Erythropoietin and Friedreich Ataxia: Time for a Reappraisal?

Abstract

Friedreich ataxia (FRDA) 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 FRDA. Several mechanisms of action of EPO may be beneficial in FRDA. First of all, EPO exposure results in 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 FRDA. The majority of these studies had a proof-of-concept design. Considering the natural history of FRDA, 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). Despite several clinical trials in the past, no treatment is available for the treatment of FRDA. Current lines of research focus on gene therapy, frataxin replacement strategies and on regulation of key metabolic checkpoints such as NrF2. Due to potential crosstalk with all these mechanisms, interventions on the EPO pathway still represent a valuable research field. 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 FRDA.

Erythropoietin in Spinocerebellar Ataxia Type 2: Feasibility and Proof‐of‐Principle Issues from a Randomized Controlled Study

“…[7][8][9] Therefore, recombinant formulations of EPO (rhEpo) are under clinical research in neurovascular and neurodegenerative diseases, 6 including Friedreich ataxia. 10 However, safety concerns have been raised about systemic administration of rhEpo due to the induction of serious side effects such as hypertension, polycythemia, myocardial infarction, stroke, and increased thromboembolic risk. 11,12 NeuroEPO is a nasal solution containing low sialicacid rhEPO developed as a neuroprotective candidate.…”

Drug Repositioning in Friedreich Ataxia

“…Moreover, STS-E412 and STS-E424 stimulate frataxin expression in the brain of KIKO mice without exerting effect on hematopoiesis. Their ability to cross the blood brain barrier, together with their favorable safety profile and lack of hematopoiesis stimulation, encourage further studies on these compounds ( Miller et al, 2017 ; Boesch and Indelicato, 2019 ).…”

Molecular Defects in Friedreich’s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities

“…EPO treatment in FRDA patients increased lymphocyte FXN levels, reduced levels of 8-OHdG back to baseline, and promoted neurological score improvement over 8 weeks ( Boesch et al, 2007 ). However, challenges in follow-up studies include reaching statistically significant increases in FXN expression, changes in blood-iron levels, defining proper dosage amounts, or proving any clinical benefit, thus complicating its otherwise rational application in FRDA ( Boesch and Indelicato, 2019 ).…”