Poison exon

PEs are generally highly conserved elements of the genome and are thought to have important regulatory roles in biology.

In this model, coupling alternative splicing to NMD (AS-NMD) is thought to tune transcript levels to regulate protein expression.

[13] Many proteins whose corresponding genes contain PEs autoregulate PE inclusion in their respective transcripts and thereby control their own levels via a feedback loop.

[9] The neuronal RBPs NOVA1/2 are translocated from the nucleus to the cytoplasm during pilocarpine-induced seizure in mice, and it was found that NOVA1/2 regulates the expression of cryptic PEs.

[33] It has been frequently observed that pharmacological or genetic perturbations that elevate cellular O-GlcNAc levels increase PE inclusion in the OGT transcript.

Mutations in the splicing factor SF3B1 have been found to promote PE inclusion in BRD9, reducing BRD9 mRNA and protein levels and leading to melanomagenesis.

[36] Mutations in U2AF1 promote PE inclusion in EIF4A2, leading to impaired global mRNA translation and acute myeloid leukemia (AML) chemoresistance through the integrated stress response pathway.

[25] In RAD50, TGAGT deletion is associated with a cryptic poison exon that occurs 30 nucleotides downstream within intron 21 mediated by altered U2AF recognition.

[43] SRSF2 mutations have been found to promote PE inclusion in the epigenetic regulator EZH2, resulting in impaired hematopoietic differentiation.

[52] Stoke Therapeutics is evaluating a strategy termed Targeted Augmentation of Nuclear Gene Output (TANGO).

In mouse models of Dravet syndrome, which is driven by mutations in SCN1A,[40][41][56] zorevunersen was able to reduce incidence of electrographic seizures and sudden unexpected death in epilepsy and prolong survival.

[60] Also in December 2024, Stoke Therapeutics disclosed that zorevunersen is generally well tolerated and shows substantial and sustained reductions in convulsive seizure frequency.

[63] Remix Therapeutics developed REM-422, which is an oral small molecule that promotes PE inclusion in the oncogene MYB.

Subsequent in vitro experiments showed that REM-422 selectively facilitates binding of the U1 snRNP complex to oligonucleotides containing the MYB 5' splice site sequence.

[69] Rgenta Therapeutics has also developed RGT-61159, an oral small molecule that promotes PE inclusion in MYB, as a potential treatment for adenoid cystic carcinoma (ACC).