Journal ArticleDOI
Designing phase II clinical trials in Friedreich ataxia.
Layne N Rodden,David A. Lynch +1 more
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In this paper, the authors summarize data from major phase II clinical trials in Friedreich ataxia published between 2015 and 2020 which includes A0001/EPI743, Omaveloxolone, RT001, and Actimmune.Abstract:
Introduction : Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by deficiency of frataxin, an essential mitochondrial protein involved in iron sulfur cluster biogenesis, oxidative phosphorylation and other processes. FRDA most notably affects the heart, sensory neurons, spinal cord, cerebellum and other brain regions and manifests clinically as ataxia, sensory loss, dysarthria, spasticity and hypertrophic cardiomyopathy. Therapeutic approaches in FRDA have consisted of two different approaches: (1) augmenting or restoring frataxin production and (2) modulating a variety of downstream processes related to mitochondrial dysfunction, including reactive oxygen species production, ferroptosis, or Nrf2 activation. Areas covered : In this review, we summarize data from major phase II clinical trials in FRDA published between 2015 and 2020 which includes A0001/EPI743, Omaveloxolone, RT001, and Actimmune. Expert opinion : A growing number of drug candidates are being tested in phase II clinical trials for FRDA; however, most have not met their primary endpoints, and none have received FDA approval. In this review, we aim to summarize completed phase II clinical trials in FRDA, outlining critical lessons that have been learned and that should be incorporated into future trial design to ultimately optimize drug development in FRDA.read more
Citations
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Drug Repositioning in Friedreich Ataxia
TL;DR: 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.
Journal ArticleDOI
Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia
Wing-Hang Tong,Hayden Ollivierre,Audrey Noguchi,Manik C. Ghosh,Danielle A. Springer,Tracey A. Rouault +5 more
TL;DR: In this article , the authors showed that rapamycin, a specific inhibitor of mTOR signaling, enhanced the survival of the Fxn cKO mice, providing proof of concept for the potential of m TOR inhibition to ameliorate cardiac disease in patients with defective ISC biogenesis.
Journal ArticleDOI
Perspectives on current models of Friedreich’s ataxia
TL;DR: The outlook and the remaining challenges in the context of FRDA iPSC-based models are discussed, including the current challenges in using FRDA animal models and patient-derived cells.
Journal ArticleDOI
NRF2 activation suppresses motor neuron ferroptosis induced by the SOD1G93A mutation and exerts neuroprotection in amyotrophic lateral sclerosis
Biying Yang,Jingrui Pan,Xiaoni Zhang,Hongxuan Wang,Lei He,Xiaoming Rong,Xiangpen Li,Ying Peng +7 more
TL;DR: In this paper , the role of ferroptosis in motor neurons and its regulation in mutant human Cu/Zn-superoxide dismutase (HSOD1G93A) cells and mouse models was further explored.
Journal ArticleDOI
Recent Advances on Therapeutic Approaches for Friedreich’s Ataxia: New Pharmacological Targets, Protein, and Gene Therapy
TL;DR: The most common mutation in Friedreich ataxia is caused by a (GAA)n triplet repeat expansion in the first intron of the frataxin gene as mentioned in this paper .
References
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Journal ArticleDOI
Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion
Victoria Campuzano,Laura Montermini,María Dolores Moltó,Luigi Pianese,Mireille Cossée,F Cavalcanti,Eugenia Monros,François Rodius,Franck Duclos,Antonella Monticelli,Federico Zara,Joaquín Cañizares,Hana Koutnikova,Sanjay I. Bidichandani,Cinzia Gellera,Alexis Brice,Paul Trouillas,Giuseppe De Michele,Alessandro Filla,Rosa de Frutos,Francisco Palau,Pragna Patel,Stefano Di Donato,Jean-Louis Mandel,Sergio Cocozza,Michel Koenig,Massimo Pandolfo +26 more
TL;DR: 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.
Journal ArticleDOI
Clinical and Genetic Abnormalities in Patients with Friedreich's Ataxia
Alexandra Durr,Mireille Cossée,Yves Agid,Victoria Campuzano,Claude Mignard,C. Penet,Jean-Louis Mandel,Alexis Brice,Michel Koenig +8 more
TL;DR: The clinical spectrum of Friedreich's ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion on chromosome 9 is useful for diagnosis, determination of prognosis, and genetic counseling.
Journal Article
The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia.
Alessandro Filla,G. De Michele,F Cavalcanti,Luigi Pianese,Antonella Monticelli,Giuseppe Campanella,Sergio Cocozza +6 more
TL;DR: The length of FA alleles ranged from 201 to 1,186 repeat units, with no overlap with the normal range, and showed a negatively skewed distribution with a peak between 800 and 1,000 repeats, and the FA repeat showed meiotic instability with a median variation of 150 repeats.
Journal ArticleDOI
The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.
TL;DR: Using cloned repeat sequences from FRDA patients, it is shown that the GAA repeat per se interferes with in vitro transcription in a length-dependent manner, with both prokaryotic and eukaryotic enzymes.
Journal ArticleDOI
Friedreich's ataxia: Point mutations and clinical presentation of compound heterozygotes
Mireille Cossée,Alexandra Durr,Michèle Schmitt,Niklas Dahl,Paul Trouillas,P Allinson,M Kostrzewa,A Nivelon-Chevallier,K H Gustavson,Alfried Kohlschütter,Ulrich Müller,Jean-Louis Mandel,Alexis Brice,Michel Koenig,F Cavalcanti,Angela Tammaro,G. De Michele,Alessandro Filla,Sergio Cocozza,Malgorzata Labuda,Laura Montermini,John T. Poirier,Massimo Pandolfo +22 more
TL;DR: The identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families are reported, suggesting that the only two missense mutations located in the amino‐terminal half of mature fratxin cause an atypical and milder clinical presentation.