Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia

Abstract

Background 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. Objectives 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. Methods 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. Results 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. Conclusions 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

Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia

“…Etravirine Using a cell-based screen for compounds that increase frataxin protein levels, Alfredi and colleagues identified etravirine, an antiviral drug that is in use in anti-HIV therapy, among a library of 853 FDA-approved drugs [113]. Etravirine was shown to function by increasing translation of existing FXN mRNA, rather than by increasing FXN gene expression, but just how etravirine functions to increase frataxin levels was not addressed in this study.…”

Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders

“…Of the 853 compounds examined, 19 were able to promote at least 2-fold increase in frataxin levels. From those, etravirine was the most potent frataxin inducer in cells derived from FRDA patients (Alfedi et al, 2019). Indeed, this molecule was able to importantly induce frataxin precursor levels by selectively enhancing the translation efficiency of frataxin transcripts by promoting a shift of frataxin mRNA from silent isolated ribosomes toward translationally active polysomal subsets.…”

“…Etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy, was identified as a potential frataxin-inducing molecule during the screening of a library of 853 US FDA-approved compounds using a high-throughput cell-based reporter assay to monitor variations in frataxin levels (Alfedi et al, 2019). Of the 853 compounds examined, 19 were able to promote at least 2-fold increase in frataxin levels.…”

Inferring Drug-Related Diseases Based on Convolutional Neural Network and Gated Recurrent Unit

“…Because FDA-approved drugs undergo biological experiments, clinical trials, and are evaluated for safety, drugs are often repositioned. Repositioning existing drugs for new indications or uses requires only 6.5 years, and the cost is $300 million, which is far less than the cost of developing a new drug [7,8,9].…”