ASOptimizer: Optimizing antisense oligonucleotides through deep learning for IDO1 gene regulation

• Main Authors: Gyeongjo Hwang (Author), Mincheol Kwon (Author), Dongjin Seo (Author), Dae Hoon Kim (Author), Daehwan Lee (Author), Kiwon Lee (Author), Eunyoung Kim (Author), Mingeun Kang (Author), Jin-Hyeob Ryu (Author)
• Format: Book
• Published: Elsevier, 2024-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2162-2531; 10.1016/j.omtn.2024.102186
• Keywords: MT: Bioinformatics; antisense oligonucleotide; gapmer; optimization of RNA drugs; chemical modification; deep learning; Therapeutics. Pharmacology; RM1-950
• Source: Molecular Therapy: Nucleic Acids, Vol 35, Iss 2, Pp 102186- (2024)

Recent studies have highlighted the effectiveness of using antisense oligonucleotides (ASOs) for cellular RNA regulation, including targets that are considered undruggable; however, manually designing optimal ASO sequences can be labor intensive and time consuming, which potentially limits their broader application. To address this challenge, we introduce a platform, the ASOptimizer, a deep-learning-based framework that efficiently designs ASOs at a low cost. This platform not only selects the most efficient mRNA target sites but also optimizes the chemical modifications for enhanced performance. Indoleamine 2,3-dioxygenase 1 (IDO1) promotes cancer survival by depleting tryptophan and producing kynurenine, leading to immunosuppression through the aryl-hydrocarbon receptor (Ahr) pathway within the tumor microenvironment. We used ASOptimizer to identify ASOs that target IDO1 mRNA as potential cancer therapeutics. Our methodology consists of two stages: sequence engineering and chemical engineering. During the sequence-engineering stage, we optimized and predicted ASO sequences that could target IDO1 mRNA efficiently. In the chemical-engineering stage, we further refined these ASOs to enhance their inhibitory activity while reducing their potential cytotoxicity. In conclusion, our research demonstrates the potential of ASOptimizer for identifying ASOs with improved efficacy and safety.