Epoetin alfa increases frataxin production in Friedreich's ataxia without affecting hematocrit

Saccà, Francesco; Piro, Raffaele; Michele, Giuseppe De; Acquaviva, Fabio; Antenora, Antonella; Carlomagno, Guido; Cocozza, Sérgio; Denaro, Alessandra; Guacci, Anna; Marsili, Angela; Perrotta, Gaetano; Puorro, Giorgia; Cittadini, Antonio; Filla, Alessandro

doi:10.1002/mds.23435

Cited by 42 publications

(29 citation statements)

References 19 publications

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“…Long-term assessment of frataxin levels showed cumulative significant frataxin increase. This is in line with findings by Sacca and co-workers who found a sustained frataxin upregulation up to 6 months after rhuEPO single-dose application [22]. In contrast to our earlier studies that favoured continuous low-dose rhuEPO stimulation [12,13], we found a more pronounced frataxin increase using this single-dose regimen.…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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

et al. 2011

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“…Similar studies using HDAC inhibitors and erythropoietin have reported increases in frataxin protein expression in primary cells derived from patients with FRDA in vitro [9], [10], [13], [14], with studies showing increases in frataxin protein with and without corresponding increases in frataxin mRNA [9], [13]. Increases in frataxin protein expression have also been confirmed using recombinant erythropoietin in clinical studies in FRDA patients [11], [33], [34]. To determine if MSCs secrete erythropoietin, thus a possible mechanism by which they promote an increase in frataxin expression, we analyzed several different MSC-conditioned medium samples using an erythropoietin ELISA.…”

Section: Discussionmentioning

confidence: 54%

Mesenchymal Stem Cells Restore Frataxin Expression and Increase Hydrogen Peroxide Scavenging Enzymes in Friedreich Ataxia Fibroblasts

et al. 2011

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Dramatic advances in recent decades in understanding the genetics of Friedreich ataxia (FRDA)—a GAA triplet expansion causing greatly reduced expression of the mitochondrial protein frataxin—have thus far yielded no therapeutic dividend, since there remain no effective treatments that prevent or even slow the inevitable progressive disability in affected individuals. Clinical interventions that restore frataxin expression are attractive therapeutic approaches, as, in theory, it may be possible to re-establish normal function in frataxin deficient cells if frataxin levels are increased above a specific threshold. With this in mind several drugs and cytokines have been tested for their ability to increase frataxin levels. Cell transplantation strategies may provide an alternative approach to this therapeutic aim, and may also offer more widespread cellular protective roles in FRDA. Here we show a direct link between frataxin expression in fibroblasts derived from FRDA patients with both decreased expression of hydrogen peroxide scavenging enzymes and increased sensitivity to hydrogen peroxide-mediated toxicity. We demonstrate that normal human mesenchymal stem cells (MSCs) induce both an increase in frataxin gene and protein expression in FRDA fibroblasts via secretion of soluble factors. Finally, we show that exposure to factors produced by human MSCs increases resistance to hydrogen peroxide-mediated toxicity in FRDA fibroblasts through, at least in part, restoring the expression of the hydrogen peroxide scavenging enzymes catalase and glutathione peroxidase 1. These findings suggest, for the first time, that stem cells may increase frataxin levels in FRDA and transplantation of MSCs may offer an effective treatment for these patients.

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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%

miR-886-3p Levels Are Elevated in Friedreich Ataxia

Mahishi

Hart²,

Lynch³

et al. 2012

Journal of Neuroscience

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Epoetin alfa increases frataxin production in Friedreich's ataxia without affecting hematocrit

Cited by 42 publications

References 19 publications

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

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

Mesenchymal Stem Cells Restore Frataxin Expression and Increase Hydrogen Peroxide Scavenging Enzymes in Friedreich Ataxia Fibroblasts

miR-886-3p Levels Are Elevated in Friedreich Ataxia

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