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Therapies

Friedreich ataxia (FA) is a rare, inherited neurodegenerative disorder caused by a mutation in the frataxin (FXN) gene, which leads to a deficiency in frataxin, a mitochondrial protein that plays a critical role in the energy metabolism of cells. Frataxin deficiency leads to the degeneration of the nervous system, particularly the spinal cord and nerves that control movement, as well as cardiac dysfunction.¹

Manifestations of FA typically appear in puberty and can include a progressive loss of coordination and balance, weakness in the limbs, and slurred speech. In addition to these neurological symptoms, FA can also cause cardiac problems, such as heart enlargement and heart failure. Some individuals with FA may also experience diabetes and scoliosis.¹

Symptomatic treatment for FA includes physical therapy, speech therapy, and occupational therapy to help individuals maintain their independence and quality of life. Currently, there are no US Food and Drug Administration (FDA)-approved therapies for FA that can slow or halt the progression of the disease. However, there are several treatment options available for off-label use to help manage the symptoms of the disorder, including agents that enhance mitochondrial function with the addition of free radical scavengers and iron chelators. These agents are designed to address mitochondrial function and oxidative tissue damage, which may be affected by FXN mutations.^1,2

Coenzyme Q10 and Vitamin E

Coenzyme Q10 (also known as ubiquinone) is a small lipophilic molecule located in the inner mitochondrial membrane that acts as a free radical scavenger. This molecule plays an antioxidant role by preventing the oxidation of cellular structures and maintaining other antioxidant molecules such as vitamins C and E.³ It has been used by patients with FA due to its favorable tolerance and reduced side effects.⁴

An open-label study including 10 patients with FA was performed to evaluate the influence of a combined coenzyme Q10 and vitamin E (an antioxidant) antioxidant therapy in FA. Patients using coenzyme Q10-vitamin E therapy for 6 months saw improved results in both cardiac and skeletal muscle bioenergetics that were maintained over the treatment period of 47 months.⁵

A different double-blind randomized trial involving 50 patients with FA investigated high and low doses of coenzyme Q10-vitamin E combined therapy. Of the patients who completed the study, 49% presented with slower degeneration and clinical improvement.⁶

Read more about FA clinical trials

Idebenone

Idebenone is a structural and synthetic analogue of coenzyme Q10.² It has antioxidant properties as a reactive oxygen species scavenger and lipid peroxidation inhibitor, and it has been shown to improve mitochondrial function and increase adenosine triphosphate (ATP) production.³ Like coenzyme Q10, idebenone has been used in patients with FA because it is well tolerated and has reduced side effects.²

Previous studies have shown the ability of idebenone to improve cardiac outcomes in patients with FA, while reports on neurological outcomes are limited.¹ Other studies have shown a lack of changes in neurological and cardiac function.^1,2

Read more about FA experimental therapies

Iron Chelators

The accumulation of iron in the mitochondria of FA patients may result in their decreased expression of frataxin protein. The use of iron chelators may therefore be considered as a potential therapy in patients with FA.¹

Ferriprox® (deferiprone) is an iron chelator capable of crossing the blood-brain barrier and other cellular membranes.³ A phase 2 clinical trial in which patients with FA were treated with this agent demonstrated a reduction in iron content after a 6-month treatment period.⁷ Additional studies are needed to ascertain the efficacy of this therapeutic approach in FA.

Read more about FA clinical features

Other Therapies

Other therapies may be recommended for the management of cardiac symptoms in patients with FA. These include diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, aldosterone antagonists, and Lanoxin® (digoxin). Pacerone® (amiodarone) and Rythmol® (propafenone) may be used to address arrhythmias derived from cardiomyopathy. Insulin may also be recommended for patients with FA experiencing diabetes mellitus.¹

Read more about FA complications

References

1. Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009;5(4):222-234. doi:10.1038/nrneurol.2009.26

2. Tai G, Corben LA, Yiu EM, Milne SC, Delatycki MB. Progress in the treatment of Friedreich ataxia. Neurol Neurochir Pol. 2018;52(2):129-139. doi:10.1016/j.pjnns.2018.02.003

3. 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

4. Kearney M, Orrell RW, Fahey M, Pandolfo M. Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev. 2012;4:CD007791. doi:10.1002/14651858.CD007791.pub3

5. 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. doi:10.1002/ana.1001

6. 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):1371-1379. doi:10.1111/j.1468-1331.2008.02318.x

7. Boddaert N, Le Quan Sang KH, Rötig A, et al. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 2007;110(1):401-408. doi:10.1182/blood-2006-12-065433

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

Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.

Friedreich Ataxia (FA)