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.
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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.
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.
Tuesday, February 12, 2013
Cognition in Late-Onset Friedreich Ataxia.
Cognition in Late-Onset Friedreich Ataxia. Nieto A, Correia R, de Nóbrega E, Montón F, Barroso J.; Cerebellum. 2013 Feb 9. DOI 10.1007/s12311-013-0457-z.
Keywords: Friedreich ataxia (FRDA), Friedreich ataxia-LOFA, processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions, and language.
Keywords: Friedreich ataxia (FRDA), Friedreich ataxia-LOFA, processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions, and language.
Australian families living with rare disease: experiences of diagnosis, health services use and needs for psychosocial support
Australian families living with rare disease: experiences of diagnosis, health services use and needs for psychosocial support. Matilda Anderson, Elizabeth J Elliott, Yvonne A Zurynski, Orphanet Journal of Rare Diseases 2013, 8:22 doi:10.1186/1750-1172-8-22. Published: 11 February 2013.
Families of children living with a rare disease report significant health and social burden, however, few studies have systematically examined family needs by using validated tools to assess the scope and extent of this burden. Our aim was to develop a comprehensive survey to assess health, psychosocial and financial impacts on Australian families caring for a child with a rare disease.
Australian families caring for children with genetic metabolic disorders are adversely impacted by delays in diagnosis, lack of easy access to peer support groups and lack of psychological support. Further research is needed to estimate economic impact and to analyse health service delivery models for children with rare diseases in Australia.
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Families of children living with a rare disease report significant health and social burden, however, few studies have systematically examined family needs by using validated tools to assess the scope and extent of this burden. Our aim was to develop a comprehensive survey to assess health, psychosocial and financial impacts on Australian families caring for a child with a rare disease.
Australian families caring for children with genetic metabolic disorders are adversely impacted by delays in diagnosis, lack of easy access to peer support groups and lack of psychological support. Further research is needed to estimate economic impact and to analyse health service delivery models for children with rare diseases in Australia.
OPEN ACCESS FULL TEXT PDF
Monday, February 11, 2013
Review about ataxias
ATAXIA, Dr. M. Yasser Metwally, Professor of neurology, Ain Shams university, Cairo, Egypt
Interesting paper about ataxia diagnosis. The site also contains extensive information on neurology, diagnostic imaging, etc.
Friedreich's ataxia pg 21-28
Site: http://yassermetwally.com/
Interesting paper about ataxia diagnosis. The site also contains extensive information on neurology, diagnostic imaging, etc.
Friedreich's ataxia pg 21-28
Site: http://yassermetwally.com/
Sunday, February 10, 2013
Scientists Find Way to Knockup Genes
Scientists Find Way to Knockup Genes. PR Newswire, CAMBRIDGE, England, Jan. 31, 2013 /PRNewswire/
"In many ways, the technique is the opposite of RNAi"
Italian scientists use molecular RNA Chaperones to increase protein production from individual genes. The technique is being hailed as a breakthrough in biotechnology that will transform cell science, accelerating the development of new medicines.
A non-coding RNA specifically binds to messenger RNA (mRNA) from the target gene. It then acts as a chaperone, efficiently escorting the target mRNA to ribosomes, where proteins are made.
"In many ways, the technique is the opposite of RNAi"
Italian scientists use molecular RNA Chaperones to increase protein production from individual genes. The technique is being hailed as a breakthrough in biotechnology that will transform cell science, accelerating the development of new medicines.
A non-coding RNA specifically binds to messenger RNA (mRNA) from the target gene. It then acts as a chaperone, efficiently escorting the target mRNA to ribosomes, where proteins are made.
Saturday, February 9, 2013
Upregulation of the Mitochondrial Lon Protease Allows Adaptation to Acute Oxidative Stress but Dysregulation is Associated with Chronic Stress, Disease, and Aging
Upregulation of the Mitochondrial Lon Protease Allows Adaptation to Acute Oxidative Stress but Dysregulation is Associated with Chronic Stress, Disease, and Aging. Jenny K. Ngo, Laura C.D. Pomatto, Kelvin J.A. Davies. Redox Biology, Available online 9 February 2013. http://dx.doi.org/10.1016/j.redox.2013.01.015.
Keywords: Adaptation, Hormesis, Lon Protease, Protein Degradation and Oxidation, Mitochondria, Oxidative Stress.
In a Friedreich Ataxia mouse model, in which frataxin has been deleted in striated muscles, an increase in ClpP and Lon mRNA, protein, and activity was observed in the isolated mitochondria of mice between 5 and 10 weeks of age [55]. The upregulation of Lon and ClpP was accompanied by a progressive loss of mitochondrial Fe-S proteins with no change in mRNA levels, suggesting degradation.
See also: Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins
Keywords: Adaptation, Hormesis, Lon Protease, Protein Degradation and Oxidation, Mitochondria, Oxidative Stress.
In a Friedreich Ataxia mouse model, in which frataxin has been deleted in striated muscles, an increase in ClpP and Lon mRNA, protein, and activity was observed in the isolated mitochondria of mice between 5 and 10 weeks of age [55]. The upregulation of Lon and ClpP was accompanied by a progressive loss of mitochondrial Fe-S proteins with no change in mRNA levels, suggesting degradation.
See also: Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins
The Gait Variability Index: A new way to quantify fluctuation magnitude of spatiotemporal parameters during gait
The Gait Variability Index: A new way to quantify fluctuation magnitude of spatiotemporal parameters during gait. Arnaud Gouelle, Fabrice Mégrot, Ana Presedo, Isabelle Husson, Alain Yelnik, Georges-François Penneçot. Gait & Posture, Available online 8 February 2013. http://dx.doi.org/10.1016/j.gaitpost.2013.01.013
Keywords: Gait variability, Fluctuation magnitude, Spatiotemporal parameters, Friedreich's Ataxia
Keywords: Gait variability, Fluctuation magnitude, Spatiotemporal parameters, Friedreich's Ataxia
Hypoxia inducible factor prolyl hydroxylases as targets for neuroprotection by “antioxidant” metal chelators: From ferroptosis to stroke
Hypoxia inducible factor prolyl hydroxylases as targets for neuroprotection by “antioxidant” metal chelators: From ferroptosis to stroke. Rachel E. Speer, Saravanan S. Karuppagounder, Manuela Basso, Sama Sleiman, Amit Kumar, David Brand, Natalya Smirnova, Irina Gazaryan, Soah J. Khim, Rajiv R. Ratan. Free Radical Biology and Medicine, Available online 31 January 2013. http://dx.doi.org/10.1016/j.freeradbiomed.2013.01.026
Keywords: Metal chelators, Neurodegeneration, Hypoxia inducible factors, Transcription, Prolyl hydroxylases.
See also:
Frataxin participates to the hypoxia-induced response in tumors
Neuroprotective Multifunctional Iron Chelators: From Redox-Sensitive Process to Novel Therapeutic Opportunities
Keywords: Metal chelators, Neurodegeneration, Hypoxia inducible factors, Transcription, Prolyl hydroxylases.
See also:
Frataxin participates to the hypoxia-induced response in tumors
Neuroprotective Multifunctional Iron Chelators: From Redox-Sensitive Process to Novel Therapeutic Opportunities
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