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Friedreich Ataxia (FA)

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Experimental Therapies

Friedreich ataxia (FA) is a rare, inherited neurodegenerative disorder that affects the nervous system, leading to problems with movement and coordination as well as cardiomyopathy and diabetes. Currently, there is no cure for FA, and treatment options are limited to managing symptoms. There are, however, experimental therapies in development that aim to treat the underlying causes of FA.1

Agents That Enhance Mitochondrial Function

Friedreich ataxia is characterized by decreased levels of frataxin, a mitochondrial protein involved in iron homeostasis. Low levels of frataxin promote mitochondrial dysfunction with the generation of reactive oxygen species (ROS), increased oxidative stress, and cellular damage. In addition to the current therapies of idebenone and coenzyme Q10, another antioxidant with potential activity in FA is EPI-743.1

EPI-743 (also known as alpha-tocotrienol quinone) inhibits the activity of 15-lipoxygenase, a key player in inflammation, oxidative stress, and ferroptosis. A double-blind, multicenter clinical trial evaluated two EPI-743 doses in patients with FA. This trial consisted of a 6-month placebo-controlled phase followed by an 18-month open-label phase. The study reported that EPI-743 was well tolerated and safe, with no adverse events reported, and that significant improvements in neurological function were observed.2

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Epicatechin is a polyphenolic flavonoid found in fruits that has been investigated for use in FA. An open-label trial was performed to study the safety and efficacy of epicatechin in 10 patients with FA for 2 weeks.3 The primary outcome measures of this trial included changes from baseline in Friedreich Ataxia Rating Scale (FARS) score and ventricular hypertrophy. Epicatechin was well tolerated and improved the mean left ventricular ejection fraction as an indicator of cardiac function. However, no improvements in FARS scores were reported.4

Actos® (pioglitazone) is a peroxisome proliferator-activated receptor (PPAR)-γ agonist that increases insulin sensitivity and normalizes serum glucose levels.1 PPARγ agonists may improve mitochondrial function biogenesis and increase frataxin levels, and they have been evaluated in patients with FA.1,2 A randomized, double-blind trial with Actos has been performed to evaluate the effects of the drug on neurological defects, while the effects of leriglitazone, a metabolite of pioglitazone, have been studied in a phase 2, randomized, double-blind, placebo-controlled trial (FRAMES).5,6

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Nrf2 Activators

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor with an important role in the reduction of oxidative stress. Nrf2 deficiency renders the cells more susceptible to oxidative stress and the effects of ROS. The Nrf2 signaling pathway is affected in patients with FA, making it a potential therapeutic target.1

Resveratrol is a polyphenolic phytoalexin with antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective properties. It participates in many cellular processes, including Nrf2 activation, and it has been studied in an open-label clinical trial involving 27 participants. Although frataxin levels did not change, a high-tested dose of resveratrol decreased the lipid peroxidation biomarker F2-isoprostane and led to improvements in neurological function. Frequent gastrointestinal side effects were observed, however, pointing to the need for optimizing the tolerability and bioavailability of this potential therapy.9

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Agents That Interfere With Lipid Metabolism

RT001, a deuterated polyunsaturated fatty acid (PUFA), is a deuterated form of linoleic acid that slows the rate of PUFA oxidation. A pilot phase 1/2, double-blind, placebo-controlled clinical trial included 18 patients who were randomized to receive the experimental treatment or a matching comparator dose of placebo. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of RT001 and reported a favorable safety profile with several gastrointestinal-related adverse events.10

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Agents That Increase Frataxin Expression 

The low expression of frataxin is the hallmark feature of FA.11 Increasing frataxin expression at the genetic level has been envisioned through genome editing (by the excision of large expansion repeats), oligonucleotide-based approaches (using antisense oligonucleotides complementary to the GAA repeats in the FXN gene), and synthetic transcription factors (such as Syn-TEF1, which enables transcription across GAA repeats that block frataxin expression).1,11 Potential gene therapy is also under development, making use of adeno-associated viruses (AAV) to deliver vectors expressing frataxin.1

Histone deacetylase (HDAC) inhibitors such as nicotinamide increase histone acetylation of the FXN gene and therefore promote an increase in frataxin. Interferon-gamma, a medication approved by the US Food and Drug Administration (FDA) for the treatment of malignant osteopetrosis and chronic granulomatous disease, has also been shown to increase frataxin levels in the cells of patients with FA. Intelence® (etravirine), an antiviral medication used for the treatment of human immunodeficiency virus (HIV), is also able to increase frataxin levels in FA patient-derived cells. Additional testing is required to establish the effects and mechanisms of action of these agents in FA.1 

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References

1. Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. Emerging therapies in Friedreich’s ataxia. Expert Rev Neurother. 2020;20(12):1215-1228. doi:10.1080/14737175.2020.1821654

2. Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant therapies and oxidative stress in Friedreich’s ataxia: the right path or just a diversion? Antioxidants (Basel). 2020;9(8):664. doi:10.3390/antiox9080664

3. Indelicato E, Bösch S. Emerging therapeutics for the treatment of Friedreich’s ataxia. Expert Opin Orphan Drugs. 2018;6(1):57-67. doi:10.1080/21678707.2018.1409109

4. Qureshi 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):502-514. doi:10.1002/jimd.12285

5. García-Giménez JL, Sanchis-Gomar F, Pallardó FV. Could thiazolidinediones increase the risk of heart failure in Friedreich’s ataxia patients? Mov Disord. 2011;26(5):769-771. doi:10.1002/mds.23711

6. A clinical study to evaluate the effect of MIN-102 on the progression of Friedreich’s ataxia in male and female patients (FRAMES). ClinicalTrials.gov. April 17, 2019. Updated October 13, 2022. Accessed January 24, 2023.

7. RTA 408 capsules in patients with Friedreich’s ataxia – MOXIe. ClinicalTrials.gov. October 2, 2014. Updated December 6, 2022. Accessed January 24, 2023.

8. Lynch DR, Farmer J, Hauser L, et al. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol. 2018;6(1):15-26. doi:10.1002/acn3.660

9. 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. doi:10.1007/s00415-015-7719-2

10. Zesiewicz 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):1000-1005. doi:10.1002/mds.27353

11. Zhang S, Napierala M, Napierala JS. Therapeutic prospects for Friedreich’s ataxia. Trends Pharmacol Sci. 2019;40(4):229-233. doi:10.1016/j.tips.2019.02.001

Reviewed by Hasan Avcu, MD, on 1/28/2023.

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