Details

Autor(en) / Beteiligte

• González-Martínez, Irene
• Cerro-Herreros, Estefanía
• Moreno, Nerea
• García-Rey, Andrea
• Espinosa-Espinosa, Jorge
• Carrascosa-Sàez, Marc
• Piqueras-Losilla, Diego
• Arzumanov, Andrey
• Seoane-Miraz, David
• Jad, Yahya
• Raz, Richard
• Wood, Matthew J.
• Varela, Miguel A.
• Llamusí, Beatriz
• Artero, Rubén

Titel

Peptide-conjugated antimiRs improve myotonic dystrophy type 1 phenotypes by promoting endogenous MBNL1 expression

Ist Teil von

• Molecular therapy. Nucleic acids, 2023-12, Vol.34, p.102024, Article 102024

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2023

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the DMPK gene that generates toxic RNA with a myriad of downstream alterations in RNA metabolism. A key consequence is the sequestration of alternative splicing regulatory proteins MBNL1/2 by expanded transcripts in the affected tissues. MBNL1/2 depletion interferes with a developmental alternative splicing switch that causes the expression of fetal isoforms in adults. Boosting the endogenous expression of MBNL proteins by inhibiting the natural translational repressors miR-23b and miR-218 has previously been shown to be a promising therapeutic approach. We designed antimiRs against both miRNAs with a phosphorodiamidate morpholino oligonucleotide (PMO) chemistry conjugated to cell-penetrating peptides (CPPs) to improve delivery to affected tissues. In DM1 cells, CPP-PMOs significantly increased MBNL1 levels. In some candidates, this was achieved using concentrations less than two orders of magnitude below the median toxic concentration, with up to 5.38-fold better therapeutic window than previous antagomiRs. In HSALR mice, intravenous injections of CPP-PMOs improve molecular, histopathological, and functional phenotypes, without signs of toxicity. Our findings place CPP-PMOs as promising antimiR candidates to overcome the treatment delivery challenge in DM1 therapy. [Display omitted] Cerro-Herreros and colleagues designed a new type of antimiRs conjugated with peptides that improved ability to enhance MBNL levels compared with pre-existing candidates. Upregulation of MBNL proteins is a promising therapeutic approach for myotonic dystrophy, blocking endogenous miRNAs that suppress MBNL expression, rescue MBNL levels and correct disease alterations.