Bispecific aptamers target thyrotropin receptor (TSHR) and insulin growth factor-1 receptor (IGF-1R) for the improvement of orbital fibroblasts activation in the treatment of thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is a prominent extrathyroidal manifestation of Graves' disease that presents significant clinical challenges due to its organ-specific autoimmune nature. The condition may lead to orbital fibrosis and hyperplasia of fat tissue. Orbital fibroblasts (OFs) play a pivotal role in TAO pathogenesis, with the thyrotropin receptor (TSHR) and insulin growth factor-1 receptor (IGF-1R) being key in OF activation and the subsequent inflammatory and fibrotic responses. This study aimed to develop and evaluate a bispecific aptamer (Biapt), XW-7-IX-3, targeting TSHR and IGF-1R, leveraging the high affinity and specificity of nucleic acid aptamers. Our comprehensive in vitro and in vivo analyses demonstrated that Biapt XW-7-IX-3 exhibits superior binding to OFs, effectively attenuates OFs activation, fibrotic changes, and adipogenic differentiation, and significantly modulates the PI3K/AKT and ERK signaling pathway. Furthermore, in a TAO mouse model, Biapt XW-7-IX-3 treatment resulted in reduced fibrotic changes in orbital tissues, without affecting the mouse body weight. XW-7-IX-3 exhibited a favorable biological safety profile in vivo. These findings highlight the therapeutic potential of Biapt XW-7-IX-3 in addressing both local and systemic effects of TAO, underscoring the promise of bispecific aptamers as innovative treatments for complex autoimmune disorders.