Navigating molecular therapies: The emerging role of mRNA in treating inherited metabolic diseases

Abstract

Inherited metabolic diseases (IMDs) are a diverse group of rare genetic disorders caused by enzymatic deficiencies that disrupt essential biochemical pathways. Current treatments remain largely supportive and fail to address the molecular root cause. Messenger RNA (mRNA)-based therapeutics, delivered by lipid nanoparticles (LNPs), have recently emerged as a powerful treatment strategy: mRNA enables transient and programmable protein expression, while LNPs provide an effective, non-viral vehicle with natural liver tropism. Initial phase I/II clinical trials and n = 1 cases in liver-dominant IMDs have shown encouraging results. Yet, given the rarity of each IMD and the small patient numbers in individual trials, definitive insights into efficacy and safety require integrating evidence across multiple disorders. In this review, we synthesize the emerging clinical trial evidence of mRNA-LNP therapies across IMDs, highlighting both enzyme replacement and genome editing strategies. We discuss the clinical promise and modularity of these approaches, alongside remaining challenges related to durability, immunogenicity, and extrahepatic delivery. The recent and anticipated evolving developments position mRNA-LNP therapeutics at the forefront of precision medicine, offering a flexible therapeutic platform with applications ranging from bridge therapy to long-term stabilization or potential one-time disease-modifying interventions, transforming the prospect of IMD management.