FA is a rare neurological disorder due to deficiency of the mitochondrial protein frataxin. Frataxin deficiency results in impaired mitochondrial function and iron deposition in affected tissues. Erythropoietin (EPO) is a cytokine which was mostly known as a key regulator of erythropoiesis until cumulative evidence showed additional neurotrophic and neuroprotective properties. These features offered the rationale for advancement of EPO in clinical trials in different neurological disorders in the past years, including FA. Several mechanisms of action of EPO may be beneficial in FA. First of all, EPO exposure results in some frataxin upregulation in vitro and in vivo. By promoting erythropoiesis, EPO influences iron metabolism and induces shifts in iron pool which may ameliorate conditions of free iron excess and iron accumulation. Furthermore, EPO signaling is crucial for mitochondrial gene activation and mitochondrial biogenesis. Up to date nine clinical trials investigated the effects of EPO and derivatives in FA. The majority of these studies had a proof-of-concept design. Considering the natural history of FA, all of them were too short in duration and not powered for clinical changes. However, these studies addressed significant issues in the treatment with EPO, such as (1) the challenge of the dose finding, (2) stability of frataxin up-regulation, (3) continuous versus intermittent stimulation with EPO/regimen, or (4) tissue changes after EPO exposure in humans in vivo (muscle biopsy, brain imaging). The recent development of small EPO mimetics which maintain cytoprotective properties without erythropoietic action may open a new era in EPO research for the treatment of FA.
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