CNS Drugs

, Volume 23, Issue 3, pp 213–223 | Cite as

Pharmacotherapy for Friedreich Ataxia

  • Amy Y. Tsou
  • Lisa S. Friedman
  • Robert B. Wilson
  • David R. Lynch
Review Article


Friedreich ataxia (FA) is a progressive genetic neurological disorder associated with degeneration of the dorsal columns, spinocerebellar tracts and other regions of the nervous system. The disorder results from mutations in the gene referred to as FXN. Almost all mutations are expansions of an intronic GAA repeat in this gene, which gives rise to decreased transcription of the gene product (called frataxin). Following these discoveries, drug discovery has moved at a rapid pace. Therapeutic trials in the next 5 years are expected to address amelioration of the effects of frataxin deficiency and methods for increasing frataxin expression. These therapies are directed at all levels of biochemical dysfunction in FA. Agents such as idebenone potentially improve mitochondrial function and decrease production of reactive oxygen species. Idebenone is presently in a phase III trial in the US and in Europe, with the primary outcome measure being neurological function. Deferiprone, an atypical iron chelator, may decrease build-up of toxic iron in the mitochondria in patients. It has entered a phase II trial in Europe, Australia and Canada directed toward improvement of neurological abilities. Finally, targeted histone deacetylase (HDAC) inhibitors and erythropoietin increase levels of frataxin when used in vitro, suggesting that they may provide methods for increasing frataxin levels in patients. Erythropoietin has been tested in a small phase II trial in Austria, while HDAC inhibitors are still at a preclinical stage. Symptomatic therapies are also in use for specific symptoms such as spasticity (baclofen). Thus, there is substantial optimism for development of new therapies for FA in the near future, and we suggest that one or several may be available over the next few years. However, continued development of new therapies will require creation of new, more sensitive measures for neurological dysfunction in FA, and clinically relevant measures of cardiac dysfunction.


  1. 1.
    Babady NE, Carelle N, Wells RD, et al. Advancements in the pathophysiology of Friedreich’s ataxia and new prospects for treatments. Molec Genet Metabolism 2007; 92: 23–35CrossRefGoogle Scholar
  2. 2.
    Cooper JM, Schapira AH. Friedreich’s ataxia: disease mechanisms, antioxidant and coenzyme Q10 therapy. BioFactors 2003; 18: 163–71PubMedCrossRefGoogle Scholar
  3. 3.
    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: 589–620PubMedCrossRefGoogle Scholar
  4. 4.
    Lynch DR, Farmer JM, Balcer LJ, et al. Friedreich ataxia: effects of genetic understanding on clinical evaluation and therapy. Arch Neurol 2002; 59: 743–7PubMedCrossRefGoogle Scholar
  5. 5.
    Pandolfo M. Molecular pathogenesis of Friedreich ataxia. Arch Neurol 1999; 56: 1201–8PubMedCrossRefGoogle Scholar
  6. 6.
    Singh G, Binstadt BA, Black DF, et al. Electroconvulsive therapy and Friedreich’s ataxia. J Electroconvuls Ther 2001; 17: 53–4Google Scholar
  7. 7.
    Bhidayasiri R, Perlman SL, Pulst SM, et al. Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging findings, and review of the literature. Arch Neurol 2004; 62: 1865–9CrossRefGoogle Scholar
  8. 8.
    Monrós E, Moltó MD, Martínez F, et al. Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. Amer J Hum Genet 1997; 61: 101–10PubMedCrossRefGoogle Scholar
  9. 9.
    Santoro L, De Michele G, Perretti A, et al. Relation between trinucleotide GAA repeat length and sensory neuropathy in Friedreich’s ataxia. J Neurol Neurosurg Psych 1999; 66:93–6CrossRefGoogle Scholar
  10. 10.
    Ragno M, De Michele G, Cavalcanti F, et al. Broadened Friedreich’s ataxia phenotype after gene cloning: minimal GAA expansion causes late-onset spastic ataxia. Neurology 1997; 49:1617–20PubMedCrossRefGoogle Scholar
  11. 11.
    Campuzano V, Montermini L, Moltò MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271:1423–7PubMedCrossRefGoogle Scholar
  12. 12.
    Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Amer J Human Genet 1997; 60: 1251–6Google Scholar
  13. 13.
    McCormack ML, Guttmann RP, Schumann M, et al. Frataxin point mutations in two patients with Friedreich’s ataxia and unusual clinical features. J Neurol Neurosurg Psychiatry 2000; 68: 661–4PubMedCrossRefGoogle Scholar
  14. 14.
    Cossée M, Dürr A, Schmitt M, et al. Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol 1999; 45: 200–6PubMedCrossRefGoogle Scholar
  15. 15.
    Isaya G, O’Neill HA, Gakh O, et al. Functional studies of frataxin. Acta Paediatr 2004; 93Suppl.: 68–71CrossRefGoogle Scholar
  16. 16.
    Cavadini P, O’Neill HA, Benada O, et al. Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet 2002; 11: 217–27PubMedCrossRefGoogle Scholar
  17. 17.
    Tan G, Chen LS, Lonnerdal B, et al. Frataxin expression rescues mitochondrial dysfunctions in FRDA cells. Hum Mol Genet 2001; 10: 2099–107PubMedCrossRefGoogle Scholar
  18. 18.
    Wilson RB. Iron dysregulation in Friedreich ataxia. Semin Pediatr Neurol 2006; 13: 166–75PubMedCrossRefGoogle Scholar
  19. 19.
    Martelli A, Wattenhofer-Donzé M, Schmucker S, et al. Non-mitochondrial proteins: frataxin is essential for extra-mitochondrial Fe-S cluster proteins in mammalian tissues. Hum Mol Genet 2007; 16(22): 2651–8PubMedCrossRefGoogle Scholar
  20. 20.
    Bulteau AL, O’Neill HA, Kennedy MC, et al. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science 2004; 305(5681): 242–5PubMedCrossRefGoogle Scholar
  21. 21.
    Chapela SP, Burgos HI, Salazar AI, et al. Biochemical study of idebenone effect on mitochondrial metabolism of yeast. Cell Biol Internat 2008 Jan; 32(1): 146–50CrossRefGoogle Scholar
  22. 22.
    McDaniel DH, Neudecker BA, Dinardo JC, et al. Idebenone, a new antioxidant: part I. Relative assessment of oxidative stress protection capacity compared to commonly known antioxidants. J Cosmetic Derm 2005; 4: 10–7CrossRefGoogle Scholar
  23. 23.
    Rustin P. The use of antioxidants in Friedreich’s ataxia treatment. Expert Opin Investig Drugs 2003; 12: 569–75PubMedCrossRefGoogle Scholar
  24. 24.
    Idebenone: monograph. Altern Med Rev 2001; 6: 83–6Google Scholar
  25. 25.
    Rustin P, Munnich A, Rötig A. Quinone analogs prevent enzymes targeted in Friedreich ataxia from iron-induced injury in vitro. BioFactors 1999; 9: 247–51PubMedCrossRefGoogle Scholar
  26. 26.
    Imada I, Fujita T, Sugiyama Y, et al. Effects of idebenone and related compounds on respiratory activities of brain mitochondria, and on lipid peroxidation of their membranes. Arch Gerontol Geriatr 1989; 8(3): 323–41PubMedCrossRefGoogle Scholar
  27. 27.
    Sugiyama Y, Fujita T, Matsumoto M, et al. Effects of idebenone (CV-2619) and its metabolites on respiratory activity and lipid peroxidation in brain mitochondria from rats and dogs. J Pharmacobio-dynamics 1985; 8(12): 1006–17CrossRefGoogle Scholar
  28. 28.
    Geromel V, Darin N, Chrétien D, et al. Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab 2002 Sep–Oct; 77(1–2): 21–30PubMedCrossRefGoogle Scholar
  29. 29.
    Seznec H, Simon D, Monassier L, et al. Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia. Human Molec Genet 2004; 13: 1017–24CrossRefGoogle Scholar
  30. 30.
    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: 477–9PubMedCrossRefGoogle Scholar
  31. 31.
    Rustin P, Bonnet D, Rötig A, et al. Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology 2004; 6: 524–5CrossRefGoogle Scholar
  32. 32.
    Rustin P, Rötig A, Munnich A, et al. Heart hypertrophy and function are improved by idebenone in Friedreich’s ataxia. Free Rad Res 2002; 36: 467–9CrossRefGoogle Scholar
  33. 33.
    Schöls L, Vorgerd M, Schillings M, et al. Idebenone in patients with Friedreich ataxia. Neurosci Lett 2001; 306:169–72PubMedCrossRefGoogle Scholar
  34. 34.
    Filla A, Moss AJ. Idebenone for treatment of Friedreich’s ataxia? Neurology 2003; 60: 1569–70PubMedCrossRefGoogle Scholar
  35. 35.
    Buyse G, Mertens L, Di Salvo G, et al. Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring. Neurology 2003; 60: 1679–81PubMedCrossRefGoogle Scholar
  36. 36.
    Artuch R, Aracil A, Mas A, et al. Friedreich’s ataxia: idebenone treatment in early stage patients. Neuropediatrics 2002; 33: 190–3PubMedCrossRefGoogle Scholar
  37. 37.
    Mariotti C, Solari A, Torta D, et al. Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology 2003; 60: 1676–9PubMedCrossRefGoogle Scholar
  38. 38.
    Hausse AO, Aggoun Y, Bonnet D, et al. Idebenone and reduced cardiac hypertrophy in Friedreich’s ataxia. Heart 2002; 87: 346–9PubMedCrossRefGoogle Scholar
  39. 39.
    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: 878–86CrossRefGoogle Scholar
  40. 40.
    Di Prospero NA, Sumner CJ, Penzak SR, et al. Safety, tolerability, and pharmacokinetics of high-dose idebenone in patients with Friedreich ataxia. Arch Neurol 2007; 64: 803–8CrossRefGoogle Scholar
  41. 41.
    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 Nov; 12(6): 470–5PubMedCrossRefGoogle Scholar
  42. 42.
    Ribaï P, Pousset F, Tanguy ML, et al. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol 2007; 64: 558–64PubMedCrossRefGoogle Scholar
  43. 43.
    Myers L, Farmer JM, Wilson RB, et al. Antioxidant use in Friedreich ataxia. J Neurol Sci 2008; 267: 174–6PubMedCrossRefGoogle Scholar
  44. 44.
    Lynch DR, Farmer JM, Wilson RL, et al. Performance measures in Friedreich ataxia: potential utility as clinical outcome tools. Movement Dis 2005; 20: 777–82PubMedCrossRefGoogle Scholar
  45. 45.
    Lynch DR, Farmer JM, Tsou AY, et al. Measuring Friedreich ataxia: complementary features of examination and performance measures. Neurology 2006; 66: 1711–6PubMedCrossRefGoogle Scholar
  46. 46.
    Fahey MC, Corben LA, Collins V, et al. The 25-foot walk velocity accurately measures real world ambulation in Friedreich ataxia. Neurology 2007; 68: 705–6PubMedCrossRefGoogle Scholar
  47. 47.
    Tauskela JS. Mitoquinone: a mitochondria-targeted antioxidant. IDrugs 2007; 10: 399–412PubMedGoogle Scholar
  48. 48.
    Kelso GF, Porteous CM, Coulter CV, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chemistry 2001; 276(7): 4588–96CrossRefGoogle Scholar
  49. 49.
    Kelso GF, Porteous CM, Hughes G, et al. Prevention of mitochondrial oxidative damage using targeted anti-oxidants. Ann N Y Acad Sci 2002; 959: 263–74PubMedCrossRefGoogle Scholar
  50. 50.
    Dhanasekaran A, Kotamraju S, Kalivendi SV, et al. Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem 2004; 279(36): 37575–87PubMedCrossRefGoogle Scholar
  51. 51.
    Jauslin ML, Meier T, Smith RA, et al. Mitochondria-targeted antioxidants protect Friedreich ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J 2003; 17: 1972–4PubMedGoogle Scholar
  52. 52.
    James AM, Cochemé HM, Smith RA, et al. Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species: implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem 2005; 280: 21295–312PubMedCrossRefGoogle Scholar
  53. 53.
    Doughan AK, Dikalov SI. Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis. Antioxid Redox Signal 2007; 9(11): 1825–36PubMedCrossRefGoogle Scholar
  54. 54.
    Glickstein H, El RB, Shvartsman M, et al. Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells. Blood 2005; 106(9): 3242–50PubMedCrossRefGoogle Scholar
  55. 55.
    Porcu M, Landis N, Salis S, et al. Effects of combined deferiprone and desferrioxamine iron chelating therapy in beta-thalassemia major end-stage heart failure: a case report. Eur J Heart Fail 2007; 9: 320–2PubMedCrossRefGoogle Scholar
  56. 56.
    Liu P, Yao YN, Wu SD, et al. The efficacy of deferiprone on tissues aluminum removal and copper, zinc, manganese level in rabbits. J Inorg Biochem 2005; 99: 1733–7PubMedCrossRefGoogle Scholar
  57. 57.
    Boddaert N, Le Quan Sang KH, Rötig A, et al. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 2007; 110: 401–8PubMedCrossRefGoogle Scholar
  58. 58.
    Cohen AR, Galaello R, Piga A, et al. Safety and effectiveness of long term therapy with the oral iron chelator deferiprone. Blood 2003; 102: 1583–7PubMedCrossRefGoogle Scholar
  59. 59.
    Koeppen AH, Michael SC, Knutson MD, et al. The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins. Acta Neuropathol 2007; 114: 163–73PubMedCrossRefGoogle Scholar
  60. 60.
    Sturm B, Stupphann D, Kaun C, et al. Recombinant human erythropoietin: effects on frataxin expression in vitro. Eur J Clin Invest 2005; 35: 711–7PubMedCrossRefGoogle Scholar
  61. 61.
    Boesch S, Sturm B, Hering S, et al. Friedreich’s ataxia: clinical pilot trial with recombinant human erythropoietin. Ann Neurol 2007; 62: 521–4PubMedCrossRefGoogle Scholar
  62. 62.
    Tefferi A. Pharmaceutical erythropoietin use in patients with cancer: is it time to abandon ship or just drop anchor? Mayo Clin Proc 2007; 82: 1316–8PubMedCrossRefGoogle Scholar
  63. 63.
    Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008; 299: 914–24PubMedCrossRefGoogle Scholar
  64. 64.
    Sytkowski AJ. Does erythropoietin have a dark side? Epo signaling and cancer cells. Sci STKE 2007 Jul; (395): pe38CrossRefGoogle Scholar
  65. 65.
    Pollock C, Johnson DW, Hörl WH, et al. Pure red cell aplasia induced by erythropoiesis-stimulating agents. Clin J Am Soc Nephrol 2008; 3: 193–9PubMedCrossRefGoogle Scholar
  66. 66.
    Aapro M, Leonard RC, Barnadas A, et al. Effect of once-weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy: results of the Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study. J Clin Oncol 2008 Feb 1;26(4): 592–8PubMedCrossRefGoogle Scholar
  67. 67.
    Thomas G, Ali S, Hoebers FJ, et al. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 2008 Feb; 108(2): 317–25PubMedCrossRefGoogle Scholar
  68. 68.
    Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005 Sep 1; 23(25): 5960–72PubMedCrossRefGoogle Scholar
  69. 69.
    Cossée M, Puccio H, Gansmuller A, et al. Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum Mol Genet 2000; 9: 1219–26PubMedCrossRefGoogle Scholar
  70. 70.
    Campuzano V, Montermini L, Lutz Y, et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 1997; 6:1771–80PubMedCrossRefGoogle Scholar
  71. 71.
    Wells RD. DNA triplexes and Friedreich ataxia. FASEB J 2008 Jun; 22(6): 1625–34PubMedCrossRefGoogle Scholar
  72. 72.
    Herman D, Jenssen K, Burnett R, et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat Chem Biol 2006; 2: 551–8PubMedCrossRefGoogle Scholar
  73. 73.
    Grant L, Sun J, Xu H, et al. Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich’s ataxia. FEBS Lett 2006; 580: 5399–405PubMedCrossRefGoogle Scholar
  74. 74.
    Burnett R, Melander C, Puckett JW, et al. DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA-TTC repeats in Friedreich’s ataxia. Proc Natl Acad Sci U S A 2006; 103: 11497–502PubMedCrossRefGoogle Scholar
  75. 75.
    Kosutic J, Zamurovic D. High-dose beta-blocker hypertrophic cardiomyopathy therapy in a patient with Frie-dreich taxia. Pediatr Cardiol 2001; 26: 727–30CrossRefGoogle Scholar
  76. 76.
    Delatycki MB, Fahey MC, Corben L, et al. Friedreich ataxia. In: Lynch DR, Farmer JM, editors. Neurogenetics: scientific and clinical advances. New York: Taylor & Francis, 2006:299–310Google Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Amy Y. Tsou
    • 1
  • Lisa S. Friedman
    • 1
    • 2
    • 3
  • Robert B. Wilson
    • 4
  • David R. Lynch
    • 1
    • 2
    • 3
  1. 1.Department of NeurologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of PediatricsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Division of NeurologyChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  4. 4.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations