Global Analysis of Peptide-PMO as a Therapeutic Modulator for Myotonic Dystrophy Type 1 - Repeat Expansions & Myotonic Dystrophy (REDs) Accéder directement au contenu
Poster De Conférence Année : 2019

Global Analysis of 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 a pathogenic CTG repeat expansion in the 3' untranslated region of the DMPK gene. Toxic RNA, containing repeat CUG expansions, sequester proteins required for regulation of mRNA splicing and translation. These perturbations result in a multisystemic disorder characterized by myotonia, progressive muscle weakness, cardiac arrhythmias, cataracts and impaired endocrine and nervous system function. To date, there is no cure for DM1. Antisense oligonucleotides (ASO) are promising therapies, however progress has been limited by their poor uptake. To increase potency and improve target tissue uptake we have conjugated a cell-penetrating peptide to a PMO designed to specifically target DM1 toxic CUG repeats. In vitro and in vivo analysis of PPMO treatment of DM1 model systems has demonstrated prolonged correction of the DM1 phenotype by amelioration of myotonia, restoration of mis-splicing events, reduction of disease specific foci and liberation of MBNL1. Here we analysed the global effect of repeated PPMO administration on HSALA skeletal muscle transcriptome and proteome by deep paired-end NA sequencing and label-free mass spectrometry proteomics. Therapeutic modulation of HSALR quadriceps muscle by PPMO induced a widespread shift in transcriptomic and proteomic expression towards wild-type profiles and illustrated minimal off-target effects. This data highlights significant pre-clinical impact with both specific and global resolve by PPMO treatment on DM1 pathology and demonstrates encouraging therapeutic potential for DM1.
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Dates et versions

hal-04020127 , version 1 (08-03-2023)

Identifiants

  • HAL Id : hal-04020127 , version 1

Citer

Ashling Holland, Arnaud F Klein, Miguel Varela, R. Raz, Mike Gait, et al.. Global Analysis of Peptide-PMO as a Therapeutic Modulator for Myotonic Dystrophy Type 1. 6th International Congress of Myology, Mar 2019, Bordeaux, France. ⟨hal-04020127⟩
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