Friedreich Ataxia: Pathophysiology and Treatment

Friedreich ataxia (FRDA), a progressive multisystem neurodegenerative disease, is the most common autosomal recessive ataxia, with a prevalence of 1 in 50,000.¹ FRDA most commonly results from a biallelic trinucleotide (GAA) repeat expansion of the frataxin gene (FXN) on chromosome 9,² which results in transcriptional silencing of FXN and a decreased level of frataxin protein. The other 4% of cases result from compound heterozygosity, with 1 expanded allele and 1 point variation. One in 100 individuals is a carrier for the variant FXN allele.³

FRDA pathology affects the dorsal root ganglia (DRG), spinocerebellar tracts, dentate nuclei, and posterior columns.⁴ FRDA is characterized by gait and limb ataxia, dysarthria, sensory changes, areflexia, and muscle weakness; non-neurologic symptoms include sensorineural hearing loss, diabetes, pes cavus, optic neuropathy, scoliosis, and cardiomyopathy. Age at onset of disease is inversely related to, and disease severity related to, repeat length of the shorter allele.^5,6 Assessment often is conducted using the Friedreich’s Ataxia Rating Scale (FARS), including an overall neurologic examination, assessment of activities of daily living and mobility, and focused physical tests.⁷ The modified FARS (mFARS) is an abbreviated version that assesses bulbar function, upper and lower limb coordination, and upright stability.⁸

Frataxin, a mitochondrial protein with an important role in ATP production, assists in formation of iron-sulfur clusters, which act as cofactors in the electron transport chain. Frataxin plays a role in mitochondrial oxidative stress mitigation. Frataxin deficiency results in disruption of iron homeostasis, buildup of oxidative stress, decreased ATP production, and cellular damage.^9,10 FRDA carriers have 50% of the normal frataxin level but are asymptomatic.¹¹

Despite the discovery of the gene that causes FRDA in 1996, and decades of research, there is no cure for FRDA. However, the first drug to treat FRDA (omaveloxolone; Skylarys, Reata Pharmaceuticals, Plano, TX) was approved by the Food and Drug Administration (FDA) in 2023. This review focuses on FRDA treatments.

Antioxidation

Frataxin reduction results in a buildup of reactive oxygen species, leading to mitochondrial oxidative stress. Antioxidant molecules have been evaluated as a possible treatment.

Idebenone

Idebenone, a benzoquinone derivative and an analog of coenzyme Q10 (CoQ10), has been studied to determine its efficacy as an antioxidant FRDA treatment. Clinical trials have yielded conflicting neurologic and cardiac results. In 1 study evaluating the effect of idebenone in children, no decrease in left ventricular (LV) hypertrophy or neurologic benefit was noted,¹² but cardiac hypertrophy, interventricular septal thickness, and LV mass were significantly reduced in 2 follow-up studies.^13,14 A phase 3 trial did not report improvements in neurologic symptoms,¹⁵ in contrast with several trials that showed significant neurologic benefits with idebenone in high doses.¹⁶ A randomized treatment withdrawal study of idebenone or placebo showed that individuals were not able to identify treatment assignment.¹⁷

Coenzyme Q10

CoQ10 is a small lipophilic molecule responsible for movement of electrons within the mitochondria.¹⁸ As with its antioxidant analog, CoQ10’s treatment efficacy in FRDA is undetermined.¹⁹ Despite conflicting results from trials evaluating CoQ10, approximately 50% of people with FRDA report taking CoQ10.¹⁹

Vatiquinone

A para-benzoquinone and a catalytic antioxidant, vatiquinone (formerly known as EPI-743; alpha-tocotrienolol quinone) was evaluated as its original analog A0001 (α-tocopheryl quinone) as a treatment for FRDA.²³ One of the first studies of A0001 assessed neurologic function and glucose metabolism.²³ No difference was noted in glucose metabolism but a significant improvement (P<.01) was observed in FARS neurologic scores compared with placebo. A0001 was safe and tolerable.²³

Promising results from this A0001 study spurred a follow-up study in which 60 participants were randomized to placebo or A0001.²⁴ Outcome measures included low-contrast visual acuity assessment, FARS neurologic score, 9-hole peg test, 25-foot walk test, and echocardiography.²⁴ No significant differences were observed at the 6-month end point, but post hoc analysis of FARS neurologic scores revealed that 73% of participants randomized to the A0001 groups had at least a 3-point improvement (P=.047) compared with 43% of individuals receiving placebo.²⁵ A 5-point or greater improvement (P=.047) was noted in 64% of individuals taking A0001 in comparison with 33% of individuals on placebo.²⁵

This study was followed by a 2-part extension phase. For the first 6 months, participants randomized to drug maintained their current A0001 dose. Placebo-treated individuals were randomized to receive low-dose or high-dose A0001.²⁵ For the next 12 months, all participants were dosed with 400 mg A0001. FARS neurologic data from the extension were compared with those of matched individuals in a natural history cohort. Scores in the natural history study worsened (mean, 4.8 points); A0001 participants had improved scores (P<.001) (mean, 1.8 points).²⁵

Vatiquinone was evaluated in 146 children and adults with FRDA. The primary end point was change in mFARS scores from baseline compared with placebo.²⁶ The study did not meet its primary end point, but improvements were noted in mFARS subscores, including upright stability (P=.021) and bulbar (P=.044).²⁷

Nrf2 Activation

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a role in oxidative stress mitigation. Nrf2 levels usually are monitored and regulated by the Kelch-like ECH associated protein 1 (KEAP1) through ubiquitination and degradation. With oxidative stress buildup, Nrf2 ubiquitination is disrupted, and the molecule works to activate transcription of genes that protect against oxidative stress.^28-30 A lack of Nrf2 would leave the cell susceptible to inflammation and reactive oxygen species.³¹ Analysis of FRDA animal and cell models has revealed a link between decreased frataxin levels and Nrf2 levels.³² Fibroblasts from individuals with FRDA are hypersensitive to oxidative damage, demonstrating that the Nrf2 signaling pathway in FRDA is damaged. Nrf2 activators prevent Nrf2 ubiquitination and destruction to increase activity and expression level.³³

Omaveloxolone

The Nrf2 activator omaveloxolone is the first FDA-approved drug for FRDA treatment, confirmed in 2023. Omaveloxolone prevents Nrf2 ubiquitination, thereby allowing Nrf2 to activate antioxidative genes and mitigate effects of oxidative stress. The phase 2 dose-finding MOXIe study (NCT02255435, EudraCT2015-002762-23) evaluated safety, tolerability, and pharmacokinetics of this Nrf2 activator in 69 people with FRDA.^34,35 Participants were randomized to doses ranging from 2.5 to 300 mg/d of omaveloxolone or placebo. After 12 weeks, no change in mFARS score was noted with omaveloxolone versus placebo.³⁵ However, a dose-dependent 3.8-point improvement in mFARS scores was noted in the 160-mg dose group (P<.001) compared with baseline and a 2.3-point improvement (P=.06) compared with placebo.³⁵ Omaveloxolone was safe and well-tolerated.³⁵

Following the results from the first part of the MOXIe trial, 103 people with FRDA were randomized to receive 150 mg of omaveloxolone or placebo in a trial to investigate the benefits of 150 mg of omavelolone.³⁶ An .85-point increase in mFARS score in participants receiving placebo and a 1.55-point decrease in participants receiving 150 mg omaveloxolone were reported (P=.014).³⁶ Post hoc analysis of a 3-year extension demonstrated that individuals taking omaveloxolone performed better on mFARS than individuals in the natural history cohort.³⁶

Dimethyl Fumarate

Dimethyl fumarate (DMF) is an Nrf2 activator used to treat psoriasis and multiple sclerosis (MS). A study of DMF use in 14 people with MS showed an 85% increase in expression of frataxin. Similar results were noted in cell and mice models of FRDA with DMF administration.³⁷ DMF increases gene expression and mitochondrial biogenesis, which could be related to FXN induction.³⁷

Promotion of Biogenesis

PPARγ Agonists

Peroxisome proliferator-activated receptor γ (PPARγ) is a part of a family of receptors that modulate cellular functions, such as metabolism of reactive oxygen species and mitochondrial biogenesis.³⁸ PPARγ agonists are antidiabetic molecules that increase insulin sensitivity and stabilize glucose levels.³⁹ Because of its role in mitochondrial biogenesis, PPARγ has been investigated as a therapy for FRDA. Azelaoyl PAF increased FXN mRNA expression in FRDA and healthy control primary fibroblasts.³⁸ Leriglitazone protected DRG in vitro and improved motor function in mouse models.⁴⁰ Leriglitazone can cross the blood-brain barrier.⁴¹ These results led to development of a phase 1 trial investigating leriglitazone (MIN-102; FRAMES, NCT 03917225). Leriglitazone was safe, tolerable, and effective in decreasing plasma inflammatory markers.⁴² A follow-up phase 2 trial randomized 39 people with FRDA to placebo or leriglitazone.⁴¹ At the 48-week end point, leriglitazone did not meet its primary outcome measure of change in spinal cord area.⁴¹ Iron accumulation in the dentate nucleus was greater in the placebo than the leriglitazone group (P=.05).⁴¹

Epicatechin

Epicatechin, an antioxidant flavonoid that promotes mitochondrial biogenesis, is being evaluated as a treatment for FRDA. One phase 2 trial in 10 people with FRDA assessed the effect of epicatechin 75 mg (escalated to 150 mg at 12 weeks if no improvement was noted) on cardiac and neurologic endpoints.⁴³ mFARS scores did not show significant improvements, but LV mass index decreased (P=.045) and LV ejection fraction increased (P=.008).⁴³

Lipid Metabolism Manipulation

RT001

Low frataxin levels in FRDA result in lipid peroxidation and oxidative damage to lipid membranes secondary to mitochondrial dysfunction. RT001 is a form of linoleic acid that reduces oxidation of polyunsaturated fatty acids. In a phase 1/2 study, peak workload in cardiopulmonary exercise testing improved with RT001 compared with placebo (P=.008).⁴⁴ A subsequent phase 2 trial that assessed RT001 efficacy did not meet its primary outcome of change in maximum oxygen consumption in cardiopulmonary exercise testing.⁴⁵ Analysis of secondary outcome measures and post hoc data did not reveal improvement with RT001.⁴⁵

Iron Chelation

Deferiprone

Frataxin facilitates formation of mitochondrial iron-sulfur clusters, which are critical for the electron transport chain and ATP production.⁴⁶ With the frataxin deficiency seen in FRDA, iron accumulation has been noted. One avenue for FRDA treatment is iron chelation. In 1 study evaluating deferiprone,⁴⁷ 72 people with FRDA were randomized to receive placebo or 20, 40, or 60 mg/kg/d of deferiprone. At 20 mg/kg/d, deferiprone was tolerable and safe. Two individuals in the 60 mg/kg/d group experienced ataxia worsening. Individuals at all doses experienced a decrease in cardiac hypertrophy, but no changes were noted in FARS assessments in the 20 and 40 mg/kg/d groups.⁴⁷ The benefit of iron chelation for FRDA treatment is unclear.

Channel Modulation

Riluzole

Riluzole, a potassium channel modulator and glutamate inhibitor used to treat amyotrophic lateral sclerosis,⁴⁸ aids in neuronal excitability regulation by opening calcium-activated potassium channels. The pathophysiology of cerebellar ataxias has been linked to abnormal firing of Purkinje cells.⁴⁹ Encouraging results from studies investigating cerebellar ataxia treatment^49,50 with riluzole have prompted interest in its potential as a treatment for FRDA.

One double-blind placebo-controlled pilot trial of participants with varying etiologies of cerebellar ataxia (3 with FRDA) assessed riluzole treatment.⁴⁹ Neurologic function was assessed over 8 weeks. Treated participants experienced a decrease in International Cooperative Ataxia Rating Scale score (P<.001).⁴⁹ A follow-up study extended treatment to 12 months in 100 mg/d riluzole and placebo groups.⁵⁰ Individuals receiving riluzole treatment experienced a decrease in Scale for the Assessment and Rating of Ataxia (SARA) scores (P=.002).⁵⁰

Increased Frataxin Expression

HDAC Inhibitors

The GAA repeat expansion responsible for FRDA results in transcriptional FXN silencing and heterochromatic formation.⁵¹ Histone deacetylase inhibitors (HDAC) increase FXN histone acetylation, disrupting gene silencing and increasing frataxin.^52,53 HDAC inhibitors have been evaluated in FRDA pluripotent stem cells and lymphocytes and demonstrated upregulation of FXN expression.^52,54 A phase 1 trial of a HDAC inhibitor, RGFP109 (RG2833), evaluated doses in 4 FRDA cohorts.⁵⁵ Peripheral blood mononuclear cells (PBMCs) demonstrated an increase in FXN mRNA and histone acetylation after treatment with RGFP109.⁵⁵ A small trial assessed nicotinamide (another HDAC inhibitor).⁵⁶ Frataxin transcript increased in a dose-dependent manner, and there was a significant decrease in heterochromatic modifications and increase in frataxin expression, but no changes in clinical rating scale scores.⁵⁶

TAT-Frataxin

Human immunodeficiency virus (HIV)–trans-activator of transcription (TAT) is a small HIV-derived protein that is used as a carrier to bring frataxin to the mitochondrial matrix.⁵⁷ TAT-frataxin functions as a protein replacement therapy for people with FRDA with inadequate frataxin levels. Preclinical data evaluating TAT-frataxin in FRDA animal models are promising. In 1 study using FRDA mouse models studying the effect of TAT-frataxin on frataxin-depleted DRG neurons, treated DRG had significantly improved survival and the mice had increased lifespans.⁵⁸ In an FXN-KO mouse heart, TAT-FXN increased aconitase and improved heart function.⁵⁷ A phase 1 placebo-controlled dose-ascending clinical trial evaluated safety and efficacy of CTI-1601, a recombinant fusion protein, in FRDA.⁵⁹ Twenty-seven participants were randomized to receive 25, 50, or 100 mg of CTI-1601 or matching placebo.⁵⁹ Analysis revealed a dose-dependent increase in frataxin levels in all evaluated tissues, including platelets, skin, and buccal cells.⁶⁰

Interferon-Gamma

Interferon-gamma (IFNγ) is an FDA-approved treatment for chronic granulomatous disease and malignant osteopetrosis that has shown efficacy in upregulating frataxin in FRDA cell and mouse models.⁶¹ One pilot trial tested IFNγ 1b in 12 children with FRDA.⁶² Significant mean improvements in FARS scores (P=.008) were noted as were changes in frataxin expression in platelets, erythrocytes, and PBMCs after 12 weeks.⁶² Following this pilot study, a 6-month study of 92 individuals with FRDA evaluated IFNγ 1b starting at 10 mcg/m² titrated to 100 mcg/m².⁶³ No improvements were noted in mFARS scores, 25-foot timed walk test, 9-hole peg test, or frataxin levels, but open-label data revealed that treated participants had a more stable clinical course than untreated individuals.⁶³

Erythropoietin

Erythropoietin is a renal cytokine that promotes erythrocyte production. Its potential to treat FRDA is in increase of frataxin expression, mitochondrial biogenesis, and iron mobilization.⁶⁴ Preclinical data in FRDA lymphocytes, neurons, and cardiac cells showed that cytokine-recombinant human erythropoietin increased frataxin expression.⁶³ One study found no increase in frataxin levels or neurologic scores in participants receiving treatment versus placebo.⁶⁵ Many of these studies were small and underpowered.

Resveratrol

Resveratrol is an antioxidant, HDAC inhibitor,⁶⁶ and polyphenol that increased frataxin in preclinical FRDA models. A study assessing resveratrol use did not find a frataxin change but noted a change in FARS scores (P=.036),⁶⁷ decrease in oxidative stress marker plasma F2-isoprostane, and hearing and speech improvements. One trial of micronized resveratrol is evaluating 25 people with FRDA randomized to drug or placebo.⁶⁸

Etravirine

Etravirine is an antiviral drug used to treat HIV infection that is being studied for FRDA. Preclinical studies of FRDA cells found an increase of frataxin following etravirine administration, presumably by increasing translation and decreasing degradation.⁶⁹

Unknown Mechanism of Action

Steroids

Frataxin may play a role in steroidogenesis by means of decreased ferredoxin activity.⁷⁰ One pilot trial of 11 people with FRDA evaluated a methylprednisolone dose of 48 mg, tapering by 8 mg every day.⁷¹ Methylprednisolone was well-tolerated, but 1-meter walking improvement was only observed in children (P<.05).⁷¹

Gene Therapy

One study showed that adeno-associated virus (AAV) designed to carry human FXN and deliver the gene to the target cells in 2 FRDA mouse models prevented, and reversed, cardiomyopathy.⁷² An ongoing phase 1 trial is evaluating AAVrh10 to treat FRDA cardiomyopathy.⁷³ Research is needed to determine whether these vectors can be used to target DRG and peripheral nerves. Preliminary findings from a gene therapy trial using DT-216 to target GAA repeat expansions and restore frataxin expression showed that DT-216 was safe and tolerable and increased FXN mRNA at 24 hours postdose.⁷⁴

Conclusion

Antioxidants, NRF2 activators, iron chelators, channel modulators, HDAC inhibitors, and gene therapy agents are being studied for FRDA treatment. Because FRDA is marked by neurologic and cardiac dysfunction, potential therapies should target both systems. Challenges in FRDA trials include the rarity of the disease, limiting the number of potential participants; requiring trialists to have FRDA expertise; and identifying biomarkers and end points for clinical trials.