureau, Aurélien Cordier, et al.. Decoy gene therapy to reverse RNA toxicity in DM1. International Myotonic Dystrophy Consortium Meeting IDMC-13, International Myotonic Dystrophy Consortium, May 2022, Osaka, Japan. ⟨hal-03999213⟩
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