双特异性核酸适体抑制CD34+眼眶成纤维细胞活化治疗Graves’眼病的功能和机制研究

Graves’眼病（GO）是成人最常见的眼眶疾病，可对患者外观和视功能产生巨大影响，但目前尚无有效根治手段。机制研究发现TSHR和IGF-1R介导PI3K-Akt通路诱导CD34+眼眶成纤维细胞（OFs）分化是GO进展的重要原因。而申请人和相关团队发现核酸适体可与靶蛋白高特异性结合治疗眼部疾病，因此在前期筛选并构建了靶向TSHR和IGF-1R的双特异性核酸适体XW-7-IX-3，实验显示其可与CD34+ OFs结合并抑制PI3K-Akt激活。因此提出假说XW-7-IX-3可结合并阻断TSHR和IGF-1R介导的P13K/Akt通路传导，抑制CD34+ OFs活化，治疗GO。通过对XW-7-IX-3靶向性和特异性、CD34+ OFs活化抑制效果、GO治疗效果和体内毒性及作用机制等的研究，揭示XW-7-IX-3治疗GO的功能及机制，为GO治疗提供新的策略，也为核酸适体可成药性研究提供新思路。

Graves ’ ophthalmopathy (GO) is the most common orbital disease in adults, which can have a huge impact on the appearance and visual function of patients, but there is currently no effective cure. TSHR and IGF-1R mediate the PI3K-Akt pathway to induce the differentiation of CD34+ orbital fibroblasts (OFs), which proved to be an important cause of GO progression. The applicant and related groups found that the aptamer can bind to the target protein with high specificity to treat eye diseases, so in the early stage, the bispecific nucleic acid aptamer XW-7-IX-3 targeting TSHR and IGF-1R was identified and constructed. Experiments show that it can bind to CD34+ OFs and inhibit PI3K-Akt activation. Therefore, the project proposed the hypothesis that XW-7-IX-3 could bind to and block TSHR and IGF-1R-mediated P13K/Akt pathway activation, inhibit CD34+ OFs activation, and treat GO. Through the research on the targeting and specificity of XW-7-IX-3, the inhibitory effect of XW-7IX-3 on CD34+ OFs activation, the therapeutic effect of XW-7IX-3 on GO, the toxicity in vivo and the mechanism, the function and pharmacological mechanism of XW-7-IX-3 in the treatment of GO were revealed. It provides new strategies for the treatment of GO, and also provides new ideas for the research on the drugability of aptamers.