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Poster De Conférence Année : 2019

Peptide-PMO as a Therapeutic Modulator for Myotonic Dystrophy Type 1

Résumé

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. DM1 is caused by the pathological microsatellite (CTG) repeat expansion in the 3’ untranslated region of the DMPK gene. Mutant RNAs containing the repeat CUG expansions are retained in the nucleus as foci and sequester proteins required for the regulation of mRNA splicing and translation. These perturbations result in a multisystemic disorder characterised by myotonia, progressive muscle weakness, cardiac arrhythmias, cataracts and impaired endocrine and nervous system function. To date there is no cure for DM1 only supportive care aimed at managing specific symptoms. Antisense oligonucleotides (ASO) like phosphorodiamidate morpholino oligomers (PMO) are a promising therapy for RNA gain-of function diseases like DM1. However, antisense approaches have been limited by their poor uptake. A strategy for enhanced ASO mediated delivery system is the addition of a cell-penetrating peptide (CPP) to the ASO to increased their potency and improved their uptake in target tissues. Our research has performed a pre-clinical investigation of the therapeutic ability for peptide-PMO (PPMO) treatment in DM1. We conjugated an arginine-rich cell-penetrating peptide to a disease targeting PMO designed to specifically target the toxic RNA CUG repeat expansion. In vitro analysis of PPMO treatment of differentiated DM1 patient myoblasts has shown correction of key mis-splicing events, reduction of disease specific foci and liberation of MBNL1. PMO versus PPMO comparative studies in the HSALR mouse model have demonstrated prolonged correction of the DM1 phenotype by amelioration of myotonia, restoration of mis-splicing events, and normalisation of global expression at the transcriptomic and proteomic level. This data highlights PPMO treatment, in vitro and in vivo, of DM1 has a significant pre-clinical impact and demonstrates encouraging therapeutic potential for DM1.
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Dates et versions

hal-04000595 , version 1 (22-02-2023)

Identifiants

  • HAL Id : hal-04000595 , version 1

Citer

Ashling Holland, Arnaud F Klein, Miguel Varela, R. Raz, Mike J Gait, et al.. Peptide-PMO as a Therapeutic Modulator for Myotonic Dystrophy Type 1. 6th International Congress of Myology, Mar 2019, Bordeaux, France. ⟨hal-04000595⟩
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