Friedreich's ataxia: clinical pilot trial with recombinant human erythropoietin

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

doi:10.1002/ana.21177

Cited by 103 publications

(100 citation statements)

References 20 publications

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“…Sturm et al [228] showed that the recombinant human erythropoietin (rhuEPO) significantly increases frataxin expression in primary lymphocytes from FRDA patients by a still unknown mechanism. In a recent open-label clinical pilot study treatment of 12 FRDA patients with recombinant human erythropoietin led to a persistent and significant increase in frataxin levels after 8 weeks (P \ 0.01) [229]. HDAC inhibitors have been shown to increase frataxin expression.…”

Section: Natural Antioxidants Vitagenes and Neurodegenerative Disordersmentioning

confidence: 99%

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

Calabrese

Cornelius

Mancuso³

et al. 2008

Neurochem Res

254

227

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The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer's and Parkinson's diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called "protein conformational diseases". The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-L-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.

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Section: Natural Antioxidants Vitagenes and Neurodegenerative Disordersmentioning

confidence: 99%

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

Calabrese

Cornelius

Mancuso³

et al. 2008

Neurochem Res

254

227

View full text Add to dashboard Cite

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“…There are several studies just con-cluded, still ongoing or planned worldwide, applying EPO for treatment of human nervous system diseases. These include: trials on neurotrauma, subarachnoid hemorrhage, spinal cord injury, cerebral malaria, optic neuritis, Friedreich's ataxia, 123 chemotherapy induced peripheral neuropathy, and diabetes-associated complications of the nervous system (for overview, see Table 2). To our knowledge, no EPO variants other than rhEPO itself have thus far been published in relation to the treatment of human nervous system diseases.…”

Section: Erythropoietin As Neuroprotective/ Neuroregenerative Treatmementioning

confidence: 99%

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

et al. 2009

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Summary:The growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, antiapoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

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“…Thus, a persistent and significant increase in frataxin levels was found in peripheral blood lymphocytes of seven (among 10) patients with FRDA who received 5.000 units of rhuEPO subcutaneously, three times a week during 8 weeks; reductions in the urinary oxidative stress marker 8-hydroxi-2'-deoxyguanosine excretion, and in SARA scores, were also found (132). The same favourable results (that reached statistical significance) were replicated in a study involving 8 patients with FRDA, who received 2.000 units of rhuEPO three times a week during six months; unfortunately, the design of the trial could not rule out a placebo effect of the drug (133).…”

Section: Spinocerebellar Atrophiesmentioning

confidence: 84%