Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: A clinical pilot trial

Boesch, Sylvia; Sturm, Brigitte; Hering, Sascha; Scheiber-Mojdehkar, Barbara; Steinkellner, Hannes; Goldenberg, Hans; Poewe, Werner

doi:10.1002/mds.22294

Cited by 75 publications

(58 citation statements)

References 23 publications

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“…The 5,000 IU rhuEPO dose was chosen because of its efficacy in previous trials [12,13], 10,000 and 30,000 IU rhuEPO doses to detect effects of supra-maximal rhuEPO stimulation. Detailed study schedule and laboratory assessments are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…In a clinical in vivo "proof of concept study", we were able to detect frataxin upregulation and reduction of oxidative stress markers in rhuEPO-treated FRDA patients [12]. An open label long-term follow-up study revealed clinical improvement in response to rhuEPO treatment [13]. In the aforementioned trials, rhuEPO doses of 2,000 to 5,000 IU were administered subcutaneously thrice weekly.…”

Section: Introductionmentioning

confidence: 96%

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

et al. 2011

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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

et al. 2011

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“…[26,27]. Established markers of oxidative stress such as urine 8-OHdG, a marker for oxidative mitochondrial and nuclear DNA damage, and serum Peroxide levels remained significantly reduced in FA patients after a six months treatment period [28]. Interestingly, a substantial reduction of indicators for oxidative stress was also found in patients who did not show a rise in Frataxin levels.…”

Section: The Possible Impact Of Rhuepo Treatment In Famentioning

confidence: 68%

Review: Friedreich Ataxia and Erythropoietin

Boesch¹,

Sturm²,

Nachbauer³

et al. 2010

TODDISJ

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Abstract:In vitro and in vivo studies have provided evidence for neuroprotective properties of Erythropoietin in neurodegenerative disorders. Although the magnitude of effect is still controversial, very recent findings point to neuronal protection in the central nervous system by Erythropoietins. Erythropoietin is a powerful growth factor which enhances cellular size and ultimatively increases the number of mitochondria. Friedreich Ataxia (FA), an inherited neurodegenerative disorder is caused by a loss of function mutation in the first intron on chromosome 9. FA patients therefore suffer a marked reduction of Frataxin, a mitochondrial protein which is involved in mitochondrial iron homeostasis and/or assembly of iron-sulfur (FeS) proteins and heme synthesis. Mitochondrial dysfunction results in a deleterious energy deficit especially in tissues highly dependent on oxidative phosphorylation such as neurons, muscle cells or pancreatic insular cells. Beneficial effects of recombinant human Erythropoietin (rhuEPO) may derive from an increase in Frataxin levels through currently unknown post-transcriptional and/or post-translational mechanisms. Moreover, additional effects via BDNF and through mitochondrial iron chelation may complete the spectrum of rhuEPOs actions in FA and may be part of its beneficial treatment effects. However, there are clear limitations to chronic rhuEPO treatment. Apart from hematopoietic side effects, tumor growth may be enhanced by rhuEPO application. In this review we provide an overview of studies using rhuEPO in FA and discuss potential beneficial effects of Erythropoietin in FA.

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“…According to miRanda software, Epo is a target for miR-886 (John et al, 2004). Moreover, Epo has been shown to increase frataxin levels in FRDA patient cells and in clinical trials (Sturm et al, 2005;Boesch et al, 2008;Saccà et al, 2011). It is possible that the anti-miR transfection affects the Epo levels which in turn lead to increase in frataxin levels (Fig.…”

Section: Discussionmentioning

confidence: 99%