RNA-Based Therapies for Inherited Metabolic Disorders

Inherited metabolic disorders (IMDs) are a diverse and complex group of genetic conditions resulting from deficiencies in enzymes, transporters, or cofactors. These deficiencies lead to metabolic dysfunction and severe clinical consequences. Despite significant progress in understanding their molecular basis, treatment options remain limited for many IMDs. RNA-based therapies including antisense oligonucleotides (AONs), small interfering RNAs (siRNAs), and messenger RNA (mRNA) therapeutics have emerged as promising treatment strategies for modulating gene expression, silencing pathogenic transcripts, and restoring deficient proteins, offering new avenues for disease intervention. In this review, we summarise the chemistry and mechanisms of action of different RNA therapy modalities including splice-modulating and gene silencing AONs, siRNAs, and mRNA therapies. The delivery of these RNA-based therapies remains a significant challenge. Here, we outline the development of various delivery methods, including lipid nanoparticle (LNP) packaging, ligand conjugation, and tissue-specific delivery systems as well as their clinical applications in treating IMDs. We also summarise the clinical application of RNA therapies in rare diseases, an area that has grown rapidly in the last few years, as exemplified by the success of some n-of-1 therapies for IMDs, which have redefined personalised medicine by enabling rapid, patient-specific drug development. As RNA-based therapeutics continue to evolve, their clinical applications in IMDs will require continued innovation in novel chemistries, advanced delivery technologies, and streamlined regulatory frameworks to unlock their full potential.