synthetic intron-HSV-TK

synthetic intron-HSV-TK is an experimental gene therapy construct in which the herpes simplex virus thymidine kinase (HSV-TK) suicide gene is interrupted by a designed synthetic intron that is preferentially spliced in cancer cells bearing specific RNA splicing factor mutations, such as SF3B1, but remains largely unspliced in wild-type cells. In SF3B1‑mutant tumor cells, efficient excision of the synthetic intron restores functional HSV-TK expression, enabling phosphorylation and activation of the prodrug ganciclovir into toxic nucleoside triphosphates that inhibit DNA synthesis and induce cell death, while sparing wild-type cells that fail to express HSV-TK at sufficient levels.[1][2][6] This platform has been demonstrated preclinically using lentiviral delivery to selectively kill SF3B1‑mutant leukemia, breast cancer, uveal melanoma, and pancreatic cancer cells in vitro and in xenograft models upon ganciclovir administration, illustrating a mutation-dependent suicide gene strategy that exploits tumor-specific splicing dysregulation for targeted cancer therapy.[1]