Recombinant human erythropoietin: effects on frataxin expression <i>in vitro</i>

Sturm, Brigitte; Stupphann, Daniela; Kaun, Christoph; Boesch, Sylvia; Schranzhofer, Matthias; Wojta, Johann; Goldenberg, Hans; Scheiber-Mojdehkar, Barbara

doi:10.1111/j.1365-2362.2005.01568.x

Cited by 98 publications

(78 citation statements)

References 38 publications

(42 reference statements)

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“…Therefore, the correlation between GAA repeat number and disease is estimated to account for only approximately 50-70% of the variance in age of onset of FA [7,[10][11][12]. An additional significant shortcoming of genomic testing is that the tests cannot be used to monitor molecular efficacy of new therapies designed to treat or prevent onset of FA by boosting levels of the frataxin protein [26,27,29,30].…”

Section: Discussionmentioning

confidence: 99%

“…It is clear that such tests could have diagnostic, prognostic and theranostic utility, as FA is caused by a reduction in frataxin levels and therapeutic interventions are being designed to increase levels of frataxin. Most data to data has shown that this can be achieved by boosting mRNA levels, although other mechanisms may exist to alleviate the reduced levels of frataxin seen in FA patients, as seems to be the case with recombinant human erythropoietin [30].…”

Section: Discussionmentioning

confidence: 99%

“…This opens the possibility of using small molecule drugs to boost frataxin concentrations by increasing transcription of the unaltered, normal coding sequence and recent experimental advances have demonstrated the feasibility of this approach in vitro [26][27][28][29]. In addition, other compounds, such as recombinant human erythropoietin, have been shown to increase frataxin protein levels in vitro by a presently unknown mechanism [30].…”

Section: Introductionmentioning

confidence: 99%

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Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

Willis¹,

Isaya

Gakh

et al. 2008

Molecular Genetics and Metabolism

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Friedreich's Ataxia (FA) is an inherited neurodegenerative disease caused by reduction in levels of the mitochondrial protein frataxin. Currently there are no simple, reliable methods to accurately measure the concentrations of frataxin protein. We designed a lateral-flow immunoassay that quantifies frataxin protein levels in a variety of sample materials. Using recombinant frataxin we evaluated the accuracy and reproducibility of the assay. The assay measured recombinant human frataxin concentrations between 40 and 4000 pg/test or approximately 0.1 -10 nM of sample. The intra and inter-assay error was < 10% throughout the working range. To evaluate clinical utility of the assay we used genetically defined lymphoblastoid cells derived from FA patients, FA carriers and controls. Mean frataxin concentrations in FA patients and carriers were significantly different from controls and from one another (p = 0.0001, p = 0.003, p = 0.005, respectively) with levels, on average, 29% (patients) and 64% (carriers) of the control group. As predicted, we observed an inverse relationship between GAA repeat number and frataxin protein concentrations within the FA patient cohort. The lateral flow immunoassay provides a simple, accurate and reproducible method to quantify frataxin protein in whole cell and tissue extracts, including primary samples obtained by non-invasive means, such as cheek swabs and whole blood. The assay is a novel tool for FA research that may facilitate improved diagnostic and prognostic evaluation of FA patients and could also be used to evaluate efficacy of therapies designed to cure FA by increasing frataxin protein levels.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

Willis¹,

Isaya

Gakh

et al. 2008

Molecular Genetics and Metabolism

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“…These include cisplatin (Ghazizadeh, 2003), 3-nitroproprionic acid (Turano et al, 2003), sodium butyrate and hemin ( (Sarsero et al, 2003), see above), and erythropoietin (Sturm et al, 2005). In the case of the chemotherapeutic agent cisplatin, Ghazizadeh discovered through a cDNA microarray analysis that the frataxin gene was often over-expressed in cisplatin-resistant cell lines, compared to parental cell lines.…”

Section: Discovery Of Molecules That Increase Frataxin Mrna or Proteinmentioning

confidence: 99%

Small molecules affecting transcription in Friedreich ataxia

Gottesfeld

2007

Pharmacology & Therapeutics

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This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin, and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While anti-oxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA·TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts as well as the molecular basis for gene silencing in FRDA.

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“…Other approaches to treat FRDA are centered upon increasing the expression of frataxin. For example, a recent study has found that recombinant human erythropoietin increases frataxin levels, by an unknown mechanism, in cultured cells from FRDA patients [12]. Another strategy to increase frataxin involves using reagents that can attenuate the recalcitrant conformations (triplex or sticky DNA) expanded GAA repeats are thought to take, thereby increasing transcription and elevating frataxin levels.…”

Section: Introductionmentioning

confidence: 99%

Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia

Grant¹,

Sun²,

Xu³

et al. 2006

FEBS Letters

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Friedreich's ataxia (FRDA) is an autosomal recessive trinucleotide repeat disease with no effective therapy. Expanded GAA repeats in the first intron of the FRDA gene are thought to form unusual non-B DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. Frataxin plays a crucial role in iron metabolism and detoxification. To discover small molecules that increase transcription through the GAA repeat region in FRDA, we have made stable cell lines containing a portion of expanded intron 1 fused to a GFP reporter. Small molecules identified using the competition dialysis method were found to increase FRDA-intron 1-reporter gene expression. One of these compounds, pentamidine, increases frataxin levels in patient cells. Thus our approach can be used to detect small molecules of potential therapeutic value in FRDA.

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Recombinant human erythropoietin: effects on frataxin expression in vitro

Abstract: Our results provide a scientific basis for further studies examining the effectiveness of this agent for the treatment of FRDA patients.

Cited by 98 publications

References 38 publications

Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

Small molecules affecting transcription in Friedreich ataxia

Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia

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