The traditional role of
iron chelation therapy has been to reduce body
iron burden via chelation of excess
metal from organs and fluids and its excretion via biliary-fecal and/or urinary routes. In their present use for
hemosiderosis, chelation regimens might not be suitable for treating disorders of
iron maldistribution, as those are characterized by toxic islands of
siderosis appearing in a background of normal or subnormal
iron levels (e.g.,
sideroblastic anemias, neuro- and cardio-
siderosis in
Friedreich ataxia- and neurosiderosis in
Parkinson's disease). We aimed at clearing local
siderosis from aberrant labile
metal that promotes oxidative damage, without interfering with essential local functions or with hematological
iron-associated properties. For this purpose we introduced a conservative mode of
iron chelation of dual activity, one based on scavenging labile
metal but also redeploying it to cell acceptors or to physiological
transferrin. The "scavenging and redeployment" mode of action was designed both for correcting aberrant
iron distribution and also for minimizing/preventing systemic loss of chelated
metal. We first examine cell models that recapitulate
iron maldistribution and associated dysfunctions identified with
Friedreich ataxia and
Parkinson's disease and use them to explore the ability of the double-acting agent
deferiprone, an orally active
chelator, to mediate
iron scavenging and redeployment and thereby causing functional improvement. We subsequently evaluate the concept in translational models of disease and finally assess its therapeutic potential in prospective double-blind pilot clinical trials. We claim that any
chelator applied to diseases of regional
siderosis, cardiac, neuronal or endocrine ought to preserve both systemic and regional
iron levels. The proposed
deferiprone-based
therapy has provided a paradigm for treating regional types of
siderosis without affecting hematological parameters and systemic functions.