Nucleic Acid Therapeutics in Rare Disease: From Precision Medicine to Programmable Platforms

ABSTRACT

Nucleic acid therapeutics (NATs), including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), messenger RNA (mRNA) therapeutics and programmable editing technologies, are reshaping the therapeutic landscape for inherited metabolic and genetic disease. Unlike conventional small molecules or biologics, NATs enable sequence‐directed modulation of target gene expression and therefore provide unprecedented flexibility for targeting pathogenic mechanisms previously considered undruggable. Recent clinical successes have established proof of concept for multiple NAT modalities across neurological, hepatic, muscular and metabolic disorders. However, broader implementation remains constrained by challenges in tissue‐specific delivery, biomarker validation, natural‐history infrastructure and evidence generation in ultra‐rare populations. In parallel, increasing platform reproducibility is beginning to challenge traditional product‐based regulatory paradigms. This review examines the principal classes of NATs and proposes a practical framework for modality selection based on disease biology, tissue accessibility, durability, reversibility and clinical context. We discuss key translational bottlenecks beyond delivery, including biomarker–outcome relationships, small‐population trial design and the limitations of conventional evidentiary frameworks in rare disease. A central theme of this review is the growing transition from isolated precision medicines towards increasingly programmable therapeutic platforms. We explore how advances in extrahepatic delivery, computational oligonucleotide design, artificial intelligence‐assisted optimisation and programmable editing technologies may progressively support more scalable and individualised therapeutic development. Finally, we discuss emerging regulatory frameworks that may better accommodate platform‐level predictability while maintaining rigorous evaluation of sequence‐specific and disease‐specific risks.