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MBNL derivatives for therapeutic application in myotonic dystrophy

Abstract : Myotonic dystrophy (DM) is an autosomal neuromuscular disease encompassing two distinct forms, type 1 (DM1) and type 2 (DM2), which are caused by abnormal microsatellite expansions of C(C)TG repeats in the 3’UTR of the DMPK and first intron of ZNF9 genes, respectively. Mutant RNAs carrying expanded repeats are retained in the nucleus as riboprotein aggregates that abnormally sequester MBNL splicing factors leading to alternative splicing misregulations associated with clinical symptoms. Although various therapeutic approaches for DM are under development, there is no effective therapy available so far. In this study, we designed a novel gene therapy strategy with the use of an engineered MBNL RNA-binding protein derivative that acts as a CUGexp-decoy to release sequestered endogenous MBNL factors and restore their proper functions. Expression of the decoy results in the correction of DM1-associated features in both in vitro and in vivo models of the disease. Subsequent optimization processes were applied to the engineered decoy and the most potent derivate that increases its functional capacity was selected for further therapeutic application. Additionally, we developed an autoregulatory system based on a splice-sensor strategy to control transgene product expression and provided a proof-of-concept of its efficacy in both in vitro and in vivo systems. In conclusion, my work establishes the potency of gene therapy treatment for DM and support the use of the decoy-based approach as an alternate or complementary therapeutic intervention for DM.
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Submitted on : Wednesday, September 15, 2021 - 1:01:14 AM
Last modification on : Saturday, January 8, 2022 - 3:22:29 AM
Long-term archiving on: : Thursday, December 16, 2021 - 6:06:27 PM


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  • HAL Id : tel-03344359, version 1


Magdalena Matloka. MBNL derivatives for therapeutic application in myotonic dystrophy. Molecular biology. Sorbonne Université, 2019. English. ⟨NNT : 2019SORUS269⟩. ⟨tel-03344359⟩



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