331
Views
12
CrossRef citations to date
0
Altmetric
Review

Emerging therapeutics for the treatment of Friedreich’s ataxia

&
Pages 57-67 | Received 20 Oct 2017, Accepted 21 Nov 2017, Published online: 29 Nov 2017

References

  • Vankan P. Prevalence gradients of Friedreich’s ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge. J Neurochem. 2013;126(Suppl 1):11–20.
  • Parkinson MH, Boesch S, Nachbauer W, et al. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J Neurochem. 2013;126(Suppl 1):103–117.
  • Delatycki MB, Paris DB, Gardner RJ, et al. Clinical and genetic study of Friedreich ataxia in an Australian population. Am J Med Genet. 1999;87(2):168–174.
  • Filla A, DeMichele G, Caruso G, et al. Genetic data and natural history of Friedreich’s disease: a study of 80 Italian patients. J Neurol. 1990;237(6):345–351.
  • Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain. 1981;104(3):589–620.
  • Tsou AY, Paulsen EK, Lagedrost SJ, et al. Mortality in Friedreich ataxia. J Neurol Sci. 2011;307(1–2):46–49.
  • Weidemann F, Rummey C, Bijnens B, et al. The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms. Circulation. 2012;125(13):1626–1634.
  • Cnop M, Mulder H, Igoillo-Esteve M. Diabetes in Friedreich ataxia. J Neurochem. 2013;126(Suppl 1):94–102.
  • Reetz K, Dogan I, Costa AS, et al. Biological and clinical characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data. Lancet Neurol. 2015;14(2):174–182.
  • Campuzano V, Montermini L, Molto MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423–1427.
  • Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335(16):1169–1175.
  • Pastore A, Puccio H. Frataxin: a protein in search for a function. J Neurochem. 2013;126(Suppl 1):43–52.
  • Rotig A, De Lonlay P, Chretien D, et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997;17(2):215–217.
  • Adinolfi S, Iannuzzi C, Prischi F, et al. Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS. Nat Struct Mol Biol. 2009;16(4):390–396.
  • Schmucker S, Martelli A, Colin F, et al. Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PLoS One. 2011;6(1):e16199.
  • Yandim C, Natisvili T, Festenstein R. Gene regulation and epigenetics in Friedreich’s ataxia. J Neurochem. 2013;126(Suppl 1):21–42.
  • Kumari D, Biacsi RE, Usdin K. Repeat expansion affects both transcription initiation and elongation in Friedreich ataxia cells. J Biol Chem. 2011;286(6):4209–4215.
  • Al-Mahdawi S, Pinto RM, Ismail O, et al. The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues. Hum Mol Genet. 2008;17(5):735–746.
  • Sakamoto N, Ohshima K, Montermini L, et al. Sticky DNA, a self-associated complex formed at long GAA*TTC repeats in intron 1 of the frataxin gene, inhibits transcription. J Biol Chem. 2001;276(29):27171–27177.
  • Heidenfelder BL, Makhov AM, Topal MD. Hairpin formation in Friedreich’s ataxia triplet repeat expansion. J Biol Chem. 2003;278(4):2425–2431.
  • Shan Y, Cortopassi G. HSC20 interacts with frataxin and is involved in iron-sulfur cluster biogenesis and iron homeostasis. Hum Mol Genet. 2012;21(7):1457–1469.
  • Shan Y, Napoli E, Cortopassi G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet. 2007;16(8):929–941.
  • Gerber J, Muhlenhoff U, Lill R. An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. EMBO Rep. 2003;4(9):906–911.
  • Lodi R, Cooper JM, Bradley JL, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A. 1999;96(20):11492–11495.
  • Ristow M, Pfister MF, Yee AJ, et al. Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Proc Natl Acad Sci U S A. 2000;97(22):12239–12243.
  • Koeppen AH, Mazurkiewicz JE. Friedreich ataxia: neuropathology revised. J Neuropathol Exp Neurol. 2013;72(2):78–90.
  • Babcock M, De Silva D, Oaks R, et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997;276(5319):1709–1712.
  • Reetz K, Dogan I, Hilgers RD, et al. Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study. Lancet Neurol. 2016;15(13):1346–1354.
  • Patel M, Isaacs CJ, Seyer L, et al. Progression of Friedreich ataxia: quantitative characterization over 5 years. Ann Clin Transl Neurol. 2016;3(9):684–694.
  • Burk K, Schulz SR, Schulz JB. Monitoring progression in Friedreich ataxia (FRDA): the use of clinical scales. J Neurochem. 2013;126(Suppl 1):118–124.
  • Trouillas P, Takayanagi T, Hallett M, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci. 1997;145(2):205–211.
  • Metz G, Coppard N, Cooper JM, et al. Rating disease progression of Friedreich’s ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database. Brain. 2013;136(Pt 1):259–268.
  • Subramony SH, May W, Lynch D, et al. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology. 2005;64(7):1261–1262.
  • Fahey MC, Corben L, Collins V, et al. How is disease progress in Friedreich’s ataxia best measured? A study of four rating scales. J Neurol Neurosurg Psychiatry. 2007;78(4):411–413.
  • Schmitz-Hubsch T, Du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66(11):1717–1720.
  • Burk K, Malzig U, Wolf S, et al. Comparison of three clinical rating scales in Friedreich ataxia (FRDA). Mov Disord. 2009;24(12):1779–1784.
  • Filipovic Pierucci A, Mariotti C, Panzeri M, et al. Quantifiable evaluation of cerebellar signs in children. Neurology. 2015;84(12):1225–1232.
  • Mariotti C, Solari A, Torta D, et al. Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology. 2003;60(10):1676–1679.
  • Buyse G, Mertens L, Di Salvo G, et al. Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring. Neurology. 2003;60(10):1679–1681.
  • Arpa J, Sanz-Gallego I, Rodriguez-de-Rivera FJ, et al. Triple therapy with darbepoetin alfa, idebenone, and riboflavin in Friedreich’s ataxia: an open-label trial. Cerebellum. 2013;12(5):713–720.
  • Reata Pharmaceuticals, Inc. Announces positive data from part one of moxie trial of omaveloxolone for Friedreich’s Ataxia [press release]. Available from: http://news.reatapharma.com/phoenix.zhtml?c=254306&p=irol-newsArticle&ID=2278245.
  • Heerinck F, Shaw J, Shchepinov M, et al. RT001 first-in human clinical trial demonstrates safety, favorable pharmacokinetics, and early signals of efficacy in Friedreich’s Ataxia. International Ataxia Research Conference 2017; 2017; Pisa, Italy.
  • Drinkard BE, Keyser RE, Paul SM, et al. Exercise capacity and idebenone intervention in children and adolescents with Friedreich ataxia. Arch Phys Med Rehabil. 2010;91(7):1044–1050.
  • Chateauvieux S, Grigorakaki C, Morceau F, et al. Erythropoietin, erythropoiesis and beyond. Biochem Pharmacol. 2011;82(10):1291–1303.
  • Miller JL, Church TJ, Leonoudakis D, et al. Discovery and characterization of nonpeptidyl agonists of the tissue-protective erythropoietin receptor. Mol Pharmacol. 2015;88(2):357–367.
  • Tan CC, Eckardt KU, Firth JD, et al. Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol. 1992;263(3 Pt 2):F474–81.
  • Sturm B, Stupphann D, Kaun C, et al. Recombinant human erythropoietin: effects on frataxin expression in vitro. Eur J Clin Invest. 2005;35(11):711–717.
  • Sturm B, Helminger M, Steinkellner H, et al. Carbamylated erythropoietin increases frataxin independent from the erythropoietin receptor. Eur J Clin Invest. 2010;40(6):561–565.
  • Miller JL, Rai M, Frigon NL, et al. Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo. Neuropharmacology. 2017;123:34–45.
  • Acquaviva F, Castaldo I, Filla A, et al. Recombinant human erythropoietin increases frataxin protein expression without increasing mRNA expression. Cerebellum. 2008;7(3):360–365.
  • Boesch S, Sturm B, Hering S, et al. Friedreich’s ataxia: clinical pilot trial with recombinant human erythropoietin. Ann Neurol. 2007;62(5):521–524.
  • Boesch S, Sturm B, Hering S, et al. Neurological effects of recombinant human erythropoietin in Friedreich’s ataxia: a clinical pilot trial. Mov Disord. 2008;23(13):1940–1944.
  • Nachbauer W, Hering S, Seifert M, et al. Effects of erythropoietin on frataxin levels and mitochondrial function in Friedreich ataxia–a dose-response trial. Cerebellum. 2011;10(4):763–769.
  • Mariotti C, Fancellu R, Caldarazzo S, et al. Erythropoietin in Friedreich ataxia: no effect on frataxin in a randomized controlled trial. Mov Disord. 2012;27(3):446–449.
  • Boesch S, Nachbauer W, Mariotti C, et al. Safety and tolerability of carbamylated erythropoietin in Friedreich’s ataxia. Mov Disord. 2014;29(7):935–939.
  • Herman D, Jenssen K, Burnett R, et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat Chem Biol. 2006;2(10):551–558.
  • Saveliev A, Everett C, Sharpe T, et al. DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing. Nature. 2003;422(6934):909–913.
  • Soragni E, Gottesfeld JM. Translating HDAC inhibitors in Friedreich’s ataxia. Expert Opin Orphan Drugs. 2016;4(9):961–970.
  • Chan PK, Torres R, Yandim C, et al. Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich’s ataxia can be reduced upon HDAC inhibition by vitamin B3. Hum Mol Genet. 2013;22(13):2662–2675.
  • Libri V, Yandim C, Athanasopoulos S, et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. Lancet. 2014;384(9942):504–513.
  • NICOFA - Nicotinamide for the treatment of Friedreich ataxia. Available from: http://www.erare.eu/financed-projects/nicofa
  • Soragni E, Miao W, Iudicello M, et al. Epigenetic therapy for Friedreich ataxia. Ann Neurol. 2014;76(4):489–508.
  • Martin AS, Abraham DM, Hershberger KA, et al. Nicotinamide mononucleotide supplementation in a model of Friedreich’s Ataxia cardiomyopathy improves cardiac function and bioenergetics in a SIRT3-dependent manner. International Ataxia Research Conference; Pisa, Italy; 2017.
  • Vang O, Ahmad N, Baile CA, et al. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One. 2011;6(6):e19881.
  • Li L, Voullaire L, Sandi C, et al. Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia. PLoS One. 2013;8(2):e55940.
  • Yiu EM, Tai G, Peverill RE, et al. An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels. J Neurol. 2015;262(5):1344–1353.
  • Ren J, Fan C, Chen N, et al. Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats. Neurochem Res. 2011;36(12):2352–2362.
  • Cottart CH, Nivet-Antoine V, Beaudeux JL. Review of recent data on the metabolism, biological effects, and toxicity of resveratrol in humans. Mol Nutr Food Res. 2014;58(1):7–21.
  • Young HA, Bream JH. IFN-gamma: recent advances in understanding regulation of expression, biological functions, and clinical applications. Curr Top Microbiol Immunol. 2007;316:97–117.
  • Ganz T. Iron in innate immunity: starve the invaders. Curr Opin Immunol. 2009;21(1):63–67.
  • Tomassini B, Arcuri G, Fortuni S, et al. Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model. Hum Mol Genet. 2012;21(13):2855–2861.
  • Seyer L, Greeley N, Foerster D, et al. Open-label pilot study of interferon gamma-1b in Friedreich ataxia. Acta Neurol Scand. 2015;132(1):7–15.
  • Marcotulli C, Fortuni S, Arcuri G, et al. GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFN gamma administration in FRDA patients. Neurol Sci. 2016;37(3):361–364.
  • Horizon pharma plc announces topline results from phase 3 study of ACTIMMUNE® (interferon gamma-1b) in Friedreich’s Ataxia. Available from: http://ir.horizon-pharma.com/news-releases/news-release-details/horizon-pharma-plc-announces-topline-results-phase-3-study
  • Perdomini M, Belbellaa B, Monassier L, et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia. Nat Med. 2014;20(5):542–547.
  • Piguet F, Vaucamps N, De Montigny C, et al. Correction of sensory ataxia in a novel mouse model of Friedreich ataxia using gene therapy approach. International Ataxia Research Conference; Pisa, Italy; 2017.
  • Ouellet DL, Cherif K, Rousseau J, et al. Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich ataxia. Gene Ther. 2017;24(5):265–274.
  • Nabhan JF, Wood KM, Rao VP, et al. Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich’s ataxia. Sci Rep. 2016;6:20019.
  • Li L, Matsui M, Corey DR. Activating frataxin expression by repeat-targeted nucleic acids. Nat Commun. 2016;7:10606.
  • Vyas PM, Tomamichel WJ, Pride PM, et al. A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich’s ataxia mouse model. Hum Mol Genet. 2012;21(6):1230–1247.
  • Benini M, Fortuni S, Condo I, et al. E3 ligase RNF126 directly ubiquitinates frataxin, promoting its degradation: identification of a potential therapeutic target for Friedreich Ataxia. Cell Rep. 2017;18(8):2007–2017.
  • Wong A, Yang J, Cavadini P, et al. The Friedreich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet. 1999;8(3):425–430.
  • Orsucci D, Mancuso M, Ienco EC, et al. Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues. Curr Med Chem. 2011;18(26):4053–4064.
  • Esposti MD, Ngo A, Ghelli A, et al. The interaction of Q analogs, particularly hydroxydecyl benzoquinone (idebenone), with the respiratory complexes of heart mitochondria. Arch Biochem Biophys. 1996;330(2):395–400.
  • Cooper JM, Korlipara LV, Hart PE, et al. Coenzyme Q10 and vitamin E deficiency in Friedreich’s ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy. Eur J Neurol. 2008;15(12):1371–1379.
  • Hart PE, Lodi R, Rajagopalan B, et al. Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol. 2005;62(4):621–626.
  • Lodi R, Hart PE, Rajagopalan B, et al. Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich’s ataxia. Ann Neurol. 2001;49(5):590–596.
  • Artuch R, Aracil A, Mas A, et al. Friedreich’s ataxia: idebenone treatment in early stage patients. Neuropediatrics. 2002;33(4):190–193.
  • Brandsema JF, Stephens D, Hartley J, et al. Intermediate-dose idebenone and quality of life in Friedreich ataxia. Pediatr Neurol. 2010;42(5):338–342.
  • Hausse AO, Aggoun Y, Bonnet D, et al. Idebenone and reduced cardiac hypertrophy in Friedreich’s ataxia. Heart. 2002;87(4):346–349.
  • Pineda M, Arpa J, Montero R, et al. Idebenone treatment in paediatric and adult patients with Friedreich ataxia: long-term follow-up. Eur J Paediatr Neurol. 2008;12(6):470–475.
  • Rustin P, Rotig A, Munnich A, et al. Heart hypertrophy and function are improved by idebenone in Friedreich’s ataxia. Free Radic Res. 2002;36(4):467–469.
  • Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, et al. Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary study. Lancet. 1999;354(9177):477–479.
  • Di Prospero NA, Baker A, Jeffries N, et al. Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 2007;6(10):878–886.
  • Lagedrost SJ, Sutton MS, Cohen MS, et al. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am Heart J. 2011;161(3):639–45 e1.
  • Lynch DR, Perlman SL, Meier T. A phase 3, double-blind, placebo-controlled trial of idebenone in Friedreich ataxia. Arch Neurol. 2010;67(8):941–947.
  • Meier T, Perlman SL, Rummey C, et al. Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich’s ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. J Neurol. 2012;259(2):284–291.
  • Parkinson MH, Schulz JB, Giunti P. Co-enzyme Q10 and idebenone use in Friedreich’s ataxia. J Neurochem. 2013;126(Suppl 1):125–141.
  • Hawi A, Heald S, Sciascia T. Use of an adaptive study design in single ascending-dose pharmacokinetics of A0001 (alpha-tocopherylquinone) in healthy male subjects. J Clin Pharmacol. 2012;52(1):65–77.
  • Lynch DR, Willi SM, Wilson RB, et al. A0001 in Friedreich ataxia: biochemical characterization and effects in a clinical trial. Mov Disord. 2012;27(8):1026–1033.
  • Martinelli D, Catteruccia M, Piemonte F, et al. EPI-743 reverses the progression of the pediatric mitochondrial disease–genetically defined Leigh Syndrome. Mol Genet Metab. 2012;107(3):383–388.
  • Zesiewicz T, Perlman S, Sullivan K, et al., editors. EPI-743 (Alpha-tocotrienol Quinone) Demonstrates Long-Term Improvement in Neurological Function and Disease Progression in Friedreich’s Ataxia AAN 69th Annual Meeting; Boston; 2017.
  • Sullivan K, Freeman M, Shaw J, et al., editors. EPI-743 for Friedreich’s Ataxia Patients with Point Mutations AAN 69th Annual Meeting; Boston;2017.
  • Chyan YJ, Poeggeler B, Omar RA, et al. Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid. J Biol Chem. 1999;274(31):21937–21942.
  • Safety and Pharmacology Study of VP 20629 in Adults With Friedreich’s Ataxia. Available from: https://clinicaltrials.gov/ct2/show/results/NCT01898884?term=VP-20629&rank=12016
  • Cotticelli MG, Crabbe AM, Wilson RB, et al. Insights into the role of oxidative stress in the pathology of Friedreich ataxia using peroxidation resistant polyunsaturated fatty acids. Redox Biol. 2013;1:398–404.
  • A First in Human Study of RT001 in Patients With Friedreich’s Ataxia. Available from: https://clinicaltrials.gov/ct2/show/NCT02445794?term=RT001&draw=1&rank=2
  • Retrotope Announces Phase I/II Clinical Trial Results of RT001 in Treatment of Friedreich’s ataxia [press release]. Available from: https://static1.squarespace.com/static/549af14ae4b004237f7bb71a/t/57dd7786f7e0ab741930775f/1474131955350/PR+Retrotope+Phase+1+Results.pdf
  • Efficacy of EGb761 in Patients Suffering From Friedreich Ataxia Available from: https://clinicaltrials.gov/ct2/show/NCT00824512?cond=EGb761&draw=1&rank=1.
  • Infante JP, Huszagh VA. Secondary carnitine deficiency and impaired docosahexaenoic (22: 6n-3)acid synthesis: a common denominator in the pathophysiology of diseases of oxidative phosphorylation and beta-oxidation. FEBS Lett. 2000;468(1):1–5.
  • Schols L, Zange J, Abele M, et al. L-carnitine and creatine in Friedreich’s ataxia. A randomized, placebo-controlled crossover trial. J Neural Transm (Vienna). 2005;112(6):789–796.
  • An Open-label Study of the Effects of Acetyl-L-Carnitine on Cardiovascular Outcomes in Friedreich’s Ataxia 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT01921868?recrs=ab&cond=An+Open-label+Study+of+the+Effects+of+Acetyl-L-Carnitine+on+Cardiovascular+Outcomes+in+Friedreich%27s+Ataxia&rank=1.
  • Moreno-Ulloa A, Nogueira L, Rodriguez A, et al. Recovery of indicators of mitochondrial biogenesis, oxidative stress, and aging with (−)-epicatechin in senile mice. J Gerontol A Biol Sci Med Sci. 2015;70(11):1370–1378.
  • Ramirez-Sanchez I, Rodriguez A, Moreno-Ulloa A, et al. (−)-Epicatechin-induced recovery of mitochondria from simulated diabetes: potential role of endothelial nitric oxide synthase. Diab Vasc Dis Res. 2016;13(3):201–210.
  • (+) Epicatechin to Treat Friedreich’s Ataxia. 2017 Available from: https://clinicaltrials.gov/ct2/show/NCT02660112?cond=%28%2B%29+Epicatechin+to+Treat+Friedreich%27s+Ataxia&rank=1
  • Wahli W, Braissant O, Desvergne B. Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more. Chem Biol. 1995;2(5):261–266.
  • Coppola G, Marmolino D, Lu D, et al. Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPAR gamma pathway as a therapeutic target in Friedreich’s ataxia. Hum Mol Genet. 2009;18(13):2452–2461.
  • Marmolino D, Manto M, Acquaviva F, et al. PGC-1alpha down-regulation affects the antioxidant response in Friedreich’s ataxia. PLoS One. 2010;5(4):e10025.
  • Probst BL, Trevino I, McCauley L, et al. RTA 408, a novel synthetic triterpenoid with broad anticancer and anti-inflammatory activity. PLoS One. 2015;10(4):e0122942.
  • Baird L, Dinkova-Kostova AT. The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol. 2011;85(4):241–272.
  • Paupe V, Dassa EP, Goncalves S, et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS One. 2009;4(1):e4253.
  • RTA 408 Capsules in Patients With Friedreich’s Ataxia - MOXIe Availble from: https://clinicaltrials.gov/ct2/show/NCT02255435?term=moxie&rank=1
  • Reilly JF, Yanez G, Bista P, et al. CAT-4001 improves mitochondrial function in a Friedreich’s ataxia model. International Ataxia Research Conference; Pisa, Italy; 2017.
  • Kakhlon O, Manning H, Breuer W, et al. Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation. Blood. 2008;112(13):5219–5227.
  • Sohn YS, Breuer W, Munnich A, et al. Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications. Blood. 2008;111(3):1690–1699.
  • Goncalves S, Paupe V, Dassa EP, et al. Deferiprone targets aconitase: implication for Friedreich’s ataxia treatment. BMC Neurol. 2008;8:20.
  • Pandolfo M, Hausmann L. Deferiprone for the treatment of Friedreich’s ataxia. J Neurochem. 2013;126(Suppl 1):142–146.
  • Boddaert N, Le Quan Sang KH, Rotig A, et al. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 2007;110(1):401–408.
  • Pandolfo M, Arpa J, Delatycki MB, et al. Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial. Ann Neurol. 2014;76(4):509–521.
  • Wilson RB, Lynch DR, Fischbeck KH. Normal serum iron and ferritin concentrations in patients with Friedreich’s ataxia. Ann Neurol. 1998;44(1):132–134.
  • Swarup V, Srivastava AK, Padma MV, et al. Quantitative profiling and identification of differentially expressed plasma proteins in Friedreich’s ataxia. J Neurosci Res. 2013;91(11):1483–1491.
  • Rosuvastatin (Crestor) in Friedreich Ataxia. 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT02705547?cond=Rosuvastatin+%28Crestor%29+in+Friedreich+Ataxia&rank=1
  • Pilot Study of Varenicline (Chantix®) in the Treatment of Friedreich’s Ataxia. 2012. Available from: https://clinicaltrials.gov/ct2/show/NCT00803868?cond=Pilot+Study+of+Varenicline+%28Chantix%C2%AE%29+in+the+Treatment+of+Friedreich%27s+Ataxia&rank=1
  • Costantini A, Laureti T, Pala MI, et al. Long-term treatment with thiamine as possible medical therapy for Friedreich ataxia. J Neurol. 2016;263(11):2170–2178.
  • Shinnick JE, Isaacs CJ, Vivaldi S, et al. Friedreich Ataxia and nephrotic syndrome: a series of two patients. BMC Neurol. 2016;16:3.
  • Methylprednisolone Treatment of Friedreich Ataxia. 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT02424435?cond=Methylprednisolone+Treatment+of+Friedreich+Ataxia&rank=1.
  • Schulz JB, Boesch S, Burk K, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009;5(4):222–234.
  • Ilg W, Synofzik M, Brotz D, et al. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology. 2009;73(22):1823–1830.
  • Milne SC, Corben LA, Roberts M, et al. Can rehabilitation improve the health and well-being in Friedreich’s ataxia: a randomized controlled trial?. Clin Rehabil. 2017;269215517736903. [Epub ahead of print].
  • Si B, Delatycki MB. Friedreich Ataxia. In: Adam MP, Ardinger HH, Pagon RA, et al. editors. GeneReviews(R). Seattle (WA): NCBI Bookshelf. 1993.
  • Friedman LS, Farmer JM, Perlman S, et al. Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. Mov Disord. 2010;25(4):426–432.
  • Pousset F, Legrand L, Monin ML, et al. A 22-Year follow-up study of long-term cardiac outcome and predictors of survival in Friedreich Ataxia. JAMA Neurol. 2015;72(11):1334–1341.
  • De Michele G, Perrone F, Filla A, et al. Age of onset, sex, and cardiomyopathy as predictors of disability and survival in Friedreich’s disease: a retrospective study on 119 patients. Neurology. 1996;47(5):1260–1264.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.