Current Pharmaceutical DesignCurrent Pharmaceutical DesignCurrent Pharmaceutical Design1381-61281873-4286Bentham Science64573410.2174/0113816128288707240404051856Immunology, Inflammation & AllergyResearch ArticleRecent Advances in the Treatment Strategies of Friedreich’s Ataxia: A Review of Potential Drug Candidates and their Underlying MechanismsSainiAmaninfo@benthamscience.netAnilNehainfo@benthamscience.netVijayArdrainfo@benthamscience.netManglaBhartiinfo@benthamscience.netJavedShamamainfo@benthamscience.netKumarPankajinfo@benthamscience.netAhsanWaquarinfo@benthamscience.netDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRUDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU),Department of Pharmaceutics, School of Pharmaceutical Sciences,, Delhi Pharmaceutical Sciences and Research University (DPSRU),Department of Pharmaceutics, College of Pharmacy,, Jazan UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy,, Jazan University2005202430191472148911012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1381-6128/article/view/645734

Background:Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder characterized by progressive ataxia, cardiomyopathy, and diabetes. The disease is caused by a deficiency of frataxin, a mitochondrial protein involved in iron-sulfur cluster synthesis and iron metabolism.

Objective:This review aims to summarize recent advances in the development of treatment strategies for FRDA, with a focus on potential drug candidates and their mechanisms of action.

Methods:A comprehensive literature search was conducted using various authentic scientific databases to identify studies published in the last decade that investigated potential treatment strategies for FRDA. The search terms used included "Friedreich's ataxia", "treatment", "drug candidates", and "mechanisms of action."

Results:To date, only one drug got approval from US-FDA in the year 2023; however, significant developments were achieved in FRDA-related research focusing on diverse therapeutic interventions that could potentially alleviate the symptoms of this disease. Several promising drug candidates have been identified for the treatment of FRDA, which target various aspects of frataxin deficiency and aim to restore frataxin levels, reduce oxidative stress, and improve mitochondrial function. Clinical trials have shown varying degrees of success, with some drugs demonstrating significant improvements in neurological function and quality of life in FRDA patients.

Conclusion:While there has been significant progress in the development of treatment strategies for FRDA, further research is needed to optimize these approaches and identify the most effective and safe treatment options for patients. The integration of multiple therapeutic strategies may be necessary to achieve the best outcomes in FRDA management.

Friedreich ataxiamolecular pathwayneurodegenerative disordercardiomyopathydiabetesmitochondrial protein.Williams CT, De Jesus O, Eds. Friedreich ataxia. StatPearls. Treasure Island, FL: StatPearls Publishing 2023.Hafiz S, De Jesus O, Eds. Ataxia. StatPearls. Treasure Island, FL: StatPearls Publishing 2023.Krasilnikova MM, Humphries CL, Shinsky EM. Friedreich’s ataxia: New insights. Emerg Top Life Sci 2023; 7(3): 313-23. doi: 10.1042/ETLS20230017 PMID: 37698160Rummey C, Farmer JM, Lynch DR. Predictors of loss of ambulation in Friedreich’s ataxia. EClinicalMedicine 2020; 18: 100213. doi: 10.1016/j.eclinm.2019.11.006 PMID: 31938785Marmolino D. Friedreich’s ataxia: Past, present and future. Brain Res Brain Res Rev 2011; 67(1-2): 311-30. doi: 10.1016/j.brainresrev.2011.04.001 PMID: 21550666Clay A, Hearle P, Schadt K, Lynch DR. New developments in pharmacotherapy for Friedreich ataxia. Expert Opin Pharmacother 2019; 20(15): 1855-67. doi: 10.1080/14656566.2019.1639671 PMID: 31311349Keita M, McIntyre K, Rodden LN, Schadt K, Lynch DR. Friedreich ataxia: Clinical features and new developments. Neurodegener Dis Manag 2022; 12(5): 267-83. doi: 10.2217/nmt-2022-0011 PMID: 35766110Zhang S, Napierala M, Napierala JS. Therapeutic prospects for Friedreich’s ataxia. Trends Pharmacol Sci 2019; 40(4): 229-33. doi: 10.1016/j.tips.2019.02.001 PMID: 30905359Cissé C, Cissé L, Samassékou O, et al. Clinical, paraclinical and genetic aspects of autosomal recessive cerebellar ataxias (ARCA) in Mali. Mali Med 2022; 37(4): 61-5. PMID: 36919030Pandolfo M. Friedreich ataxia: Detection of GAA repeat expansions and frataxin point mutations. Methods Mol Med 2006; 126: 197-216. doi: 10.1385/1-59745-088-X:197 PMID: 16930014Koeppen AH. Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics. J Neurol Sci 2011; 303(1-2): 1-12. doi: 10.1016/j.jns.2011.01.010 PMID: 21315377Aranca TV, Jones TM, Shaw JD, et al. Emerging therapies in Friedreich’s ataxia. Neurodegener Dis Manag 2016; 6(1): 49-65. doi: 10.2217/nmt.15.73 PMID: 26782317Santos R, Lefevre S, Sliwa D, Seguin A, Camadro JM, Lesuisse E. Friedreich ataxia: Molecular mechanisms, redox considerations, and therapeutic opportunities. Antioxid Redox Signal 2010; 13(5): 651-90. doi: 10.1089/ars.2009.3015 PMID: 20156111Schmucker S, Puccio H. Understanding the molecular mechanisms of Friedreich’s ataxia to develop therapeutic approaches. Hum Mol Genet 2010; 19(R1): R103-10. doi: 10.1093/hmg/ddq165 PMID: 20413654Koutnikova H, Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet 1997; 16(4): 345-51. doi: 10.1038/ng0897-345 PMID: 9241270Puccio H, Simon D, Cossée M, et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 2001; 27(2): 181-6. doi: 10.1038/84818 PMID: 11175786Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: A European perspective. Nat Rev Neurol 2009; 5(4): 222-34. doi: 10.1038/nrneurol.2009.26 PMID: 19347027Filla A, De Michele G, Coppola G, et al. Accuracy of clinical diagnostic criteria for Friedreich’s ataxia. Mov Disord 2000; 15(6): 1255-8. doi: 10.1002/1531-8257(200011)15:63.0.CO;2-C PMID: 11104216Santero OG, Nido DJ, Martín HS. Future prospects of gene therapy for Friedreich’s ataxia. Int J Mol Sci 2021; 22(4): 1815. doi: 10.3390/ijms22041815 PMID: 33670433Muthuswamy S, Agarwal S, Dalal A. Diagnosis and genetic counseling for Friedreich’s ataxia: A time for consideration of TP-PCR in an Indian setup. Hippokratia 2013; 17(1): 38-41. PMID: 23935342de Silva RN, Vallortigara J, Greenfield J, Hunt B, Giunti P, Hadjivassiliou M. Diagnosis and management of progressive ataxia in adults. Pract Neurol 2019; 19(3): 196-207. doi: 10.1136/practneurol-2018-002096 PMID: 31048364Corben LA, Collins V, Milne S, et al. Clinical management guidelines for Friedreich ataxia: Best practice in rare diseases. Orphanet J Rare Dis 2022; 17(1): 415. doi: 10.1186/s13023-022-02568-3 PMID: 36371255Tai G, Corben LA, Yiu EM, Milne SC, Delatycki MB. Progress in the treatment of Friedreich ataxia. Neurol Neurochir Pol 2018; 52(2): 129-39. doi: 10.1016/j.pjnns.2018.02.003 PMID: 29499876Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: An overview. J Med Genet 2000; 37(1): 1-8. doi: 10.1136/jmg.37.1.1 PMID: 10633128Strawser C, Schadt K, Hauser L, et al. Pharmacological therapeutics in Friedreich ataxia: The present state. Expert Rev Neurother 2017; 17(9): 895-907. doi: 10.1080/14737175.2017.1356721 PMID: 28724340Hart PE, Lodi R, Rajagopalan B, et al. Antioxidant treatment of patients with Friedreich ataxia: Four-year follow-up. Arch Neurol 2005; 62(4): 621-6. doi: 10.1001/archneur.62.4.621 PMID: 15824263Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M. Pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev 2016; 2016(8): CD007791. PMID: 27572719Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Cabo GP, Langa NJA. Antioxidant therapies and oxidative stress in Friedreich’s ataxia: The right path or just a diversion? Antioxidants 2020; 9(8): 664. doi: 10.3390/antiox9080664 PMID: 32722309Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. Emerging therapies in Friedreich’s ataxia. Expert Rev Neurother 2020; 20(12): 1215-28. doi: 10.1080/14737175.2020.1821654 PMID: 32909841Jaber S, Polster BM. Idebenone and neuroprotection: Antioxidant, pro-oxidant, or electron carrier? J Bioenerg Biomembr 2015; 47(1-2): 111-8. doi: 10.1007/s10863-014-9571-y PMID: 25262284Cores Á, Zafra CN, Clerigué J, Villacampa M, Menéndez JC. Quinones as neuroprotective agents. Antioxidants 2023; 12(7): 1464. doi: 10.3390/antiox12071464 PMID: 37508002Pradhan N, Singh C, Singh A. Coenzyme Q10 a mitochondrial restorer for various brain disorders. Naunyn Schmiedebergs Arch Pharmacol 2021; 394(11): 2197-222. doi: 10.1007/s00210-021-02161-8 PMID: 34596729Bolt J, Sandhu S, Mohammadi A. Effect of coenzyme Q10 supplementation on sarcopenia, frailty, and falls: A scoping review. J Nutr Health Aging 2023; 27(7): 586-92. doi: 10.1007/s12603-023-1943-8 PMID: 37498106Pallardó FV, Pagano G, Rodríguez LR, Gonzalez-Cabo P, Lyakhovich A, Trifuoggi M. Friedreich ataxia: Current state-of-the-art, and future prospects for mitochondrial-focused therapies. Transl Res 2021; 229(229): 135-41. doi: 10.1016/j.trsl.2020.08.009 PMID: 32841735Pallotti F, Bergamini C, Lamperti C, Fato R. The roles of coenzyme Q in disease: Direct and indirect involvement in cellular functions. Int J Mol Sci 2021; 23(1): 128. doi: 10.3390/ijms23010128 PMID: 35008564Lynch DR, Willi SM, Wilson RB, et al. A0001 in Friedreich ataxia: Biochemical characterization and effects in a clinical trial. Mov Disord 2012; 27(8): 1026-33. doi: 10.1002/mds.25058 PMID: 22744651Profeta V, McIntyre K, Wells M, Park C, Lynch DR. Omaveloxolone: An activator of Nrf2 for the treatment of Friedreich ataxia. Expert Opin Investig Drugs 2023; 32(1): 5-16. doi: 10.1080/13543784.2023.2173063 PMID: 36708320Lynch DR, Johnson J. Omaveloxolone: Potential new agent for Friedreich ataxia. Neurodegener Dis Manag 2021; 11(2): 91-8. doi: 10.2217/nmt-2020-0057 PMID: 33430645Lee A. Omaveloxolone: First approval. Drugs 2023; 83(8): 725-9. doi: 10.1007/s40265-023-01874-9 PMID: 37155124Sahdeo S, Scott BD, McMackin MZ, et al. Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich’s ataxia. Hum Mol Genet 2014; 23(25): 6848-62. doi: 10.1093/hmg/ddu408 PMID: 25113747Costantini A, Laureti T, Pala MI, et al. Long-term treatment with thiamine as possible medical therapy for Friedreich ataxia. J Neurol 2016; 263(11): 2170-8. doi: 10.1007/s00415-016-8244-7 PMID: 27488863Costantini A, Giorgi R, D’Agostino S, Pala MI. High-dose thiamine improves the symptoms of Friedreich’s ataxia. BMJ Case Rep 2013; 2013(may22 1): bcr2013009424. doi: 10.1136/bcr-2013-009424 PMID: 23704441Mangla B, Javed S, Sultan MH, et al. Sulforaphane: A review of its therapeutic potentials, advances in its nanodelivery, recent patents, and clinical trials. Phytother Res 2021; 35(10): 5440-58. doi: 10.1002/ptr.7176 PMID: 34184327Brandes MS, Gray NE. NRF2 as a therapeutic target in neurodegenerative diseases. ASN Neuro 2020; 12: 1759091419899782. doi: 10.1177/1759091419899782 PMID: 31964153La Rosa P, Russo M, D’Amico J, et al. Nrf2 induction re-establishes a proper neuronal differentiation program in Friedreich’s ataxia neural stem cells. Front Cell Neurosci 2019; 13: 356. doi: 10.3389/fncel.2019.00356 PMID: 31417369Xu L, Sun Z, Xing Z, et al. Cur@SF NPs alleviate Friedreich’s ataxia in a mouse model through synergistic iron chelation and antioxidation. J Nanobiotechnol 2022; 20(1): 118. doi: 10.1186/s12951-022-01333-9 PMID: 35264205Tiberi J, Segatto M, Fiorenza MT, La Rosa P. Apparent opportunities and hidden pitfalls: The conflicting results of restoring Nrf2-regulated redox metabolism in Friedreich’s ataxia pre-clinical models and clinical trials. Biomedicines 2023; 11(5): 1293. doi: 10.3390/biomedicines11051293 PMID: 37238963Richardson DR. Friedreich’s ataxia: Iron chelators that target the mitochondrion as a therapeutic strategy? Expert Opin Investig Drugs 2003; 12(2): 235-45. doi: 10.1517/13543784.12.2.235 PMID: 12556217Börklü E. Insights from yeast: Transcriptional reprogramming following metformin treatment is similar to that of deferiprone in a yeast Friedreich’s ataxia model. Yeast 2023; 40(3-4): 143-51. doi: 10.1002/yea.3845 PMID: 36755518Pandolfo M, Hausmann L. Deferiprone for the treatment of Friedreich’s ataxia. J Neurochem 2013; 126(S1): 142-6. doi: 10.1111/jnc.12300 PMID: 23859349Pandolfo M, Arpa J, Delatycki MB, et al. Deferiprone in Friedreich ataxia: A 6-month randomized controlled trial. Ann Neurol 2014; 76(4): 509-21. doi: 10.1002/ana.24248 PMID: 25112865Dusek P, Schneider SA, Aaseth J. Iron chelation in the treatment of neurodegenerative diseases. J Trace Elem Med Biol 2016; 38: 81-92. doi: 10.1016/j.jtemb.2016.03.010 PMID: 27033472Nuñez M, Cuevas CP. New perspectives in iron chelation therapy for the treatment of neurodegenerative diseases. Pharmaceuticals 2018; 11(4): 109. doi: 10.3390/ph11040109 PMID: 30347635Wong 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): 425-30. doi: 10.1093/hmg/8.3.425 PMID: 9949201Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: Overview and perspectives. Mol Cancer Res 2007; 5(10): 981-9. doi: 10.1158/1541-7786.MCR-07-0324 PMID: 17951399Rai M, Soragni E, Chou CJ, et al. Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin upregulation in cells from Friedreich’s ataxia patients and in a mouse model. PLoS One 2010; 5(1): e8825. doi: 10.1371/journal.pone.0008825 PMID: 20098685Lynch DR, Fischbeck KH. Nicotinamide in Friedreich’s ataxia: Useful or not? Lancet 2014; 384(9942): 474-5. doi: 10.1016/S0140-6736(14)60573-0 PMID: 24794818Libri 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): 504-13. doi: 10.1016/S0140-6736(14)60382-2 PMID: 24794816Abeti R, Jasoliya M, Mahdawi AS, et al. A drug combination rescues Frataxin-dependent neural and cardiac pathophysiology in FA models. Front Mol Biosci 2022; 9: 830650. doi: 10.3389/fmolb.2022.830650 PMID: 35664670Boesch S, Sturm B, Hering S, Goldenberg H, Poewe W, Mojdehkar SB. Friedreich’s ataxia: Clinical pilot trial with recombinant human erythropoietin. Ann Neurol 2007; 62(5): 521-4. doi: 10.1002/ana.21177 PMID: 17702040Boesch 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): 1940-4. doi: 10.1002/mds.22294 PMID: 18759345Jain P, Badgujar L, Spoorendonk J, Buesch K. Clinical evidence of interventions assessed in Friedreich ataxia: A systematic review. Therapeu Adv Rare Dis 2022; 3: 26330040221139872. doi: 10.1177/26330040221139872 PMID: 37180421Boesch S, Indelicato E. Erythropoietin and Friedreich ataxia: Time for a reappraisal? Front Neurosci 2019; 13: 386. doi: 10.3389/fnins.2019.00386 PMID: 31105516Kemper C, Behnam D, Brothers S, et al. Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM). AAPS Open 2022; 8(1): 11. doi: 10.1186/s41120-022-00058-1 PMID: 35789594Hayashi G, Jasoliya M, Sahdeo S, et al. Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Hum Mol Genet 2017; 26(15): 2864-73. doi: 10.1093/hmg/ddx167 PMID: 28460056Yiu 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): 1344-53. doi: 10.1007/s00415-015-7719-2 PMID: 25845763Georges P, Boza-Moran MG, Gide J, et al. Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide. Sci Rep 2019; 9(1): 14568. doi: 10.1038/s41598-019-49870-y PMID: 31601825Luffarelli R, Panarello L, Quatrana A, et al. Interferon gamma enhances cytoprotective pathways via Nrf2 and MnSOD induction in Friedreich’s ataxia cells. Int J Mol Sci 2023; 24(16): 12687. doi: 10.3390/ijms241612687 PMID: 37628866Vavla M, D’Angelo MG, Arrigoni F, et al. Safety and efficacy of interferon γ in Friedreich’s ataxia. Mov Disord 2020; 35(2): 370-1. doi: 10.1002/mds.27979 PMID: 31930551Wells M, Seyer L, Schadt K, Lynch DR. IFN-γ for Friedreich ataxia: present evidence. Neurodegener Dis Manag 2015; 5(6): 497-504. doi: 10.2217/nmt.15.52 PMID: 26634868Lynch DR, Hauser L, McCormick A, et al. Randomized, double-blind, placebo-controlled study of interferon-γ 1b in Friedreich ataxia. Ann Clin Transl Neurol 2019; 6(3): 546-53. doi: 10.1002/acn3.731 PMID: 30911578Seyer 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. doi: 10.1111/ane.12337 PMID: 25335475Tekin HG, Levent E. Neurological recovery with interferon-gamma treatment in Friedreich’s ataxia. J Coll Physicians Surg Pak 2022; 32(5): 671-3. doi: 10.29271/jcpsp.2022.05.671 PMID: 35546709Pizcueta P, Vergara C, Emanuele M, Vilalta A, Pascau RL, Martinell M. Development of PPARγ agonists for the treatment of neuroinflammatory and neurodegenerative diseases: Leriglitazone as a promising candidate. Int J Mol Sci 2023; 24(4): 3201. doi: 10.3390/ijms24043201 PMID: 36834611Marmolino 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. doi: 10.1371/journal.pone.0010025 PMID: 20383327Di Donfrancesco A, Berlingieri C, Giacomello M, et al. PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients. Front Pharmacol 2023; 14: 1220620. doi: 10.3389/fphar.2023.1220620 PMID: 37576821NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators. Pioglitazone in early Parkinson’s disease: A phase 2, multicentre, double-blind, randomised trial. Lancet Neurol 2015; 14(8): 795-803. doi: 10.1016/S1474-4422(15)00144-1 PMID: 26116315Corona JC, Duchen MR. PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease. Free Radic Biol Med 2016; 100: 153-63. doi: 10.1016/j.freeradbiomed.2016.06.023 PMID: 27352979Orsucci D, Mancuso M, Ienco EC, LoGerfo A, Siciliano G. Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues. Curr Med Chem 2011; 18(26): 4053-64. doi: 10.2174/092986711796957257 PMID: 21824087Apostolova N, Victor VM. Molecular strategies for targeting antioxidants to mitochondria: Therapeutic implications. Antioxid Redox Signal 2015; 22(8): 686-729. doi: 10.1089/ars.2014.5952 PMID: 25546574Liu J, Wang L. Mitochondrial enhancement for neurodegenerative movement disorders: A systematic review of trials involving creatine, coenzyme Q10, idebenone and mitoquinone. CNS Drugs 2014; 28(1): 63-8. doi: 10.1007/s40263-013-0124-4 PMID: 24242074Hui CK, Dedkova EN, Montgomery C, Cortopassi G. Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich’s ataxia model mice. Hum Mol Genet 2021; 29(24): 3954-65. doi: 10.1093/hmg/ddaa282 PMID: 33432356Jasoliya M, Sacca F, Sahdeo S, et al. Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich’s ataxia. PLoS One 2019; 14(6): e0217776. doi: 10.1371/journal.pone.0217776 PMID: 31158268Pane C, Marra AM, Aliberti L, et al. Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich ataxia (DMF-FA-201). Front Neurosci 2023; 17: 1260977. doi: 10.3389/fnins.2023.1260977 PMID: 37746147La Rosa P, Bertini ES, Piemonte F. The NRF2 signaling network defines clinical biomarkers and therapeutic opportunity in Friedreich’s ataxia. Int J Mol Sci 2020; 21(3): 916. doi: 10.3390/ijms21030916 PMID: 32019240Franko A, Irmler M, Prehn C, et al. Bezafibrate reduces elevated hepatic fumarate in insulin-deficient mice. Biomedicines 2022; 10(3): 616. doi: 10.3390/biomedicines10030616 PMID: 35327418Grings M, Moura AP, Parmeggiani B, et al. Bezafibrate prevents mitochondrial dysfunction, antioxidant system disturbance, glial reactivity and neuronal damage induced by sulfite administration in striatum of rats: Implications for a possible therapeutic strategy for sulfite oxidase deficiency. Biochim Biophys Acta Mol Basis Dis 2017; 1863(9): 2135-48. doi: 10.1016/j.bbadis.2017.05.019 PMID: 28529047Zesiewicz T, Heerinckx F, De Jager R, et al. Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich’s ataxia. Mov Disord 2018; 33(6): 1000-5. doi: 10.1002/mds.27353 PMID: 29624723Lynch DR, Mathews KD, Perlman S, et al. Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia. J Neurol 2023; 270(3): 1615-23. doi: 10.1007/s00415-022-11501-4 PMID: 36462055Perlman SL. Update on the treatment of ataxia: Medication and emerging therapies. Neurotherapeutics 2020; 17(4): 1660-4. doi: 10.1007/s13311-020-00941-3 PMID: 33021724La Rosa P, Petrillo S, Fiorenza MT, Bertini ES, Piemonte F. Ferroptosis in Friedreich’s ataxia: A metal-induced neurodegenerative disease. Biomolecules 2020; 10(11): 1551. doi: 10.3390/biom10111551 PMID: 33202971Vogel AP, Folker J, Poole ML. Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes. Cochrane Libr 2014; (10): CD008953. doi: 10.1002/14651858.CD008953.pub2 PMID: 25348587Zesiewicz TA, Wilmot G, Kuo SH, et al. Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia. Neurology 2018; 90(10): 464-71. doi: 10.1212/WNL.0000000000005055 PMID: 29440566Bondarev AD, Attwood MM, Jonsson J, et al. Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules. Front Pharmacol 2022; 13: 1057083. doi: 10.3389/fphar.2022.1057083 PMID: 36506513Shirani A, Okuda DT, Stüve O. Therapeutic advances and future prospects in progressive forms of multiple sclerosis. Neurotherapeutics 2016; 13(1): 58-69. doi: 10.1007/s13311-015-0409-z PMID: 26729332Zhao W, Xu Z, Cao J, et al. Elamipretide (SS-31) improves mitochondrial dysfunction, synaptic and memory impairment induced by lipopolysaccharide in mice. J Neuroinflammation 2019; 16(1): 230. doi: 10.1186/s12974-019-1627-9 PMID: 31747905Zhao H, Li H, Hao S, et al. Peptide SS-31 upregulates frataxin expression and improves the quality of mitochondria: Implications in the treatment of Friedreich ataxia. Sci Rep 2017; 7(1): 9840. doi: 10.1038/s41598-017-10320-2 PMID: 28852135Johnson J, Mercado-Ayón E, Clark E, Lynch D, Lin H. Drp1-dependent peptide reverse mitochondrial fragmentation, a homeostatic response in Friedreich ataxia. Pharmacol Res Perspect 2021; 9(3): e00755. doi: 10.1002/prp2.755 PMID: 33951329Singh A, Faccenda D, Campanella M. Pharmacological advances in mitochondrial therapy. EBioMedicine 2021; 65: 103244. doi: 10.1016/j.ebiom.2021.103244 PMID: 33647769Lynch DR, Farmer G. Mitochondrial and metabolic dysfunction in Friedreich ataxia: Update on pathophysiological relevance and clinical interventions. Neuronal Signal 2021; 5(2): NS20200093. doi: 10.1042/NS20200093 PMID: 34046211Qureshi MY, Patterson MC, Clark V, et al. Safety and efficacy of (+)-epicatechin in subjects with Friedreich’s ataxia: A phase II, open-label, prospective study. J Inherit Metab Dis 2021; 44(2): 502-14. doi: 10.1002/jimd.12285 PMID: 32677106Roberts AD, Wadhwa R, Eds. Orphan drug approval laws. Stat- Pearls. Treasure Island, FL: StatPearls Publishing 2023.Hustinx M, Shorrocks AM, Servais L. Novel therapeutic approaches in inherited neuropathies: A systematic review. Pharmaceutics 2023; 15(6): 1626. doi: 10.3390/pharmaceutics15061626 PMID: 37376074Zesiewicz T, Salemi JL, Perlman S, et al. Double-blind, randomized and controlled trial of EPI-743 in Friedreich’s ataxia. Neurodegener Dis Manag 2018; 8(4): 233-42. doi: 10.2217/nmt-2018-0013 PMID: 30051753Mullard A. FDA approves first Friedreich’s ataxia drug. Nat Rev Drug Discov 2023; 22(4): 258. PMID: 36890218Probst 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. doi: 10.1371/journal.pone.0122942 PMID: 25897966Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol 2021; 89(2): 212-25. doi: 10.1002/ana.25934 PMID: 33068037Lynch DR, Chin MP, Boesch S, et al. Efficacy of omaveloxolone in Friedreich’s ataxia: Delayed-start analysis of the MOXIe extension. Mov Disord 2023; 38(2): 313-20. doi: 10.1002/mds.29286 PMID: 36444905Cnop M, Esteve IM, Pandolfo M. Treatment of Freidreich's ataxia. GB Patent 2514827A 2013.Cortopassi G, Sahdeo S. Agents useful for treating Friedreich’s ataxia and other neurodegenerative diseases. US Patent 20180333386A1, 2018.Mleczek FM, Baumhof P. Methods of treating a subject having Friedreich’s ataxia with mRNA encoding frataxin. US Patent 20190175757A1, 2019.Collard J, Sherman OK. Treatment of Frataxin (Fxn) related diseases by inhibition of natural antisense transcript to fxn. CA Patent 2838588C, 2012.Ansari A, Erwin G, Grieshop M. Compounds and methods for modulating frataxin expression. US Patent 10517877B2, 2017.Wilson JM, Hinderer C, Miller N. Compositions for treating Friedreich’s ataxia. CA Patent 3162020A1, 2020.Gottesfeld JM, Jenssen AK, Herman DM. Treatment of Friedreich’s ataxia using histone deacetylase inhibitors. US Patent 20150080472A1, 2014.Testi R, Tomassini B. Compositions and methods for treating Friedreich’s ataxia with interferon gamma. EP Patent 2611457B1, 2011.Tremblay JP, Ouellet DL. Crispr-based treatment of Friedreich ataxia. WO Patent 2018098587A1, 2017.Mojdehkar SB, Sturm BN. Pharmaceutical preparation comprising EPO for the treatment of Friedreich’s ataxia. NZ Patent 555178A, 2005.Rosuvastatin (Crestor) in Friedreich ataxia. NCT Patent 02705547, 2021.Methylprednisolone treatment of Friedreich ataxia. NCT Patent 02424435, 2021.Micronised resveratrol as a treatment for Friedreich ataxia. NCT Patent 03933163, 2024.Cooper JM, Korlipara LVP, Hart PE, Bradley JL, Schapira AHV. 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): 1371-9. doi: 10.1111/j.1468-1331.2008.02318.x PMID: 19049556Safety and efficacy study of a0001 in subjects with Friedreich's Ataxia. NCT Patent 01035671, 2011.Interferon gamma-1b in Friedreich ataxia (FRDA). NCT Patent 01965327, 2021.Effect of pioglitazone administered to patients with Friedreich's ataxia: Proof of concept (ACTFRIE). NCT Patent 00811681, 2013.NAD+ precursor supplementation in Friedreich's ataxia. NCT Patent 04817111, 2023.Biomarker for Friedreich's ataxia (BioFridA) (BioFridA). NCT Patent 04548921, 2022.A study of vatiquinone for the treatment of participants with Friedreich ataxia. NCT Patent 05485987, 2024.Evaluation of the effect of artesunate in Friedreich ataxia (FA) (ARTEMIS). NCT Patent 04921930, 2023.Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). NCT Patent 04273165, 2023.