Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia
| Autor: | L. Mannucci, Dario Serio, Alessandra Rufini, Laura Pacini, Giorgia Pedini, Florence Malisan, Roberto Testi, Damiano Sergio Massaro, Luca Panarello, Monica Benini, Nicola Toschi, Ivano Condò, Giorgia Alaimo, Giulia Alfedi, Riccardo Luffarelli, Silvia Fortuni |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Drug congenital hereditary and neonatal diseases and abnormalities Ataxia medicine.drug_class media_common.quotation_subject Etravirine Bioinformatics medicine.disease_cause 03 medical and health sciences 0302 clinical medicine medicine media_common Mutation biology Cerebellar ataxia business.industry 3. Good health Drug repositioning 030104 developmental biology Neurology Frataxin biology.protein Neurology (clinical) medicine.symptom Antiviral drug business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Movement Disorders. 34:323-334 |
| ISSN: | 0885-3185 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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