Expression and processing of mature human frataxin after gene therapy in mice.

Friedreich's ataxia is a degenerative and progressive multisystem disorder caused by mutations in the highly conserved frataxin (FXN) gene that results in FXN protein deficiency and mitochondrial dysfunction. While gene therapy approaches are promising, consistent induction of therapeutic FXN protein expression that is sub-toxic has proven challenging, and numerous therapeutic approaches are being tested in animal models. FXN (hFXN in humans, mFXN in mice) is proteolytically modified in mitochondria to produce mature FXN. However, unlike endogenous hFXN, endogenous mFXN is further processed into N-terminally truncated, extra-mitochondrial mFXN forms of unknown function. This study assessed mature exogenous hFXN expression levels in the heart and liver of C57Bl/6 mice 7-10 months after intravenous administration of a recombinant adeno-associated virus encoding hFXN (AAVrh.10hFXN) and examined the potential for hFXN truncation in mice. AAVrh.10hFXN induced dose-dependent expression of hFXN in the heart and liver. Interestingly, hFXN was processed into truncated forms, but found at lower levels than mature hFXN. However, the truncations were at different positions than mFXN. AAVrh.10hFXN induced mature hFXN expression in mouse heart and liver at levels that approximated endogenous mFXN levels. These results suggest that AAVrh.10hFXN can likely induce expression of therapeutic levels of mature hFXN in mice.

Posttranslational regulation of mitochondrial frataxin and identification of compounds that increase frataxin levels in Friedreich's ataxia.

Friedreich's ataxia (FRDA) is a degenerative disease caused by a decrease in the mitochondrial protein frataxin (Fxn), which is involved in iron-sulfur cluster (ISC) synthesis. Diminutions in Fxn result in decreased ISC synthesis, increased mitochondrial iron accumulation, and impaired mitochondrial function. Here, we show that conditions that result in increased mitochondrial reactive oxygen species in yeast or mammalian cell culture give rise to increased turnover of Fxn but not of other ISC synthesis proteins. We demonstrate that the mitochondrial Lon protease is involved in Fxn degradation and that iron export through the mitochondrial metal transporter Mmt1 protects yeast Fxn from degradation. We also determined that when FRDA fibroblasts were grown in media containing elevated iron, mitochondrial reactive oxygen species increased and Fxn decreased compared to WT fibroblasts. Furthermore, we screened a library of FDA-approved compounds and identified 38 compounds that increased yeast Fxn levels, including the azole bifonazole, antiparasitic fipronil, antitumor compound dibenzoylmethane, antihypertensive 4-hydroxychalcone, and a nonspecific anion channel inhibitor 4,4-diisothiocyanostilbene-2,2-sulfonic acid. We show that top hits 4-hydroxychalcone and dibenzoylmethane increased mRNA levels of transcription factor nuclear factor erythroid 2-related factor 2 in FRDA patient-derived fibroblasts, as well as downstream antioxidant targets thioredoxin, glutathione reductase, and superoxide dismutase 2. Taken together, these findings reveal that FRDA progression may be in part due to oxidant-mediated decreases in Fxn and that some approved compounds may be effective in increasing mitochondrial Fxn in FRDA, delaying disease progression.

Cur@SF NPs alleviate Friedreich's ataxia in a mouse model through synergistic iron chelation and antioxidation.

Abnormal iron metabolism, mitochondrial dysfunction and the derived oxidative damage are the main pathogeneses of Friedrich's ataxia (FRDA), a single-gene inherited recessive neurodegenerative disease characterized by progressive cerebellar and sensory ataxia. This disease is caused by frataxin (FXN) mutation, which reduces FXN expression and impairs iron sulfur cluster biogenesis. To date, there is no effective therapy to treat this condition. Curcumin is proposed harboring excellent ability to resist oxidative stress through Nrf2 activation and its newly found ability to chelate iron. However, its limitation is its poor water solubility and permeability. Here, we synthesized slow-release nanoparticles (NPs) by loading curcumin (Cur) into silk fibroin (SF) to form NPs with an average size of 150 nm (Cur@SF NPs), which exhibited satisfactory therapeutic effects on the improvement of FRDA manifestation in lymphoblasts (1 µM) derived from FRDA patients and in YG8R mice (150 mg/kg/5 days). Cur@SF NPs not only removed iron from the heart and diminished oxidative stress in general but also potentiate iron-sulfur cluster biogenesis, which compensates FXN deficiency to improve the morphology and function of mitochondria. Cur@SF NPs showed a significant advantage in neuron and myocardial function, thereby improving FRDA mouse behavior scores. These data encourage us to propose that Cur@SF NPs are a promising therapeutic compound in the application of FRDA disease.

Mitochondrial iron and calcium homeostasis in Friedreich ataxia.

Friedreich Ataxia is a neuro-cardiodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. Many evidences indicate that frataxin deficiency causes an unbalance of iron homeostasis. Nevertheless, in the last decade many results also highlighted the importance of calcium unbalance in the deleterious downstream effects caused by frataxin deficiency. In this review, the role of these two metals has been gathered to give a whole view of how iron and calcium dyshomeostasys impacts on cellular functions and, as a result, which strategies can be followed to find an effective therapy for the disease.

A Drosophila model of Friedreich ataxia with CRISPR/Cas9 insertion of GAA repeats in the frataxin gene reveals in vivo protection by N-acetyl cysteine.

Friedreich ataxia (FA) is caused by GAA repeat expansions in the first intron of FXN, the gene encoding frataxin, which results in decreased gene expression. Thanks to the high degree of frataxin conservation, the Drosophila melanogaster fruitfly appears as an adequate animal model to study this disease and to evaluate therapeutic interventions. Here, we generated a Drosophila model of FA with CRISPR/Cas9 insertion of approximately 200 GAA in the intron of the fly frataxin gene fh. These flies exhibit a developmental delay and lethality associated with decreased frataxin expression. We were able to bypass preadult lethality using genetic tools to overexpress frataxin only during the developmental period. These frataxin-deficient adults are short-lived and present strong locomotor defects. RNA-Seq analysis identified deregulation of genes involved in amino-acid metabolism and transcriptomic signatures of oxidative stress. In particular, we observed a progressive increase of Tspo expression, fully rescued by adult frataxin expression. Thus, Tspo expression constitutes a molecular marker of the disease progression in our fly model and might be of interest in other animal models or in patients. Finally, in a candidate drug screening, we observed that N-acetyl cysteine improved the survival, locomotor function, resistance to oxidative stress and aconitase activity of frataxin-deficient flies. Therefore, our model provides the opportunity to elucidate in vivo, the protective mechanisms of this molecule of therapeutic potential. This study also highlights the strength of the CRISPR/Cas9 technology to introduce human mutations in endogenous orthologous genes, leading to Drosophila models of human diseases with improved physiological relevance.

The potential of the novel NAD+ supplementing agent, SNH6, as a therapeutic strategy for the treatment of Friedreich's ataxia.

Friedreich's ataxia (FA) is due to deficiency of the mitochondrial protein, frataxin, which results in multiple pathologies including a deadly, hypertrophic cardiomyopathy. Frataxin loss leads to deleterious accumulations of redox-active, mitochondrial iron, and suppressed mitochondrial bioenergetics. Hence, there is an urgent need to develop innovative pharmaceuticals. Herein, the activity of the novel compound, 6-methoxy-2-salicylaldehyde nicotinoyl hydrazone (SNH6), was assessed in vivo using the well-characterized muscle creatine kinase (MCK) conditional frataxin knockout (KO) mouse model of FA. The design of SNH6 incorporated a dual-mechanism mediating: (1) NAD+-supplementation to restore cardiac bioenergetics; and (2) iron chelation to remove toxic mitochondrial iron. In these studies, MCK wild-type (WT) and KO mice were treated for 4-weeks from the asymptomatic age of 4.5-weeks to 8.5-weeks of age, where the mouse displays an overt cardiomyopathy. SNH6-treatment significantly elevated NAD+ and markedly increased NAD+ consumption in WT and KO hearts. In SNH6-treated KO mice, nuclear Sirt1 activity was also significantly increased together with the NAD+-metabolic product, nicotinamide (NAM). Therefore, NAD+-supplementation by SNH6 aided mitochondrial function and cardiac bioenergetics. SNH6 also chelated iron in cultured cardiac cells and also removed iron-loading in vivo from the MCK KO heart. Despite its dual beneficial properties of supplementing NAD+ and chelating iron, SNH6 did not mitigate cardiomyopathy development in the MCK KO mouse. Collectively, SNH6 is an innovative therapeutic with marked pharmacological efficacy, which successfully enhanced cardiac NAD+ and nuclear Sirt1 activity and reduced cardiac iron-loading in MCK KO mice. No other pharmaceutical yet designed exhibits both these effective pharmacological properties.

Targeting NRF2 for the Treatment of Friedreich's Ataxia: A Comparison among Drugs.

NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich's Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules.

Ferroptosis as a Novel Therapeutic Target for Friedreich's Ataxia.

Friedreich ataxia (FRDA) is a progressive neuro- and cardio-degenerative disorder characterized by ataxia, sensory loss, and hypertrophic cardiomyopathy. In most cases, the disorder is caused by GAA repeat expansions in the first introns of both alleles of the FXN gene, resulting in decreased expression of the encoded protein, frataxin. Frataxin localizes to the mitochondrial matrix and is required for iron-sulfur-cluster biosynthesis. Decreased expression of frataxin is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. We evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. We found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (knockin/knockout) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors ethyl 3-(benzylamino)-4-(cyclohexylamino)benzoate (SRS11-92) and ethyl 3-amino-4-(cyclohexylamino)benzoate, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis [L-buthionine (S,R)-sulfoximine (BSO)], whereas caspase-3 inhibitors failed to show significant biologic activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.

Intrathecal Baclofen Therapy for Painful Muscle Spasms in a Patient with Friedreich's Ataxia.

Friedreich's ataxia (FA) is the most frequent hereditary ataxia syndrome, while painful muscle spasms and spasticity have been reported in 11-15% of FA patients. This report describes the successful management of painful spasms in a 65-year-old woman with FA via intrathecal baclofen (ITB) therapy following unsuccessful medical treatments. To our knowledge, this is the third reported case in the literature. Unfortunately, the pathophysiological characteristics of muscle spasms in FA are not well explored and understood while the therapeutic mechanisms of the different treatments are rather vague. Taking into consideration the suggested spinal atrophy in FA, the clinical resemblance of FA and chronic spinal injury muscle spasms, together with the rapid ITB therapy effectiveness in alleviating FA muscle spasms, we attempted to suggest a putative pathophysiological mechanism acting at the spinal level and possibly explained by the presence of independent spinal locomotor systems producing muscle spasms. Specifically, overexcitement of these centers, due to loss of normal regulation from upper CNS levels, may result in the uncontrolled firing of secondary motor neurons and may be the key to producing muscle spasms. However, further research under experimental and clinical settings seems to be necessary.

Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia.

Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, which is characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a Drosophila melanogaster cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions. Here, we used this model to screen in vivo the Prestwick Chemical Library, comprising 1280 compounds. Eleven drugs significantly reduced the cardiac dilatation, some of which may possibly lead to therapeutic applications in the future. The one with the strongest protective effects was paclitaxel, a microtubule-stabilizing drug. In parallel, we characterized the histological defects induced by frataxin deficiency in cardiomyocytes and observed strong sarcomere alterations with loss of striation of actin fibers, along with full disruption of the microtubule network. Paclitaxel and MB both improved these structural defects. Therefore, we propose that frataxin inactivation induces cardiac dysfunction through impaired sarcomere assembly or renewal due to microtubule destabilization, without excluding additional mechanisms. This study is the first drug screening of this extent performed in vivo on a Drosophila model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult Drosophila flies is usable for medium-scale in vivo pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.

Pharmacological therapeutics in Friedreich ataxia: the present state.

INTRODUCTION: Friedreich ataxia (FRDA) is a progressive, inherited, neurodegenerative disease for which there is currently no cure or approved treatment. FRDA is caused by deficits in the production and expression of frataxin, a protein found in the mitochondria that is most likely responsible for regulating iron-sulfur cluster enzymes within the cell. A decrease in frataxin causes dysfunction of adenosine triphosphate synthesis, accumulation of mitochondrial iron, and other events leading to downstream cellular dysfunction. Areas covered: Therapeutic development for FRDA currently focuses on improving mitochondrial function and finding ways to increase frataxin expression. Additionally, the authors will review potential approaches aimed at iron modulation and genetic modulation. Finally, gene therapy is progressing rapidly and is being explored as a treatment for FRDA. Expert commentary: The collection of multiple therapeutic approaches provides many possible ways to treat FRDA. Although the mitochondrial approaches are not thought to be curative, as the primary frataxin deficit will remain, they may still produce improvements in quality of life and slowing of progression. Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective.

Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich's Ataxia Transgenic Mice.

Friedreich's ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 µg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA.

Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia.

The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron-sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.

Long-term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia.

BACKGROUND: Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long-term effect of the drug remains unknown. METHODS: We designed a double-blind, placebo-controlled, multicenter trial to test the efficacy of epoetin alfa on 56 patients with Friedreich ataxia. The primary endpoint of the study was the effect of epoetin alfa on peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test. Secondary endpoints were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life. Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1200 IU/Kg of body weight every 12 weeks for 48 weeks. RESULTS: A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group[KG1]. VO2 max was not modified after treatment (0.01 [-0.04 to 0.05]; P = .749), as well as most of the secondary endpoint measures, including frataxin. The 9-hole peg test showed a significant amelioration in the treatment group (-17.24 sec. [-31.5 to -3.0]; P = .018). The treatment was safe and well tolerated. CONCLUSIONS: Although results are not in favor of an effect of epoetin alfa in Friedreich ataxia, this is the largest trial testing its effect. It is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance. This study provides class I evidence that erythropoietin does not ameliorate VO2 max in patients with Friedreich ataxia. © 2016 International Parkinson and Movement Disorder Society.

IFN-γ for Friedreich ataxia: present evidence.

IFN-γ-1b is currently US FDA approved as an orphan drug for the treatment of chronic granulomatous disease and severe malignant osteopetrosis. It is administered via subcutaneous injection and is a potential therapy for Friedreich ataxia (FRDA), a rare degenerative neurological condition. Ongoing Phase II and III trials in both adults and children with FRDA were preceded by a small Phase I, open-label trial in children that showed that IFN-γ-1b was reasonably well-tolerated and improved overall neurological function as measured by the Friedreich Ataxia Rating Scale after 12 weeks of treatment, though the primary outcome measure of frataxin level showed no improvement. Although there is an established dose of IFN-γ-1b prescribed for the current indications, the efficacy and tolerability of these dose levels in the FRDA population remains the subject of ongoing investigation.

Src inhibitors modulate frataxin protein levels.

Defective expression of frataxin is responsible for the inherited, progressive degenerative disease Friedreich's Ataxia (FRDA). There is currently no effective approved treatment for FRDA and patients die prematurely. Defective frataxin expression causes critical metabolic changes, including redox imbalance and ATP deficiency. As these alterations are known to regulate the tyrosine kinase Src, we investigated whether Src might in turn affect frataxin expression. We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation. Accordingly, Src inhibitors induce accumulation of frataxin but are ineffective on a non-phosphorylatable frataxin-Y118F mutant. Importantly, all the Src inhibitors tested, some of them already in the clinic, increase frataxin expression and rescue the aconitase defect in frataxin-deficient cells derived from FRDA patients. Thus, Src inhibitors emerge as a new class of drugs able to promote frataxin accumulation, suggesting their possible use as therapeutics in FRDA.

An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels.

Friedreich ataxia (FRDA) is due to a triplet repeat expansion in FXN, resulting in deficiency of the mitochondrial protein frataxin. Resveratrol is a naturally occurring polyphenol, identified to increase frataxin expression in cellular and mouse models of FRDA and has anti-oxidant properties. This open-label, non-randomized trial evaluated the effect of two different doses of resveratrol on peripheral blood mononuclear cell (PBMC) frataxin levels over a 12-week period in individuals with FRDA. Secondary outcome measures included PMBC FXN mRNA, oxidative stress markers, and clinical measures of disease severity. Safety and tolerability were studied. Twenty-four participants completed the study; 12 received low-dose resveratrol (1 g daily) and 12 high-dose resveratrol (5 g daily). PBMC frataxin levels did not change in either dosage group [low-dose group change: 0.08 pg/µg protein (95% CI -0.05, 0.21, p = 0.21); high-dose group change: 0.03 pg/µg protein (95% CI -0.10, 0.15, p = 0.62)]. Improvement in neurologic function was evident in the high-dose group [change in Friedreich Ataxia Rating Scale -3.4 points, 95% CI (-6.6, -0.3), p = 0.036], but not the low-dose group. Significant improvements in audiologic and speech measures, and in the oxidative stress marker plasma F2-isoprostane were demonstrated in the high-dose group only. There were no improvements in cardiac measures or patient-reported outcome measures. No serious adverse events were recorded. Gastrointestinal side-effects were a common, dose-related adverse event. This open-label study shows no effect of resveratrol on frataxin levels in FRDA, but suggests that independent positive clinical and biologic effects of high-dose resveratrol may exist. Further assessment of efficacy is warranted in a randomized placebo-controlled trial.

Neurodegenerative diseases and therapeutic strategies using iron chelators.

This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed.

[Therapeutic developments in chronic ataxias]. / Avances en el tratamiento de las ataxias crónicas.

Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.

Co-enzyme Q10 and idebenone use in Friedreich's ataxia.

Friedreich's ataxia is a debilitating progressive neurodegenerative disease associated with cardiomyopathy and other features. The underlying cause is a deficiency of the mitochondrial protein frataxin which causes mitochondrial iron deposition, increased oxidative stress and impaired adenosine triphosphate production. Over the last 15 years, multiple clinical trials have assessed the efficacy of antioxidant agents in this disease. This article reviews trials of the two most important agents, namely co-enzyme Q10 and idebenone.