RNA-based approaches to reverse repeat expansion toxicity in Myotonic Dystrophy - Repeat Expansions & Myotonic Dystrophy (REDs) Accéder directement au contenu
Communication Dans Un Congrès Année : 2019

RNA-based approaches to reverse repeat expansion toxicity in Myotonic Dystrophy

Résumé

Myotonic Dystrophy type 1 (DM1), one of the most common form of inherited neuromuscular disorders in adults is characterized by myotonia, progressive muscle weakness and wasting, cardiac defects, endocrine troubles and cognitive impairments. DM1 is an autosomal dominant disease caused by an expanded tract of CTG repeats located in the 3' UTR of the DMPK gene. Globally, the size of the expansion correlates with the clinical severity and the age of onset of the disease. DM1 is an RNA dominant disease and the expression of mutant DMPK transcripts containing expanded CUG repeats (CUGexp-RNAs) leads to a toxic RNA gain-of-function mechanism by altering functions of RNA binding proteins (RBP). Abnormal binding of RBPs from the MBNL family to pathologic CUG expansions and their sequestration within nuclear CUGexp-RNA foci results in their functional loss in DM1. Because MBNL1 are involved in the regulation of alternative splicing events during development, splicing misregulation of a subset of pre-mRNAs was found in striated muscles of adult DM1 patients and some of them were associated with clinical symptoms. Thus, mis-splicing of CLCN1, INSR, BIN1, DMD and SCN5A pre-mRNAs were associated respectively to myotonia, insulin resistance, muscle weakness, dystrophic process and cardiac conduction defects. To date, there is no cure for DM1 but several therapeutic strategies are under development. New gene editing technologies emerge and more advanced approaches using antisense oligonucleotides (ASO) aim to target mutant CUGexp-transcripts to reverse toxic NA dominant effects. However, ASO delivery in skeletal muscles following systemic administration remains a major challenge in DM1 since the integrity of the muscle fiber membranes is not compromised. To overcome this limitation and enhance the penetration of AS in DM1 skeletal muscles, we assessed the high potent cell delivery properties of peptide-conjugated PMO ASOs in a DM1 mouse model. Furthermore, we have also developed an novel decoy gene therapy approach based on engineered RBPs that displace MBNL1 from CUGexp- RNA and correct molecular defects in DM1 patient muscle cells. Efficacy of this CUGexp-decoy was tested in DM1 mice using AAV9 vectors that ensure efficient transduction and transgene-delivery into skeletal muscles. Altogether, our results show that the development of compounds targeting the pathologic tract of CUG repeats within the mutant transcripts represents a valuable approach for reversal of both molecular and physiologic DM1 features. We also provide new evidences that both viral or non-viral approaches could be considered for advancing towards clinical development in DM1
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Dates et versions

hal-04020148 , version 1 (08-03-2023)

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  • HAL Id : hal-04020148 , version 1

Citer

Denis Furling. RNA-based approaches to reverse repeat expansion toxicity in Myotonic Dystrophy. 6th International Congress of Myology, AFM-Telethon, Mar 2019, Bordeaux, France. ⟨hal-04020148⟩
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