RNA Therapeutics Reshape Skeletal Muscle Disorder Treatment, Highlighting Delivery and Safety Hurdles

Skeletal muscle disorders, such as Duchenne muscular dystrophy (DMD), represent a significant unmet medical need, often leading to progressive muscle wasting, loss of function, and reduced quality of life. Current therapeutic strategies frequently fall short in addressing the underlying genetic defects or providing durable, systemic relief. This gap has spurred intense research into genetic and RNA-based interventions, which offer the potential for precise modulation of gene expression or direct correction of disease-causing alleles. Understanding these emerging strategies is crucial for advancing treatments beyond symptomatic management.

This comprehensive review synthesizes recent advances in RNA-based therapeutic strategies specifically targeting skeletal muscle disorders. The authors examined various modalities, including antisense oligonucleotides (ASOs) such as phosphorodiamidate morpholino oligomers (PMOs), RNase H-active gapmers, and steric-blocking ASOs. Additionally, the review covered small interfering RNAs (siRNAs) for post-transcriptional gene silencing and advanced RNA-guided gene-modifying technologies like CRISPR systems, including base editing and prime editing. The focus was on their mechanisms, progress in clinical translation, and the practical priorities for future development and implementation.

RNA therapeutics are significantly reshaping the treatment landscape for skeletal muscle disorders. Notably, four ASOs—eteplirsen, golodirsen, viltolarsen, and casimersen—have received FDA approval for DMD, working by inducing exon skipping to restore the reading frame and enable expression of internally truncated dystrophin. Beyond these, the field encompasses a broad spectrum of RNA modalities designed for splice switching, post-transcriptional gene silencing, and direct allele correction. However, broader clinical impact remains constrained by several key challenges: inefficient delivery to skeletal and especially cardiac muscle, the need for repeat administration for most modalities, and safety considerations that limit dose escalation and durability. Next-generation approaches aim to overcome these barriers through peptide- or antibody-conjugated oligonucleotides that enhance cellular uptake and tissue distribution, alternative chemistries with improved stability and potency, and viral or non-viral platforms for durable splice modulation. In parallel, CRISPR-based strategies offer the prospect of one-time correction, while raising important questions regarding delivery, immunogenicity, editing specificity, and long-term safety. > The review highlights improved muscle/heart delivery, controllable safety mechanisms, scalable manufacturing, and standardized biomarker-to-clinical outcome relationships as critical practical priorities for translation.