splice-switching oligonucleotides targeting insulin receptor

Splice-switching oligonucleotides (SSOs) targeting the insulin receptor (IR) are a class of antisense molecules designed to modulate the alternative splicing of the INSR gene. In various cancers, such as adrenocortical carcinoma (ACC), there is a preferential expression of the IR-A isoform, which lacks exon 11 and mediates mitogenic effects through high-affinity binding to insulin-like growth factor 2 (IGF2). These SSOs are engineered to bind to specific regulatory sequences, such as the CUGBP1 binding site, to prevent splicing factors from promoting IR-A formation. By promoting the inclusion of exon 11, the SSOs shift the isoform ratio toward the metabolic IR-B isoform. Preclinical studies in ACC cell lines and primary cultures have demonstrated that this shift leads to decreased cell proliferation and migration, and increased apoptosis, suggesting a therapeutic potential for precision-based oncology.

Other names

IR-targeting SSOSSO targeting IR alternative splicing