Pre-messenger RNA non-productive exon sequences (Poison exons)

Pre-messenger RNA non-productive exon sequences, commonly referred to as "poison exons," are highly conserved segments within pre-messenger RNA that, when included in the mature transcript, introduce a premature termination codon (PTC). This inclusion triggers the nonsense-mediated decay (NMD) pathway, a cellular quality control mechanism that degrades the mRNA to prevent the translation of truncated or potentially toxic proteins (Lim et al., 2020, Nature Communications). These sequences function as natural regulatory elements that cells use to downregulate gene expression post-transcriptionally. In therapeutic contexts, these sequences are targeted to treat diseases caused by haploinsufficiency, where a single functional copy of a gene is insufficient for normal health. Antisense oligonucleotides (ASOs) are designed to bind to these non-productive sequences or their flanking splice sites, preventing their inclusion in the final mRNA (Stoke Therapeutics, 2024). By "skipping" the poison exon, the splicing machinery produces a productive, full-length mRNA transcript, thereby increasing the total amount of functional protein. This approach, known as Targeted Augmentation of Nuclear Gene Output (TANGO), is currently being evaluated in clinical trials for conditions such as Dravet syndrome and Autosomal Dominant Optic Atrophy (Lim et al., 2020).

Other names

Poison exonsCryptic exonsPseudoexonsNon-productive alternative exonsAS-NMD exonsStop-codon-containing exons

Antisense oligonucleotides bind to specific sequences within or near the non-productive exon to modulate splicing, typically promoting exon skipping to prevent the inclusion of premature termination codons and thereby avoiding nonsense-mediated decay to increase functional protein expression (Lim et al., 2020; Stoke Therapeutics, 2024).