Antioxidant Treatment of Patients With Friedreich Ataxia

Hart, Paul E.; Lodi, Raffaele; Rajagopalan, B.; Bradley, J. L.; Crilley, Jenifer; Turner, Christopher D.; Blamire, Andrew M.; Manners, David Neil; Styles, Peter; Schapira, Anthony H.V.; Cooper, Jonathan M.

doi:10.1001/archneur.62.4.621

Cited by 205 publications

(126 citation statements)

References 16 publications

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“…19 The FA patients engaged in the phase 1-2 open-label study by random selection were in the 14-to 23-year-old age range, all treated for several years with the free-radical scavenger and antioxidant idebenone. 17,46,47 These patients showed essentially no functional cardiac complication or abnormal echocardiograms and yet there were no indications for R2* changes in any area of the brain or neurologic effects attributable to antioxidant treatment. At the onset of the study, the dentate nuclei of the 9 randomly selected adolescent FA patients showed MRI-detectable alterations in shape and R2* values that were marginally but significantly different from healthy individuals (Figure 1).…”

Section: Discussionmentioning

confidence: 85%

Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Boddaert

Sang

Rötig

et al. 2007

Blood

378

317

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Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membranepermeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with agematched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s ؊1 (؎ 1.6 s ؊1 ) to 15.7 s ؊1 (؎ 0.7 s ؊1 ; P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r ‫؍‬ 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neu- IntroductionTissue iron overload and ensuing organ damage have generally been identified with transfusional hemosiderosis and genetic hemochromatosis. 1 Liver, heart, and endocrine glands are among the most affected organs in these forms of systemic iron overload. 1 The source of tissue iron overload has been traced to plasma iron originating from enteric hyperabsorption of the metal and/or enhanced red cell destruction. The labile forms of plasma iron (LPI) that appear as transferrin become saturated, permeate into particular cell types by unregulated mechanisms, and cause labile iron pools to raise and challenge cellular antioxidant capacities. 2 However, in chronic inflammation 3 and in various genetic disorders, 4 iron accumulates in particular cell types attaining toxic levels, even in the absence of circulating LPI and often even in iron-deficient plasma. In Friedreich ataxia (FA), an expansion of a GAA repeat in the first intron of the nuclear encoded frataxin gene 5,6 results in underexpression of a mitochondrial protein involved in the assembly of iron-sulphur cluster proteins (ISPs) and/or in protecting mitochondria from iron-mediated oxidative damage. 7 The defective ISP formation that causes a combined aconitase and respiratory chain deficiency (complex I-III) leads in turn to mitochondrial accumulation of labile iron 8,9 and ensuing oxidative damage in brain, heart, and endocrine glands. However, the pathophysiologic role of mitochondrial iron accumulation in oxidative damage found in FA 5,9 and other neurologic disorders [10][11][12][13] has not been resolved.In analogy to transfusional iron overload, histopathologic and magnetic resonance imaging (MRI) studies of FA patients have shown that iron accumulates not only in the heart but also in the spinocerebellar tracts (dentate nuclei) and spinal cord. 10 Those and othe...

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Section: Discussionmentioning

confidence: 85%

Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Boddaert

Sang

Rötig

et al. 2007

Blood

378

317

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“…Human frataxin is likely involved in similar processes since it is a mitochondrial protein, and FRDA patients have abnormal myocardial iron deposits (Harding, 1993). Based on these findings, antioxidant and iron-chelation based strategies appear promising in counteracting the course of the disease (Boddaert et al, 2007;Hart et al, 2005;Richardson, 2003;Rotig et al, 2002;Seznec et al, 2004). However, these strategies only treat the symptoms of the disease and not its cause; thus, pursuit of other approaches that address the cause of the disease are worthwhile.…”

mentioning

confidence: 99%

Small molecules affecting transcription in Friedreich ataxia

Gottesfeld

2007

Pharmacology & Therapeutics

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This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin, and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While anti-oxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA·TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts as well as the molecular basis for gene silencing in FRDA.

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“…125 Although no chelation trials have been performed in FA, there is evidence that the antioxidants coenzyme q10 and vitamin E may improve cardiac and skeletal muscle function. 126 Recently a novel iron chelator, 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH), has been suggested as a potential therapeutic agent for FA. The PCIH is known to enter mitochondria and bind mitochondrial iron.…”

Section: Other Chronic Brain Disordersmentioning

confidence: 99%

“…Such therapies, including coenzyme q10 and vitamin E, may improve cardiac and skeletal muscle function in FA. 126 An antioxidant similar to coenzyme q10 has also been successful in FA. 163 In AD, vitamin E (alpha tocopherol) administered to mice overexpressing amyloid precursor protein had delayed plaque formation and cognitive impairment.…”

Section: Iron-related Neurotherapeuticsmentioning

confidence: 99%

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

et al. 2007

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Summary:Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathological processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article, we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.

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Antioxidant Treatment of Patients With Friedreich Ataxia

Cited by 205 publications

References 16 publications

Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Small molecules affecting transcription in Friedreich ataxia

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

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