Duchenne muscular dystrophy (DMD), a fatal X-linked disorder, features progressive muscle fibrosis as a key driver of mortality. While CTGF represents a therapeutic target for DMD, its VWC-domain-targeting antibody (FG-3019) failed in clinical trials. Through experimental validation, we identified CT-domain as a superior target domain, as it contributed more fibrosis activity of CTGF than VWC-domain without elevating compensatory TGF- β 1 level. Aptamers are synthetic oligonucleotides identified through SELEX, which can specifically bind to flexible protein domains through their unique 3D conformations. Their small molecular size enables effective tissue penetration while maintaining high target specificity, making them ideal CT-domain inhibitors. Nevertheless, conventional SELEX involves time-consuming and inefficient multiple screening rounds. Here, we employed our generative AI model, AptGEN, to rapidly discover a potent CT-domain specific aptamer within 42 days. This chemically modified aptamer (Apc003OA) distributed and remained in muscle tissues for an extended period, whereas FG-3019 could not. Importantly, it demonstrated better fibrosis inhibitory activity in vitro and in mdx mice when compared to FG-3019. Furthermore, Apc003OA demonstrated a favorable safety profile in mdx mice. Within 10 months, we progressed from target domain discovery, aptamer drug discovery, and then obtained both Orphan Drug Designation and Pediatric Rare Disease Designation by US Food and Drug Administration. AI-powered therapeutic aptamer drug discovery: Targeting CTGF CT-domain for Duchenne muscular dystrophy
Yao et al. (2026) studied this question.