Bidou L, Hatin I, Perez N, Allamand V, Panthier J-J, Rousset J-P
1CNRS UMR 8621, Institut de Génétique et Microbiologie, Université Paris-Sud, Orsay Cedex, France.
Gene Ther. 2004 Apr;11(7):619-27. doi: 10.1038/sj.gt.3302211.
The suppression levels induced by gentamicin on premature stop codons, caused by primary nonsense mutations found in muscular dystrophy patients, were assessed using a very sensitive dual reporter gene assay. Results show that: (i) the effect of gentamicin on readthrough is similar in cultured cells and in vivo in murine skeletal muscle; (ii) a wide variability of readthrough efficiency is obtained, depending on the mutation tested; (iii) due to the complexity of readthrough regulation, efficiency cannot be predicted by the nucleotide context of the stop codon; (iv) only a minority of premature stop codons found in patients show a significant level of readthrough, and would thus be amenable to this pharmacological treatment, given our present understanding of the problem. These results probably provide an explanation for the relative failure of clinical trials reported to date using gentamicin to treat diseases due to premature stop codons, and emphasize that preliminary assays in cell culture provide valuable information concerning the potential efficiency of pharmacological treatments.
使用非常灵敏的双报告基因检测法，评估了庆大霉素对肌营养不良患者原发性无义突变导致的提前终止密码子的抑制水平。结果表明：（i）庆大霉素对通读的影响在培养细胞和小鼠骨骼肌体内相似；（ii）根据所测试的突变，获得了广泛的通读效率变异性；（iii）由于通读调控的复杂性，效率无法通过终止密码子的核苷酸上下文来预测；（iv）鉴于我们目前对该问题的理解，患者中发现的只有少数提前终止密码子显示出显著的通读水平，因此适合这种药物治疗。这些结果可能为迄今为止报道的使用庆大霉素治疗由提前终止密码子引起的疾病的临床试验相对失败提供了解释，并强调细胞培养中的初步检测为药物治疗的潜在效率提供了有价值的信息。
