Programmable target RNA sequence

A programmable target RNA sequence is a specific segment of a ribonucleic acid molecule, such as messenger RNA (mRNA) or non-coding RNA, that is targeted by sequence-specific therapeutic agents. This concept is the foundation of programmable medicines, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and CRISPR-Cas13 systems, which utilize Watson-Crick base pairing to achieve high specificity (Crooke et al., 2021; Setten et al., 2019). By binding to these sequences, therapeutic effectors can trigger various outcomes: ASOs and siRNAs typically induce RNA degradation via RNase H or the RNA-induced silencing complex (RISC), while newer technologies like ADAR-mediated editing allow for precise base changes within the transcript (Abudayyeh et al., 2017; Reautschnig et al., 2022). This approach is highly versatile, enabling the modulation of gene expression for targets that were previously considered undruggable at the protein level, such as transcription factors or scaffolding proteins (Lieberman, 2018). Clinical applications span a broad spectrum, including the treatment of spinal muscular atrophy, hereditary transthyretin-mediated amyloidosis, and various cancers (Adams et al., 2018). However, the primary therapeutic challenges involve ensuring efficient delivery to target tissues and minimizing off-target effects, where the drug binds to unintended RNA sequences with partial complementarity (Khvorova & Watts, 2017).

Other names

Target RNARNA transcriptmRNA targetProgrammable RNA substrate

RNA interference (RNAi), RNase H-mediated degradation, Splice modulation, Steric hindrance, RNA editing (e.g., A-to-I editing), and RNA cleavage.