Advancing Therapeutic Strategies for Nonsense-Related Diseases: From Small Molecules to Nucleic Acid-Based Innovations

IF 3.7 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
IUBMB Life Pub Date : 2025-05-27 DOI:10.1002/iub.70027
Davide Ricci, Ilenia Cruciata, Ignazio Fiduccia, Emanuele Vitale, Federica Corrao, Alessio Branchini, Pietro Salvatore Carollo, Ivana Pibiri, Laura Lentini
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引用次数: 0

Abstract

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.

推进无意义相关疾病的治疗策略:从小分子到基于核酸的创新
基因编码区的无义突变在mRNA转录物中引入帧内过早终止密码子(PTC),导致翻译的早期终止和产生截断的无功能蛋白质。蛋白质表达的缺失和随之而来的基本细胞功能的丧失是导致所谓的遗传性无意义相关疾病(NRDs)的严重表型的原因,如囊性纤维化、血友病、杜氏肌营养不良症、法布里病、脉膜血症、Usher综合征、Shwachman-Diamond综合征,甚至某些类型的癌症。无义突变对NRDs的治疗提出了重大挑战,因为目前还没有直接解决这种遗传缺陷的具体方法。开发新的无意义抑制治疗策略是精准医学的一个重要目标。本文综述了一些最有前途的治疗方法和新兴的NRDs治疗策略。它既考虑了使用小分子来干扰与无义突变相关的分子机制,如翻译读透诱导药物(TRIDs)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、抗密码子工程trna (ACE-tRNA)或基于mrna的治疗。未来的研究应侧重于完善这些方法,探索综合和个性化的治疗方法,以提高治疗效果,确保护理质量的持续改善。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
IUBMB Life
IUBMB Life 生物-生化与分子生物学
CiteScore
10.60
自引率
0.00%
发文量
109
审稿时长
4-8 weeks
期刊介绍: IUBMB Life is the flagship journal of the International Union of Biochemistry and Molecular Biology and is devoted to the rapid publication of the most novel and significant original research articles, reviews, and hypotheses in the broadly defined fields of biochemistry, molecular biology, cell biology, and molecular medicine.
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