Ricci Davide, Cruciata Ilenia, Fiduccia Ignazio, Vitale Emanuele, Corrao Federica, Branchini Alessio, Carollo Pietro Salvatore, Pibiri Ivana, Lentini Laura
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
Department of Life Sciences and Biotechnology and LTTA Centre, University of Ferrara, Ferrara, Italy.
IUBMB Life. 2025 May;77(5):e70027. doi: 10.1002/iub.70027.
Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.
基因编码区的无义突变会在mRNA转录本中引入框内过早终止密码子（PTC），导致翻译提前终止并产生截短的、无功能的蛋白质。在所谓的遗传性无义相关疾病（NRD），如囊性纤维化、血友病、杜氏肌营养不良症、法布里病、脉络膜血症、乌舍尔综合征、施瓦茨曼-戴蒙德综合征，甚至某些类型的癌症中，蛋白质表达的缺失以及随之而来的基本细胞功能的丧失导致了严重的表型。无义突变在NRD的治疗中构成了重大挑战，因为目前尚无直接解决这一基因缺陷的具体方法。开发新的无义抑制治疗策略是精准医学的一个关键目标。这篇综述描述了一些最有前景的治疗方法和治疗NRD的新兴策略。它既考虑了使用小分子干扰与无义突变相关的分子机制，如诱导翻译通读的药物（TRID）或无义介导的衰变（NMD）途径的抑制剂，也考虑了涉及核酸的创新方法，如基因编辑、反密码子工程化tRNA（ACE-tRNA）或基于mRNA的疗法。未来的研究应集中在完善这些方法以及探索综合和个性化治疗，以提高治疗效果并确保护理质量不断改善。
