<scp>L</scp>ong‐term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia

Saccà, Francesco; Puorro, Giorgia; Marsili, Angela; Antenora, Antonella; Pane, Chiara; Casali, Carlo; Marcotulli, Christian; Defazio, Giovanni; Liuzzi, Daniele; Tatillo, Chiara; Cambriglia, Donata Maria; Cola, Giuseppe Schiano di; Giuliani, Luigi; Guardasole, Vincenzo; Salzano, Andrea; Ruvolo, Antonio; Rosa, Anna De; Cittadini, Antonio; Michele, Giuseppe De; Filla, Alessandro

doi:10.1002/mds.26552

Cited by 28 publications

(26 citation statements)

References 34 publications

(46 reference statements)

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“…In several cell models, EPO elicited a dose-dependent increase of frataxin [113]. In human disease, randomized controlled trials failed to establish significant changes of frataxin expression or clinical parameters [114, 115]. …”

Section: Therapymentioning

confidence: 99%

Friedreich Ataxia: current status and future prospects

2017

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Friedreich ataxia (FA) represents the most frequent type of inherited ataxia. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Due to epigenetic alterations, frataxin expression is significantly reduced. Frataxin is a mitochondrial protein. Its deficiency leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species. This review gives an overview over clinical and genetic aspects of FA and discusses current concepts of frataxin biogenesis and function as well as new therapeutic strategies.

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Section: Therapymentioning

confidence: 99%

Friedreich Ataxia: current status and future prospects

2017

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“…The Scale for the Assessment and Rating of Ataxia (SARA) consisting of eight items (gait, stance, sitting, speech disturbance, finger chase, nose‐finger test, fast alternating hand movements, heel‐shin slide) and can score from 0 to 40, with 40 being the worst condition. The scale has been used to score ataxia in several neurological conditions (Bürk et al ., ; Saccà et al ., ; Schmitz‐Hübsch et al ., ).…”

Section: Methodsmentioning

confidence: 99%

Normalization of timed neuropsychological tests with the PATA rate and nine‐hole pegboard tests

Saccà

Costabile

Abate

et al. 2017

Journal of Neuropsychology

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“…Only one larger study assessed effect of rhuEPO on FRDA (Saccà et al, 2016). On the basis of their earlier pilot study Saccà et al (2011), tested rhuEPO in 56 patients randomized 1:1 to receive epoetin alfa or placebo.…”

Section: Erythropoietin and Frda: The Bedsidementioning

confidence: 99%

“…Despite being underpowered to show a difference against placebo, few EPO studies reported some clinical benefits (Boesch et al, 2008; Saccà et al, 2016). These findings may be interpreted as results of shorter-term effect of EPO on muscle strength and fitness, which may provide a partial compensation for ataxia.…”

Section: Erythropoietin and Frda: The Bedsidementioning

confidence: 99%

Erythropoietin and Friedreich Ataxia: Time for a Reappraisal?

Boesch

Indelicato

2019

Front. Neurosci.

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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.

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

Cited by 28 publications

References 34 publications

Friedreich Ataxia: current status and future prospects

Friedreich Ataxia: current status and future prospects

Normalization of timed neuropsychological tests with the PATA rate and nine‐hole pegboard tests

Erythropoietin and Friedreich Ataxia: Time for a Reappraisal?

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