CT102

Graves' ophthalmopathy (GO) is an orbital inflammatory autoimmune disease with limited treatment options. Advances in understanding of disease pathogenesis, particularly the dysregulated insulin-like growth factor-1 receptor (IGF-1R) signaling network in the orbital fibroblasts, have led to the development of targeted therapies against IGF-1R for GO. In this study, we aimed to evaluate the preclinical therapeutic potential of CT102, an IGF-1R-targeting antisense oligonucleotide. Antisense oligonucleotides represent a promising class of therapeutics due to their direct regulation of disease-causing genes and their variants, providing a compelling alternative to traditional "protein-specific" therapies. A GO-related rat model was established via intraperitoneal injection of bovine thyroglobulin and validated via the elevated serum thyroid peroxidase antibodies and suppressed serum thyroid-stimulating hormone levels. The GO-related rat model exhibited stable and consistent pathologic alterations of the extraocular muscles. Ocular administration of CT102 is well tolerated, and high-dose CT102 treatment showed therapeutic benefits as illustrated by the downregulation of IGF-1R level in ocular muscle tissue and reduction in pathologic abnormalities. Restoration of GO-associated biomarkers, including serum thyroid peroxidase antibody and serum thyroid-stimulating hormone levels, was observed in the high-dose CT102 group compared with normal controls. Furthermore, CT102 demonstrates superior modulation of GO-associated biomarkers relative to 2 positive controls: teprotumumab, the only anti-IGF-1R antibody approved by the US Food and Drug Administration, and miR-143, an RNA therapeutic targeting IGF-1R. To our knowledge, this study provides, for the first time, a rationale for clinical trials of CT102 in patients with GO and highlights the potential of anti-IGF-1R antisense oligonucleotides as a therapeutic strategy for GO. SIGNIFICANCE STATEMENT: To our knowledge, this study is the first to describe the therapeutic potential of anti- insulin-like growth factor-1 receptor antisense oligonucleotides in Graves' ophthalmopathy (GO), providing the rationale for future clinical trials in patients with GO and highlighting the potential of anti-insulin-like growth factor-1 receptor antisense oligonucleotide as a therapeutic strategy for GO.