RNA Therapeutics for Duchenne Muscular Dystrophy: Exon Skipping, RNA Editing, and Translational Insights from Genome-Edited Microminipig Models

TL;DR

This paper reviews RNA-based therapies for Duchenne muscular dystrophy and highlights the use of genome-edited microminipigs as a model for testing these treatments.

Contribution

The paper introduces genome-edited microminipigs as a novel and effective model for preclinical evaluation of RNA-based DMD therapies.

Findings

Genome-edited microminipigs exhibit key features of human Duchenne muscular dystrophy, including cardiac and skeletal muscle impairments.

RNA editing and exon skipping therapies show potential for correcting dystrophin expression in DMD.

Microminipigs provide a practical platform for evaluating therapeutic delivery to the heart and diaphragm.

Abstract

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease (NMD) caused by loss-of-function mutations in the DMD gene. RNA-based therapies, especially antisense oligonucleotides (ASO)-mediated exon skipping and adenosine deaminase acting on RNA (ADAR)-guided RNA editing, have emerged as complementary approaches that modulate pre-mRNA splicing or correct transcripts without altering genomic DNA. Current phosphorodiamidate morpholino oligomer (PMO) drugs targeting exons 51, 53, and 45 provide mutation-class-specific benefit. At the same time, next-generation delivery strategies (e.g., peptide-conjugated PMOs (PPMOs), antibody–oligonucleotide conjugates (AOC), and endosomal-escape vehicles) aim to improve skeletal, cardiac, and diaphragm exposure. In parallel, RNA editing strategies offer a route to correct select nonsense or missense variants at the base level and may, in principle, restore near-native dystrophin expression. Meaningful translation of these modalities requires predictive large-animal models. A genome-edited microminipig (MMP) bearing DMD exon-23 mutations faithfully recapitulates hallmark features of human DMD. That includes early locomotor deficits, elevated serum creatine kinase (CK) and cardiac troponin T, progressive myocardial fibrosis, and a decline in left-ventricular ejection fraction (LVEF), while maintaining a manageable lifespan of approximately 30 months suitable for long-term studies. In particular, the MMP model provides a practical platform for addressing the persistent challenge of efficient therapeutic delivery to the heart and diaphragm through longitudinal dosing, imaging, and biopsy. In this review, we synthesize clinical progress in exon skipping, outline the promise of RNA editing, and integrate recent insights from Duchenne muscular dystrophy model for microminipigs (DMD-MMPs) as an advanced surrogate for preclinical development and translational evaluation.

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