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

Area of Science:

• Molecular Biology
• RNA Metabolism
• Neuromuscular Disorders

Background:

• Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by CTG repeat expansion in the DMPK gene.
• Toxic RNA in DM1 sequesters MBNL1/2 proteins, disrupting alternative splicing and leading to fetal isoform expression in adults.

Purpose of the Study:

• To develop and evaluate novel antimiRs targeting miR-23b and miR-218 for DM1 therapy.
• To enhance the delivery of antimiRs to affected tissues using cell-penetrating peptides (CPPs) conjugated to phosphorodiamidate morpholino oligonucleotides (PMOs).

Main Methods:

• Design and synthesis of CPP-PMO conjugates targeting miR-23b and miR-218.
• In vitro assessment of MBNL1 levels in DM1 cells treated with CPP-PMOs.
• In vivo evaluation of CPP-PMO efficacy and toxicity in HSA(LR) mouse models of DM1.

Main Results:

• CPP-PMOs significantly increased MBNL1 levels in DM1 cells with an improved therapeutic window compared to previous antagomiRs.
• Intravenous administration of CPP-PMOs in HSA(LR) mice ameliorated molecular, histopathological, and functional deficits associated with DM1.
• No signs of toxicity were observed in mice treated with CPP-PMOs.

Conclusions:

• CPP-PMOs represent a promising therapeutic strategy for DM1 by effectively restoring MBNL1 levels and improving disease phenotypes.
• This approach addresses the critical challenge of drug delivery in DM1 therapy, offering a potentially effective treatment option.