Selective iron chelation in Friedreich ataxia: biologic and clinical implications

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Selective iron chelation in Friedreich ataxia: biologic and clinical implications
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  doi:10.1182/blood-2006-12-065433Prepublished online March 22, 2007; Brunelle, Daniel Sidi, Jean-Christophe Thalabard, Arnold Munnich and Zvi Ioav CabantchikNathalie Boddaert, Kim Hanh Le Quan Sang, Agnes Rotig, Anne Leroy-Willig, Serge Gallet, Francis  implicationsSelective iron chelation in Friedreich ataxia. Biological and clinical  (1174 articles)Red Cells  (3611 articles)Clinical Trials and Observations  Articles on similar topics can be found in the following Blood collections  http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests Information about reproducing this article in parts or in its entirety may be found online at:  http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at:  http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: digital object identifier (DOIs) and date of initial publication. theindexed by PubMed from initial publication. Citations to Advance online articles must include final publication). Advance online articles are citable and establish publication priority; they areappeared in the paper journal (edited, typeset versions may be posted when available prior to Advance online articles have been peer reviewed and accepted for publication but have not yet  Copyright 2011 by The American Society of Hematology; all rights reserved.20036.the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by  For personal use only.by guest on November 3, 2012. bloodjournal.hematologylibrary.orgFrom   SELECTIVE IRON CHELATION IN FRIEDREICH ATAXIA. BIOLOGICAL AND CLINICAL IMPLICATIONS Nathalie Boddaert 1 , Kim Hanh Le Quan Sang 2 , Agnès Rötig 2 , Anne Leroy-Willig 3 , Serge Gallet 4 , Francis Brunelle 1 , Daniel Sidi 5 , Jean-Christophe Thalabard 2 , Arnold Munnich 2  and Z. Ioav Cabantchik 6 1 Pediatric Radiology Unit, ERM0205, 5 Pediatric Cardiology Unit, 2 Medical Genetic Clinic and Research Unit INSERM 781. Hôpital Necker-Enfants Malades and Université Paris V René Descartes, 75743 Paris Cedex 15, France. 3 U2R2M, CNRS UMR 8081, Université Paris Sud, 91405 Orsay, France; 4 Pediatric Unit, Hôpital de Montluçon, 03113 Montluçon Cedex, France, 6 Institute of Life Sciences and Charles E. Smith Laboratory of Psychobiology, Hebrew University , Jerusalem 91904 Israel running head: Iron chelation in Friedreich ataxia 4 To whom correspondence should be addressed at the Alexander Silberman. Institute of Life Sciences. Hebrew University, Safra Campus-Givat Ram, Jerusalem 91904, Israel. voice: +972-2-6585420; fax: 6586974 ; email: ioav@cc.huji.ac.il. Blood First Edition Paper, prepublished online March 22, 2007; DOI 10.1182/blood-2006-12-065433   Copyright © 2007 American Society of Hematology  For personal use only.by guest on November 3, 2012. bloodjournal.hematologylibrary.orgFrom    2 Summary   Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich-ataxia, decreased iron-sulphur-cluster and haem formation leads to mitochondrial iron accumulation and ensuing oxidative damage that affect primarily sensory neurons, myocardium and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich-ataxia patients with a membrane-permeant chelator capable of shuttling chelated-iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain MRI of Friedreich-ataxia patients compared to age-matched controls revealed smaller and irregularly shaped dentate-nuclei with significantly (p<0.027) higher H-relaxation rates R2*, indicating regional iron accumulation. A six-month treatment with 20-30mg/kg/d deferiprone applied on nine adolescent patients with no overt cardiomyopathy reduced R2* from 18.3±1.6 to 15.7±0.7msec -1 (p<0.002) specifically in dentate nuclei and proportionally to the initial R2* (r=0.90). Chelator-treatment caused no apparent haematological or neurological side-effects, while reducing neuropathy and ataxic-gait in the youngest patients. To our knowledge, this is the first clinical demonstration of chelation removing labile iron accumulated in a specific brain area implicated in a neurodegenerative disease. The use of moderate chelation for relocating iron from areas of deposition to areas of deprivation has clinical implications for various neurodegenerative and haematological disorders. For personal use only.by guest on November 3, 2012. bloodjournal.hematologylibrary.orgFrom    3 Introduction Tissue 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 srcinating from enteric hyperabsorption of the metal and/or enhanced red cell destruction. The labile forms of plasma iron (LPI) that appear as transferrin becomes saturated, can 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 pathophysiological role of mitochondrial iron accumulation in oxidative damage found in FA (5,9) and other neurological disorders (10-13) has not been resolved. In analogy to transfusional iron overload, histopathological and magnetic resonance imaging (MRI) studies of FA patients have shown that iron accumulates not only in heart but also in the spinocerebellar tracts (dentate nuclei) and spinal cord (10). Those and other pieces of evidence implicated labile iron in the oxidative damage and called for the use of antioxidants and/or chelators of iron as possible treatments of FA and other neurological disorders (13-18). Initial studies with the antioxidant idebenone in FA indicated some cardioprotective effect, but no improvement in the ataxia (17). On the other hand iron chelation therapy has not been used in FA for two main reasons: a. lack of validated clinical methods for assessing the levels of For personal use only.by guest on November 3, 2012. bloodjournal.hematologylibrary.orgFrom    4 accumulated iron in the brain and their accessibility to chelators and b. the risk of a chelating drug being neurotoxic and/or inducing global iron depletion in haematologically normal or mildly hypoferremic patients (19,20). However, the recent adaptation of MRI for assessing iron accumulation in liver (21) and heart of siderotic patients (22,23) and in brain (10,15,24) has offered a new possibility for in situ   assessment of chelation treatment in FA and other forms of neurodegeneration (11,12) with brain iron accumulation (NBIA) (13). In the search for candidate chelators with clinical record, we focused on membrane permeant agents that demonstrably reduced the production of reactive oxygen species (ROS) in living cells by reducing the levels of intracellular labile iron (25). In specifically selecting the orally active Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one, DFP) in preference to other agents, we considered five essential properties for treating a condition of local rather than global iron accumulation (26): a. permeation, which endows the drug with the ability to cross membranes, gain access to cell organelles and reduce iron-dependent free radical formation (2); b. extra-hepatic iron chelation ability, as applied to cardiac siderosis ( 22,27); c. ability to act selectively on the most accessible iron pools defined as labile iron pools (28, 29), as well as on subcellular compartments (2), without depleting transferrin-bound iron from plasma (30); d. ability to transfer iron chelated from the labile pools of cells to biological acceptors such as circulating transferrin (30) and e. ability to cross the blood brain barrier (31). An efficacy-toxicity phase I-II open trial with DFP was performed on adolescent FA patients who have been on idebenone for several years, had normal echocardiogram but showed no improvement in brain MRI profiles or neurological indices. A treatment based on moderate chelation regimens based on oral DFP was applied with the view of reducing iron accumulated in specific brains areas, such as the dentate nuclei, and eventually ameliorating the neurological condition without adversely affecting haematological parameters. For personal use only.by guest on November 3, 2012. bloodjournal.hematologylibrary.orgFrom 
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