Friedreich's Ataxia. P.E. Hart, A.H.V. Schapira, Encyclopedia of Biological Chemistry, 2013, Pages 332-334. http://dx.doi.org/10.1016/B978-0-12-378630-2.00443-6.
Keywords: Friedreich's ataxia (FRDA), ataxia, sensory loss, cardiomyopathy, skeletal abnormalities, diabetes, optic atrophy, frataxin, neurodegenerative disorder.
Thursday, February 14, 2013
Pharmacological Screening Using an FXN-EGFP Cellular Genomic Reporter Assay for the Therapy of Friedreich Ataxia
Pharmacological Screening Using an FXN-EGFP Cellular Genomic Reporter Assay for the Therapy of Friedreich Ataxia. Lingli Li, Lucille Voullaire, Chiranjeevi Sandi, Mark A. Pook, Panos A. Ioannou, Martin B. Delatycki, Joseph P. Sarsero. PLoS ONE 8(2): e55940. doi:10.1371/journal.pone.0055940 (2013)
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Abstract
Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.
OPEN ACCESS
Abstract
Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.
Phase 2 clinical trials with OX1 (VP 20629) in patients with Friedreich's Ataxia
Phase 2 clinical trials with OX1 (VP 20629) in patients with Friedreich's Ataxia. Intellect Neurosciences Issues Letter to Shareholders, 02/13/2013 GlobeNewswire
An important event to anticipate in 2013 is the initiation of Phase 2 clinical trials with OX1 (VP 20629) in patients with Friedreich's Ataxia ("FA"), which we expect to occur mid-year based on statements Vincent Milano, CEO of ViroPharma, made during his presentation at the JP Morgan Health Care Conference in January. ViroPharma intends to file for Orphan Drug Designation upon review of the Phase 2 proof-of-concept data. February 28 marks the sixth international Rare Disease Day in 24 European countries. We are pleased ViroPharma is collaborating with FARA (Friedreich's Ataxia Research Alliance) to raise awareness about FA and Rare Disease through the media. Intellect helped forge the alliance between ViroPharma and FARA and we are proud of our role in developing OX1 and highlighting its potential for FA.
An important event to anticipate in 2013 is the initiation of Phase 2 clinical trials with OX1 (VP 20629) in patients with Friedreich's Ataxia ("FA"), which we expect to occur mid-year based on statements Vincent Milano, CEO of ViroPharma, made during his presentation at the JP Morgan Health Care Conference in January. ViroPharma intends to file for Orphan Drug Designation upon review of the Phase 2 proof-of-concept data. February 28 marks the sixth international Rare Disease Day in 24 European countries. We are pleased ViroPharma is collaborating with FARA (Friedreich's Ataxia Research Alliance) to raise awareness about FA and Rare Disease through the media. Intellect helped forge the alliance between ViroPharma and FARA and we are proud of our role in developing OX1 and highlighting its potential for FA.
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