Iron redistribution as a therapeutic strategy for treating diseases of localized iron accumulation.

Defective iron utilization leading to either systemic or regional misdistribution of the metal has been identified as a critical feature of several different disorders. Iron concentrations can rise to toxic levels in mitochondria of excitable cells, often leaving the cytosol iron-depleted, in some forms of neurodegeneration with brain accumulation (NBIA) or following mutations in genes associated with mitochondrial functions, such as ABCB7 in X-linked sideroblastic anemia with ataxia (XLSA/A) or the genes encoding frataxin in Friedreich's ataxia (FRDA). In anemia of chronic disease (ACD), iron is withheld by macrophages, while iron levels in extracellular fluids (e.g., plasma) are drastically reduced. One possible therapeutic approach to these diseases is iron chelation, which is known to effectively reduce multiorgan iron deposition in iron-overloaded patients. However, iron chelation is probably inappropriate for disorders associated with misdistribution of iron within selected tissues or cells. One chelator in clinical use for treating iron overload, deferiprone (DFP), has been identified as a reversed siderophore, that is, an agent with iron-relocating abilities in settings of regional iron accumulation. DFP was applied to a cell model of FRDA, a paradigm of a disorder etiologically associated with cellular iron misdistribution. The treatment reduced the mitochondrial levels of labile iron pools (LIP) that were increased by frataxin deficiency. DFP also conferred upon cells protection against oxidative damage and concomitantly mediated the restoration of various metabolic parameters, including aconitase activity. Administration of DFP to FRDA patients for 6 months resulted in selective and significant reduction in foci of brain iron accumulation (assessed by T2* MRI) and initial functional improvements, with only minor changes in net body iron stores. The prospects of drug-mediated iron relocation versus those of chelation are discussed in relation to other disorders involving iron misdistribution, such as ACD and XLSA/A.