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

  title={Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia},
  author={Giulia Alfedi and Riccardo Luffarelli and Ivano Cond{\`o} and Giorgia Pedini and Liliana Mannucci and Damiano Sergio Massaro and Monica Benini and Nicola Toschi and Giorgia Alaimo and Luca Panarello and Laura Pacini and Silvia Fortuni and Dario Serio and Florence Malisan and Roberto Testi and Alessandra Rufini},
  journal={Movement Disorders},
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. 
Drug Repositioning in Friedreich Ataxia
Recent efforts aimed at the identification of a therapy for Friedreich ataxia through drug repositioning are described, and the limitation of such strategies are discussed.
Etravirine in Friedreich's ataxia: Lessons from HIV?
The reconstitution of aconitase shows that the etravirine-induced increase in frataxin leads to functional enzymatic improvements that may be disease related, and there are several necessary steps before this medication could be tried widely in patients.
Friedreich ataxia: clinical features and new developments.
A novel understanding of gene silencing in FRDA, reflecting a variegated silencing pattern, will have applications to current and future therapeutic interventions and new perspectives on the neuroanatomy of FRDA will refine the time course and anatomical targeting of novel approaches.
Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia
Friedreich ataxia (FRDA), the most common inherited ataxia, is caused by transcriptional silencing of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin. Currently, there is
Emerging therapies in Friedreich’s Ataxia
Agents that enhance mitochondrial function, such as Nrf2 activators, dPUFAs and catalytic antioxidants, as well as novel methods of frataxin augmentation and genetic modulation will hopefully provide treatment for this devastating disease.
A Case Report of Friedreich's Ataxia Management in A 24-Year-Old Woman Based on Iranian Traditional Medicine
A case of Friedrich's ataxia is presented in a 24-year-old woman under treatment with conventional methods, with obvious symptoms of atAXia in walking, limb tremor and dysarthria, and within 7 months of pharmacological treatment and nutritional recommendations based on Iranian traditional medicine, mentioned symptoms decreased.
Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders
The scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington’s disease, Friedreich's ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis are discussed.
Recessive cerebellar and afferent ataxias — clinical challenges and future directions
The main developments in understanding the complex pathology that affects the sensory neurons and cerebellum, which seem to be most vulnerable to disorders that affect mitochondrial function and DNA repair mechanisms are reviewed, including the main pathophysiological mechanisms of cerebellar and afferent ataxias are mitochondrial dysfunction and DNA break repair defects.
The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases
The aim of the review is to discuss the mechanisms underlying energy production, oxidative stress generation, cell signaling, autophagy, and inflammation triggered or conditioned by the mitochondria, mainly focusing on the role of mitochondria.


Progress in the treatment of Friedreich ataxia.
Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion
A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.
Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes.
The data suggest that a reduction in frataxin results in oxidative damage, given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies.
Pharmacological therapeutics in Friedreich ataxia: the present state
Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective.
Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia
Dyclonine represents a novel therapeutic strategy that can potentially be repurposed for the treatment of FA and induces the Nrf2 [nuclear factor (erythroid-derived 2)-like 2] transcription factor, which shows binds an upstream response element in the FXN locus.
Friedreich's ataxia: Past, present and future
Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model
It is shown that frataxin levels can be upregulated by interferon gamma (IFNγ) in a variety of cell types, including primary cells derived from FRDA patients, and in vivo treatment with IFNγ increases fr ataxin expression in DRG neurons, prevents their pathological changes and ameliorates the sensorimotor performance in FRDA mice.
Translating HDAC inhibitors in Friedreich’s ataxia
The evidence that histone postsynthetic modifications and heterochromatin formation are responsible for FXN gene silencing in FRDA is reviewed, along with efforts to reverse silencing with drugs that target histone modifying enzymes.
Effect of diazoxide on Friedreich ataxia models
Diazoxide showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mammalian target of rapamycin (mTOR) pathway, and YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity.