Idebenone in Friedreich's ataxia.
Tonon C, Lodi R.Università di Bologna, Dipartimento di Medicina Interna, dell'Invecchiamento e Malattie Nefrologiche, Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy.
Abstract
BACKGROUND: Friedreich's ataxia is an autosomal recessive neurodegenerative disease where impaired mitochondrial function and excessive production of free radicals play a central pathogenetic role. Idebenone, a synthetic analogue of coenzyme Q, is a powerful antioxidant that was first administrated to Friedreich's ataxia patients less than 10 years ago. OBJECTIVE: The aim of this study was to evaluate the efficacy of idebenone administration and define the optimal dosage. METHODS: A critical evaluation of all open and double-blinded idebenone trials in Friedreich's ataxia patients was undertaken. RESULTS/CONCLUSIONS: Idebenone is well tolerated in paediatric and adult patients. Most trials demonstrated a positive effect on cardiac hypertrophy. The neurological function is in general not modified in adult patients, but a dose-dependent effect was demonstrated in young Friedreich's ataxia patients. Further double-blinded high-dose trials should evaluate idebenone in Friedreich's ataxia early in the disease course.
PMID: 18710357 [PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Substances
Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial.
Di Prospero NA, Baker A, Jeffries N, Fischbeck KH.Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-3705, USA. diprospern@ninds.nih.gov
Abstract
BACKGROUND: Friedreich's ataxia (FA) is a progressive, multisystem, degenerative disorder caused by a reduction in frataxin. Loss of frataxin results in mitochondrial dysfunction and oxidative damage in patients and model systems. Previous studies have indicated that the antioxidant idebenone (5 mg/kg daily) reduces cardiac hypertrophy, but definite improvement in neurological function has not been shown. METHODS: 48 genetically confirmed FA patients, aged 9-17 years, were enrolled in a 6-month, randomised, double-blind, placebo-controlled study. The patients received placebo or one of three doses of idebenone (approximately 5 mg/kg, 15 mg/kg, and 45 mg/kg), stratified by body weight. The primary endpoint was change from baseline in urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage. Secondary endpoints included changes in the international cooperative ataxia rating scale (ICARS), the FA rating scale (FARS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov, number NCT00229632. FINDINGS: Idebenone was generally well tolerated with similar numbers of adverse events in each group. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved after discontinuation of treatment. 8OH2'dG concentrations were not increased, and did not significantly change with idebenone treatment. Whereas an overall analysis did not show a significant difference in ICARS, FARS, or ADL total scores, there were indications of a dose-dependent response in the ICARS score. A second, pre-specified analysis, excluding patients who required wheelchair assistance, showed a significant improvement in ICARS (Bonferroni p=0.03) and suggested a dose-related response in ICARS, FARS, and ADL scores. INTERPRETATION: Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function.
PMID: 17826341 [PubMed - indexed for MEDLINE]
Friedreich's ataxia: idebenone treatment in early stage patients.
Artuch R, Aracil A, Mas A, Colomé C, Rissech M, Monrós E, Pineda M.Biochemistry Department, Hospital Sant Joan de Dèu, University of Barcelona, Spain. rartuch@hsjdbcn.org
Abstract
BACKGROUND: Antioxidant therapy has been applied to Friedreich's ataxia patients. We assessed the effect of idebenone treatment in patients with Friedreich's ataxia. METHODS: Design: open-label trial. Nine Friedreich's ataxia patients (age range 11 - 19 years) were treated with idebenone (5 mg/kg/day). Patients were evaluated before the start of the therapy and throughout one year of treatment by International Cooperative Ataxia Rating Scales (ICARS) scores, neurophysiological investigations and echocardiographic measurements. Serum idebenone concentrations were measured by HPLC with electrochemical detection. The number of GAA repeats at the frataxin gene was analyzed by PCR. RESULTS: Serum idebenone concentrations ranged between 0.04 - 0.37 micro mol/L. Significantly positive correlation was observed between idebenone values and the percentage of difference between the ICARS scores before and 12 months after the start of the therapy (r = 0.883; p = 0.002). Significant reduction was observed comparing the ICARS scores in baseline conditions and after 3 months of treatment (p = 0.017). No differences were observed in echocardiographic measurements after the start of the therapy. CONCLUSIONS: Cerebellar improvement was notable in mild patients after the first 3 months of therapy. Idebenone treatment at early stages of the disease seems to reduce the progression of cerebellar manifestations. Further blind trials with a greater number of patients and higher doses are needed to fully assess the therapeutic potential of idebenone in Friedreich's ataxia.
PMID: 12368988 [PubMed - indexed for MEDLINE]
Antioxidants and other pharmacological treatments for Friedreich ataxia.
Kearney M, Orrell RW, Fahey M, Pandolfo M.General Practice, Irish College of General Practitioners, Dunlavin, County Wicklow, Ireland.
Abstract
BACKGROUND: Friedreich ataxia is a rare inherited, autosomal recessive, neurological disorder characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, pes cavus and heart abnormalities which may cause premature death in 60 to 80% of people. There is no easily defined clinical or biochemical marker and no known treatment. OBJECTIVES: To examine the efficacy of antioxidants and other pharmacological treatments for Friedreich ataxia. SEARCH STRATEGY: We searched The Cochrane Neuromuscular Disease Group Trials Specialized Register (17 December 2008), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2008) MEDLINE (January 1950 to December 2008), EMBASE (January 1980 to December 2008) and other sources. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-randomised trials which examined drug treatment in people with genetically confirmed Friedreich ataxia were examined. The primary outcome was change in ataxia rating scale as measured by the International Co-operative Ataxia Rating Scale (ICARS) after 12 months. Secondary outcomes included change in left ventricular heart mass as measured by magnetic resonance imaging or echocardiography. DATA COLLECTION AND ANALYSIS: Three authors selected the trials and two authors extracted data. We obtained missing data from the one RCT that met our inclusion criteria. MAIN RESULTS: Over 10 studies used idebenone in the treatment of Friedreich ataxia but only one small RCT, with 29 participants using the synthetic antioxidant, idebenone 5 mg/kg, fulfilled the selection criteria for this review. Another RCT was of insufficient duration and the other studies were open clinical trials. In the included study, the primary outcome, change in ICARS scale, did not reveal any significant differences with idebenone treatment. The secondary outcome, change in left ventricular heart mass index as measured by magnetic resonance spectroscopy was not carried out. The second secondary outcome, change in left ventricular mass, as measured by echocardiography, did improve significantly (P = 0.007). There were no adverse events. A larger RCT using idebenone is in progress, of which the primary outcome is change in the ICARS scale. However, the results are not yet available. AUTHORS' CONCLUSIONS: No RCT using idebenone or any other pharmacological treatment has shown significant benefit on neurological symptoms associated with Friedreich ataxia. Idebenone has shown a positive effect on left ventricular heart mass but no research on clinical relevance of this change has been done.
PMID: 19821439 [PubMed - indexed for MEDLINE]Publication Types, MeSH Terms, Substances
Friedreich's Ataxia: disease mechanisms, antioxidant and Coenzyme Q10 therapy.
Cooper JM, Schapira AH.University Department of Clinical Neurosciences, Royal Free & University College Medical School, Rowland Hill Street, London NW3 2PF, UK. cooper@rfc.ucl.ac.uk
Abstract
Mitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis. These advances in our understanding of the disease mechanisms are enabling therapeutic avenues to be explored, in particular the use of established drugs such as antioxidants and enhancers of respiratory chain function. Vitamin E therapy has been shown to be beneficial in patients with ataxia with vitamin E deficiency, and CoQ10 therapy was effective in some patients with ataxia associated with CoQ10 deficiency. A combined therapy involving long term treatment with high doses of vitamin E and coenzyme Q10 has jointly targeted two of the major features of Friedreich's Ataxia; decreased mitochondrial respiratory chain function and increased oxidative stress. This therapy clearly showed a rapid and sustained increase in the energy generated by the FRDA heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation parallel those of the heart but to a lower level. While this therapy appeared to slow the predicted progression of some clinical symptoms a larger placebo controlled study is required to confirm these observations. Other antioxidant strategies have involved the use of Idebenone, selenium and N acetyl cysteine but only the use of Idebenone has involved structured trials with relatively large patient numbers. Idebenone clearly had an impact upon the cardiac hypertrophy in the majority of patients, although there have not been any other significant benefits reported to date.
PMID: 14695932 [PubMed - indexed for MEDLINE]Molecular insights into Friedreich's ataxia and antioxidant-based therapies.
Rötig A, Sidi D, Munnich A, Rustin P.INSERM U393 and Service de Cardiologie pédiatrique, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. roetig@necker.fr
Abstract
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease causing limb and gait ataxia and cardiomyopathy. The disease gene encodes a mitochondrial protein of unknown function, frataxin. The loss of functional frataxin is caused by a large GAA trinucleotide expansion in the first intron of the gene, thus impairing gene transcription. The lack of frataxin appears to result primarily in disabled recruitment of early antioxidant defenses, resulting in oxidative insult to the highly sensitive iron-sulfur proteins aconitase and three mitochondrial respiratory chain complexes (I-III). Accordingly, antioxidant-based therapy appears promising in counteracting the course of the disease.
PMID: 12067631 [PubMed - indexed for MEDLINE]Idebenone: an emerging therapy for Friedreich ataxia.
Meier T, Buyse G.Santhera Pharmaceuticals, Hammerstrasse 47, 4410, Liestal, Switzerland. thomas.meier@santhera.com
Abstract
This paper reviews the history and pre-clinical development of idebenone and summarises the results of clinical studies, published from 1999 to 2008, on the use of idebenone in the treatment of patients with Friedreich ataxia (FRDA). As a benzoquinone that can undergo reversible redox reactions, idebenone influences the electron balance in mitochondria. In vitro studies have shown that it acts both as an anti-oxidant, preventing damage to the mitochondrial membrane, and, more importantly, as an electron carrier, supporting mitochondrial function and adenosine triphosphate (ATP) production. In clinical studies, idebenone has been well tolerated by patients with various pathological conditions. The most common adverse events have been gastrointestinal effects of mild to moderate severity. No neurotoxic or adverse cardiac reactions have been reported in pre-clinical or clinical studies. The good safety profile of idebenone is supported by large clinical trials in Alzheimer's disease and by post-marketing surveillance. Phase 1 studies demonstrated the safety and tolerability of idebenone at relatively high doses (up to 60 mg/kg/day). Results from 11 clinical studies (randomised, controlled, and open-label trials), involving a total of about 200 patients, provide evidence of improvement in both cardiac hypertrophy and neurological symptoms among patients with FRDA treated with idebenone.
Mitochondrial dysfunction in Friedreich's ataxia: from pathogenesis to treatment perspectives.
Lodi R, Rajagopalan B, Bradley JL, Taylor DJ, Crilley JG, Hart PE, Blamire AM, Manners D, Styles P, Schapira AH, Cooper JM.
Dipartimento di Medicina Clinica e Biotecnologia Applicata, Universitá di Bologna, Policlinico S. Orsola, Italy. lodi@med.unibo.it
Abstract
Friedreich's ataxia (FRDA), the most common inherited ataxia, is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein, which is severely reduced in FRDA patients. The demonstration that deficit of frataxin in FRDA is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of cardiac and skeletal muscle tissue energy metabolism, has established FRDA as a "new" nuclear encoded mitochondrial disease. Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q10 plus Vitamin E administration in this condition and provide a strong rationale for designing larger randomized clinical trials.
PMID: 12069111 [PubMed - indexed for MEDLINE]
Clinical experience with high-dose idebenone in Friedreich ataxia.
Schulz JB, Di Prospero NA, Fischbeck K.Department of Neurology, University Medical Centre, RWTH Aachen, Pauwelsstr. 30, 52074, Aachen, Germany.
Abstract
Several reports in the literature describe the effects of low-dose (5 mg/kg/day) idebenone in significantly reducing cardiac hypertrophy in patients with Friedreich ataxia. However, the effects of idebenone on neurological function have not been reliably determined in these studies; when neurological parameters were reported, results were often inconclusive, usually because of subject heterogeneity and lack of adequate statistical power. In two of these studies, some patients showed beneficial effects of idebenone on their cardiomyopathy only when the dose was increased, prompting the systematic investigation of higher doses of idebenone. Following a phase 1 dose escalation study, a phase 2 tolerability and efficacy trial with low, intermediate, and high doses of idebenone was conducted. The results suggested that treatment with intermediate- and high-dose idebenone had beneficial effects on neurological symptoms. On the basis of these results, two phase 3 trials have been initiated, one in the United States with young ambulatory patients and one in Europe without limits on age and disease severity.