Iron Chelation For Diseases Of Regional Siderosis

The traditional role of iron chelation therapy has been the reduction of body iron burden via chelation of excess metal from organs and fluids and its excretion via biliary-fecal and/or urinary routes. While that approach is applicable to systemic iron overload, as seen in various forms of hemosiderosis, it might not be suited for treating disorders of iron maldistribution that are characterized by discrete islands of siderosis that appear in a context background of normal or subnormal iron levels (as in sideroblastic anemias, cardiosiderosis in Friedreich ataxia-FRDA and neurosiderosis in Parkinson’s disease-PD).

With the aim of clearing siderotic regions from labile (toxic) metal without interfering with essential local functions or with hematological iron-associated indices, we assessed here a conservative modality of iron chelation based on redeploying tissue chelated metal to physiological transferrin ( Sohn et al Blood 111:1690-9). As test redeployment agent we used deferiprone (DFP), a chelator with clinical proven record for correcting cardiac siderosis in systemic iron overload and in FRDA regional siderosis and for neuroprotection in a translational model of regional (brain) siderosis (that simulate key features of PD)( Moreau et al Am. J. Hematol. 2013;88:E5-E243). As part of a placebo-controlled randomized clinical trial of DFP in early stage PD patients (n=40) already stabilized with dopamine/dopaminergic regimens, we assessed whether a up to 18 month treatment (DFP 30 mg/kg/d in 2 daily syrup servings of Ferriprox) that significantly decreased substantia nigra-pars compacta siderosis (by T2* MRI) and showed neuro-functional benefits (UPDRS score), affected adversely hematological parameters. With the exception of 2 neutropenia patients that were withdrawn early in the trial (and resolved spontaneously) all others on DFP maintained steady plasma iron (80-115 ug/L), Tf- Sat (17-33%) hemoglobin levels (13.8-14.4 g/dL) and hematocrit (40-42 %) throughout the entire study, with just traces of daily sideruria but with serum ferritin that significantly dropped from 95±35 ng/ml to 30 ± 10 ng/ml during the first 12 months but not thereafter. We conclude that to the extent that iron chelation might have beneficial effects for treating neurodegenerative disorders that have a component of neurosiderosis, the modality of the DFP-based therapy provides a paradigm for treating regional siderosis without affecting hematological parameters. Supported by PHRC grants from the French Ministry of Research and the Adelina and Massimo DellaPergola Chair, HUJI, Jerusalem, Israel