Low-dose of peptide-conjugate antisense oligonucleotides targeting CUGexp-RNA in murine skeletal muscles normalizes Myotonic Dystrophy 1 phenotype - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Poster De Conférence Année : 2019

Low-dose of peptide-conjugate antisense oligonucleotides targeting CUGexp-RNA in murine skeletal muscles normalizes Myotonic Dystrophy 1 phenotype

Résumé

Antisense oligonucleotides (ASOs) targeting pathologic RNAs have shown promising therapeutic corrections for many genetic diseases including Myotonic Dystrophy type 1 (DM1). DM1 is a dominant neuromuscular disease caused by the abnormal amplification of a CTG repeated sequence in the 3’UTR of the DMPK gene. Expression of mutant transcripts containing expanded CUG repeats (CUGexp) leads to a deleterious RNA gain-of-function mechanism, in which CUGexp-transcripts are retained within the nucleus and alter the function of RNA-binding proteins such as MBNL splicing factors, leading to splicing defects and muscular dysfunction. ASO strategies can reverse the RNA toxicity induced by the expression of CUGexp-RNA. However systemic use of ASOs remains challenging for this muscular dystrophy because of the poor skeletal muscle uptake as pointed out by a recent clinical trial. Here, we show that advanced Pip6a-conjugate peptides strongly enhanced morpholino phosphorodiamidate oligomer (PMO) delivery into skeletal muscles of a DM1 mouse model (HSA-LR) after systemic administration in comparison to naked PMO. Antisense Pip6a-PMOs targeting pathologic CUGexp repeats inhibit the detrimental sequestration of MBNL1 splicing factor by nuclear CUGexp-RNA foci and consequently its functional loss. Thus low-dose of Pip6a-CAG ASOs induces a complete normalization of the myotonia in treated HSA-LR mice along with the correction of splicing defects and altered gene expression. Long-term studies reveal than the compound is still active six months after injection. In addition, the beneficial effect of the Pip6-CAG treatment was confirmed in human DM1 patient-derived muscle cells containing >2000 CTG repeats. This study demonstrates that pip6a-PMO treatment allows a lasting normalization of DM1-associated phenotypes at both molecular and functional levels supporting the use of advanced pip-conjugates for enhanced ASO systemic delivery in DM1 skeletal muscles.
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Dates et versions

hal-04000552 , version 1 (22-02-2023)

Identifiants

  • HAL Id : hal-04000552 , version 1

Citer

Arnaud F. Klein, Miguel A. Varela, Ludovic Arandel, Ashling Holland, Naira Naouar, et al.. Low-dose of peptide-conjugate antisense oligonucleotides targeting CUGexp-RNA in murine skeletal muscles normalizes Myotonic Dystrophy 1 phenotype. 6th International Congress of Myology, Mar 2019, Bordeaux, France. ⟨hal-04000552⟩
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