Effects of Erythropoietin on Frataxin Levels and Mitochondrial Function in Friedreich Ataxia – a Dose–Response Trial

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive inherited neurodegenerative disorder leading to reduced expression of the mitochondrial protein frataxin. Previous studies showed frataxin upregulation in FRDA following treatment with recombinant human erythropoietin (rhuEPO). Dose-response interactions between frataxin and rhuEPO have not been studied until to date. We administered escalating rhuEPO single doses (5,000, 10,000 and 30,000 IU) in monthly intervals to five adult FRDA patients. Measurements of frataxin, serum erythropoietin levels, iron metabolism and mitochondrial function were carried out. Clinical outcome was assessed using the "Scale for the assessment and rating of ataxia". We found maximal erythropoietin serum concentrations 24 h after rhuEPO application which is comparable to healthy subjects. Frataxin levels increased significantly over 3 months, while ataxia rating did not reveal clinical improvement. All FRDA patients had considerable ferritin decrease. NADH/NAD ratio, an indicator of mitochondrial function, increased following rhuEPO treatment. In addition to frataxin upregulation in response to continuous low-dose rhuEPO application shown in previous studies, our results indicate for a long-lasting frataxin increase after single high-dose rhuEPO administration. To detect frataxin-derived neuroprotective effects resulting in clinically relevant improvement, well-designed studies with extended time frame are required.

Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase

“…In a more recent pharmacological protocol, escalating rhuEPO single doses (5000, 10,000, and 30,000 IU) were administrated at monthly intervals. This schedule was associated with a nonsignificant short‐term frataxin change after rhuEPO single‐dose application, but with a long‐term cumulative significant frataxin increase after a few months 17…”

Long‐term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia

“…Two clinical trials tested the effect of single and very high doses of EPO on frataxin levels. They found no acute effect on frataxin; instead, a delayed and sustained increase was evident . In one study, 10 patients were treated with subcutaneous single and high doses of epoetin alfa (600 IU/Kg for the first dose and a second dose of 1200 IU/Kg 3 months later) .…”

Erythropoietin in Friedreich ataxia

“…A second single-dose study investigated the dose-response relationship in escalating single rHuEPO doses (Nachbauer et al 2011a). Five FRDA patients (one female, four males) received three rHuEPO single injections in monthly intervals.…”