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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Poly-l-aspartic Acid Enhances and Prolongs Gentamicin-mediated Suppression of the CFTR-G542X Mutation in a Cystic Fibrosis Mouse Model
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Poly-l-aspartic Acid Enhances and Prolongs Gentamicin-mediated Suppression of the CFTR-G542X Mutation in a Cystic Fibrosis Mouse Model

机译：聚-1-天冬氨酸增强并延长庆大霉素介导的作用 囊性纤维化小鼠CFTR-G542X突变的抑制。 模型

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Aminoglycosides such as gentamicin have the ability to suppress translation termination at premature stop mutations, leading to a partial restoration of protein expression and function. This observation led to studies showing that this approach may provide a viable treatment for patients with genetic diseases such as cystic fibrosis that are caused by premature stop mutations. Although aminoglycoside treatment is sometimes associated with harmful side effects, several studies have shown that the co-administration of polyanions such as poly-l-aspartic acid (PAA) can both reduce toxicity and increase the intracellular aminoglycoside concentration. In the current study we examined how the co-administration of gentamicin with PAA influenced the readthrough of premature stop codons in cultured cells and a cystic fibrosis mouse model. Using a dual luciferase readthrough reporter system in cultured cells, we found that the co-administration of gentamicin with PAA increased readthrough 20–40% relative to cells treated with the same concentration of gentamicin alone. Using a Cftr-/- hCFTR-G542X mouse model, we found that PAA also increased the in vivo nonsense suppression induced by gentamicin. Following the withdrawal of gentamicin, PAA significantly prolonged the time interval during which readthrough could be detected, as shown by short circuit current measurements and immunofluorescence. Because the use of gentamicin to suppress disease-causing nonsense mutations will require their long term administration, the ability of PAA to reduce toxicity and increase both the level and duration of readthrough has important implications for this promising therapeutic approach.
机译：氨基糖苷类如庆大霉素具有抑制过早终止突变处翻译终止的能力，从而导致蛋白质表达和功能的部分恢复。该观察结果导致研究表明，该方法可能为患有遗传性疾病（如由过早的终止突变引起的囊性纤维化）的患者提供可行的治疗方法。尽管氨基糖苷治疗有时会带来有害的副作用，但多项研究表明，聚阴离子（如聚-1-天冬氨酸（PAA））的共同给药可以降低毒性并增加细胞内氨基糖苷的浓度。在当前的研究中，我们研究了庆大霉素与PAA的共同给药如何影响培养细胞和囊性纤维化小鼠模型中过早终止密码子的通读。在培养的细胞中使用双重荧光素酶通读报告系统，我们发现与单独使用相同浓度的庆大霉素处理的细胞相比，庆大霉素与PAA的共同给药可提高通读率20–40％。使用Cftr -/- hCFTR-G542X小鼠模型，我们发现PAA还增加了庆大霉素诱导的体内无意义抑制。庆大霉素撤药后，PAA 大大延长了通读的时间间隔 检测到，如短路电流测量和 免疫荧光。因为使用庆大霉素来抑制致病 无意义的突变将需要长期管理， PAA可以降低毒性并增加通读水平和持续时间 对这种有前途的治疗方法具有重要意义。

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