Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
Laboratory of Molecular Neurobiology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
Mov Disord. 2019 Mar;34(3):323-334. doi: 10.1002/mds.27604. Epub 2019 Jan 9.
Friedreich's ataxia is an autosomal-recessive cerebellar ataxia caused by mutation of the frataxin gene, resulting in decreased frataxin expression, mitochondrial dysfunction, and oxidative stress. Currently, no treatment is available for Friedreich's ataxia patients. Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels.
With the aim to accelerate the development of a new therapy for Friedreich's ataxia, we took a drug repositioning approach to identify market-available drugs able to increase frataxin levels.
Using a cell-based reporter assay to monitor variation in frataxin amount, we performed a high-throughput screening of a library containing 853 U.S. Food and Drug Administration-approved drugs.
Among the potentially interesting candidates isolated from the screening, we focused our attention on etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy. Here, we show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron-sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients.
Considering its excellent safety profile along with its ability to increase frataxin levels and correct some of the disease-related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia. © 2019 International Parkinson and Movement Disorder Society.
弗里德赖希共济失调是一种常染色体隐性小脑共济失调，由 frataxin 基因突变引起，导致 frataxin 表达减少、线粒体功能障碍和氧化应激。目前，弗里德赖希共济失调患者尚无治疗方法。鉴于残留 frataxin 的水平对疾病严重程度有重大影响，弗里德赖希共济失调特定治疗的主要目标是增加 frataxin 水平。
为了加速弗里德赖希共济失调新疗法的开发，我们采用药物重定位方法来鉴定能够增加 frataxin 水平的市售药物。
我们使用基于细胞的报告基因检测法来监测 frataxin 数量的变化，对包含 853 种美国食品和药物管理局批准药物的文库进行高通量筛选。
在筛选出的潜在候选药物中，我们将注意力集中在依曲韦林上，它是一种目前用于抗人类免疫缺陷病毒治疗的抗病毒药物。我们发现，依曲韦林可以通过增强 frataxin 信使 RNA 的翻译，显著增加来自弗里德赖希共济失调患者的细胞中的 frataxin 水平。重要的是，在用依曲韦林处理的患者细胞系中，frataxin 的积累与未受影响的携带者细胞中的 frataxin 水平相当，这表明依曲韦林可能具有治疗相关性。事实上，依曲韦林治疗可恢复含铁-硫簇的酶 aconitase 的活性，并赋予弗里德赖希共济失调患者来源的细胞对氧化应激的抗性。
鉴于其良好的安全性、增加 frataxin 水平以及纠正一些与疾病相关缺陷的能力，依曲韦林是治疗弗里德赖希共济失调的一个很有前途的候选药物。
