A. Gouelle a, ⁎, F. Mégrot b, A. Yelnik c, G.-F. Penneçot d
a Plate-forme d’analyse du mouvement, hôpital Robert-Debré, AP–HP, 48, boulevard Sérurier, 75019 Paris, France
b Unité clinique d’analyse de la marche et du mouvement, CMPRE Bois-Larris, Lamorlaye, France
c Service de médecine physique et de réadaptation, hôpital Fernand-Widal, Paris, France
d Service de chirurgie orthopédique, hôpital Robert-Debré, Paris, France
KEYWORDS : Score, Marche, Stabilité dynamique, Paramètres spatiotemporels
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Friday, October 14, 2011
Tuesday, October 11, 2011
Friedreich ataxia: The vicious circle hypothesis revisited
BMC Medicine 2011, 9:112doi:10.1186/1741-7015-9-112, Published: 11 October 2011
Aurelien Bayot, Renata Santos, Jean-Michel Camadro and Pierre Rustin
OPEN ACCES
Abstract (provisional)
Friedreich ataxia, the most frequent progressive autosomal recessive disorder involving the central and peripheral nervous system, is mostly associated with an unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene which encodes the mitochondrial frataxin protein. Since FXN was shown to be involved in Friedreich ataxia in the late 1990s, the consequence of frataxin loss of function has been generating vigorous debate. Very early on, we suggested a unifying hypothesis according to which frataxin deficiency leads to a vicious circle of faulty iron handling, impaired iron-sulfur cluster synthesis, and increased oxygen radical production. However, data from cell and animal models now indicate that iron accumulation is an inconsistent and late event and that frataxin deficiency does not always impair the activity of iron-sulfur cluster-containing proteins. In contrast, frataxin deficiency appears consistently associated with increased sensitivity to reactive oxygen species, as opposed to increased oxygen radical production. Compiling findings from fundamental researches to clinical observations, we defend here the opinion that the very first consequence of frataxin depletion is indeed an abnormal oxidative status which initiates the pathogenic mechanism underlying Friedreich ataxia.
FULL TEXT PDF
Aurelien Bayot, Renata Santos, Jean-Michel Camadro and Pierre Rustin
OPEN ACCES
Abstract (provisional)
Friedreich ataxia, the most frequent progressive autosomal recessive disorder involving the central and peripheral nervous system, is mostly associated with an unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene which encodes the mitochondrial frataxin protein. Since FXN was shown to be involved in Friedreich ataxia in the late 1990s, the consequence of frataxin loss of function has been generating vigorous debate. Very early on, we suggested a unifying hypothesis according to which frataxin deficiency leads to a vicious circle of faulty iron handling, impaired iron-sulfur cluster synthesis, and increased oxygen radical production. However, data from cell and animal models now indicate that iron accumulation is an inconsistent and late event and that frataxin deficiency does not always impair the activity of iron-sulfur cluster-containing proteins. In contrast, frataxin deficiency appears consistently associated with increased sensitivity to reactive oxygen species, as opposed to increased oxygen radical production. Compiling findings from fundamental researches to clinical observations, we defend here the opinion that the very first consequence of frataxin depletion is indeed an abnormal oxidative status which initiates the pathogenic mechanism underlying Friedreich ataxia.
FULL TEXT PDF
Saturday, October 8, 2011
Mesenchymal Stem Cells Restore Frataxin Expression and Increase Hydrogen Peroxide Scavenging Enzymes in Friedreich Ataxia Fibroblasts
PLoS ONE 6(10): e26098. doi:10.1371/journal.pone.0026098 (2011)
Kemp K, Mallam E, Hares K, Witherick J, Scolding N, et al.
Multiple Sclerosis and Stem Cell Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
OPEN ACCESS
Abstract Top
Dramatic advances in recent decades in understanding the genetics of Friedreich ataxia (FRDA)—a GAA triplet expansion causing greatly reduced expression of the mitochondrial protein frataxin—have thus far yielded no therapeutic dividend, since there remain no effective treatments that prevent or even slow the inevitable progressive disability in affected individuals. Clinical interventions that restore frataxin expression are attractive therapeutic approaches, as, in theory, it may be possible to re-establish normal function in frataxin deficient cells if frataxin levels are increased above a specific threshold. With this in mind several drugs and cytokines have been tested for their ability to increase frataxin levels. Cell transplantation strategies may provide an alternative approach to this therapeutic aim, and may also offer more widespread cellular protective roles in FRDA. Here we show a direct link between frataxin expression in fibroblasts derived from FRDA patients with both decreased expression of hydrogen peroxide scavenging enzymes and increased sensitivity to hydrogen peroxide-mediated toxicity. We demonstrate that normal human mesenchymal stem cells (MSCs) induce both an increase in frataxin gene and protein expression in FRDA fibroblasts via secretion of soluble factors. Finally, we show that exposure to factors produced by human MSCs increases resistance to hydrogen peroxide-mediated toxicity in FRDA fibroblasts through, at least in part, restoring the expression of the hydrogen peroxide scavenging enzymes catalase and glutathione peroxidase 1. These findings suggest, for the first time, that stem cells may increase frataxin levels in FRDA and transplantation of MSCs may offer an effective treatment for these patients.
Full text PDF
Kemp K, Mallam E, Hares K, Witherick J, Scolding N, et al.
Multiple Sclerosis and Stem Cell Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
OPEN ACCESS
Abstract Top
Dramatic advances in recent decades in understanding the genetics of Friedreich ataxia (FRDA)—a GAA triplet expansion causing greatly reduced expression of the mitochondrial protein frataxin—have thus far yielded no therapeutic dividend, since there remain no effective treatments that prevent or even slow the inevitable progressive disability in affected individuals. Clinical interventions that restore frataxin expression are attractive therapeutic approaches, as, in theory, it may be possible to re-establish normal function in frataxin deficient cells if frataxin levels are increased above a specific threshold. With this in mind several drugs and cytokines have been tested for their ability to increase frataxin levels. Cell transplantation strategies may provide an alternative approach to this therapeutic aim, and may also offer more widespread cellular protective roles in FRDA. Here we show a direct link between frataxin expression in fibroblasts derived from FRDA patients with both decreased expression of hydrogen peroxide scavenging enzymes and increased sensitivity to hydrogen peroxide-mediated toxicity. We demonstrate that normal human mesenchymal stem cells (MSCs) induce both an increase in frataxin gene and protein expression in FRDA fibroblasts via secretion of soluble factors. Finally, we show that exposure to factors produced by human MSCs increases resistance to hydrogen peroxide-mediated toxicity in FRDA fibroblasts through, at least in part, restoring the expression of the hydrogen peroxide scavenging enzymes catalase and glutathione peroxidase 1. These findings suggest, for the first time, that stem cells may increase frataxin levels in FRDA and transplantation of MSCs may offer an effective treatment for these patients.
Full text PDF
Friday, October 7, 2011
Rare Diseases and Orphan Products: Accelerating Research and Development (2011)
THE NATIONAL ACADEMIES PRESS
Modeling neurological disorders by human induced pluripotent stem cells
Journal of Biomedicine and Biotechnology, Received 11 July 2011; Accepted 6 October 2011 Academic Editor: Ken-ichi Isobe
Tanut Kunkanjanawan, Rangsun Parnpai, and Parinya Noisa
Received 11 July 2011; Accepted 6 October 2011Academic Editor: Ken-ichi Isobe
Friedreich's Ataxia in pg 11.
Fulltext PDF
Tanut Kunkanjanawan, Rangsun Parnpai, and Parinya Noisa
Received 11 July 2011; Accepted 6 October 2011Academic Editor: Ken-ichi Isobe
Friedreich's Ataxia in pg 11.
Fulltext PDF
Thursday, October 6, 2011
Cell modelsof a neural lineage to study the effects of frataxin deficiency
Herbert-Worch-Foundation
A Spanish University developed cell models to study the effects of frataxin deficiency on human neuron-like cells.
Companies from all countries interested in putting on the market a new neuronal cell model for Friedreich´s ataxia are sought.
Current and Potential Domain of Application: Screening and testing of possible therapeutic compounds. Current Stage of Development: development phase - Laboratory tested.
A Spanish University developed cell models to study the effects of frataxin deficiency on human neuron-like cells.
Companies from all countries interested in putting on the market a new neuronal cell model for Friedreich´s ataxia are sought.
Current and Potential Domain of Application: Screening and testing of possible therapeutic compounds. Current Stage of Development: development phase - Laboratory tested.
Tuesday, October 4, 2011
Les effets secondaires du principe de précaution
Article in: Association française contre les myopathies (AFM) Blog (3/10/11)
Health authorities (FDA, EMEA, national agencies, etc.) have the obligation to ensure our health and safety from new drugs or treatments, but sometimes look like they know very little about our disease, in this case, in France are blocking a compassionate use due a the very remote possibility of an side effect that can appears in old age, unfortunately, few patients will reach if there is no effective treatment, and can not test it.
It is very sad, french patients which participated in the Dr. Isabelle Husson and Pierre Rustin Pioglitazone clinical trial, when they finish the two years clinical trial, they can continue with the Pioglitazone as compassionate use, now, the authorities ban this option, although as some patiens explain, they feel that get improvements. The reason, a very little possibility to develop a side effec, prostate cancer, a possibility that unfortunately is not logical for FA patiens, due to the typical disease life expectancy.
Health authorities (FDA, EMEA, national agencies, etc.) have the obligation to ensure our health and safety from new drugs or treatments, but sometimes look like they know very little about our disease, in this case, in France are blocking a compassionate use due a the very remote possibility of an side effect that can appears in old age, unfortunately, few patients will reach if there is no effective treatment, and can not test it.
It is very sad, french patients which participated in the Dr. Isabelle Husson and Pierre Rustin Pioglitazone clinical trial, when they finish the two years clinical trial, they can continue with the Pioglitazone as compassionate use, now, the authorities ban this option, although as some patiens explain, they feel that get improvements. The reason, a very little possibility to develop a side effec, prostate cancer, a possibility that unfortunately is not logical for FA patiens, due to the typical disease life expectancy.
Sunday, October 2, 2011
What is the OX1?
The OX1 or OXIGON (TM) is the Indole-3-propionic acid (IPA) (SYNONYMS: 3-Indolepropionic Acid, 1H-Indole-3-propanoic acid, beta-Indole-3-propionic acid, 3-(3-Indolyl)propanoic acid, 3-(3-Indolyl)propionic acid, 3-Indolyl propionic acid). It is a compound closely related to melatonin, but with a much more powerful antioxidant action.
Has been previously proposed as a possible Alzheimer’s disease therapy, after, it is being investigated for other neurodegenerative diseases such HD, Friedreich's Ataxia, ataxia, ..., for its neuroprotective action. As usual, the major efforts are focused in AD, and most scientific "public" information is related to AD.
Curiously, it also has application in gardening, is an auxin (plant hormone), and it is used as a growth roots stimulator . :-)
References:
Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid. Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA. J Biol Chem. 1999
Development of indole-3-propionic acid (OXIGON) for Alzheimer's disease. Bendheim PE, Poeggeler B, Neria E, Ziv V, Pappolla MA, Chain DG. J Mol Neurosci. 2002
Indole-3-propionic acid attenuates neuronal damage and oxidative stress in the ischemic hippocampus. Hwang IK, Yoo KY, Li H, Park OK, Lee CH, Choi JH, Jeong YG, Lee YL, Kim YM, Kwon YG, Won MH. J Neurosci Res. 2009
A novel endogenous indole protects rodent mitochondria and extends rotifer lifespan. Poeggeler B, Sambamurti K, Siedlak SL, Perry G, Smith MA, Pappolla MA. PLoS One. 2010
Melatonin treatment restores mitochondrial function in Alzheimer's mice: a mitochondrial protective role of melatonin membrane receptor signaling. Dragicevic N, Copes N, O'Neal-Moffitt G, Jin J, Buzzeo R, Mamcarz M, Tan J, Cao C, Olcese JM, Arendash GW, Bradshaw PC. J Pineal Res. 2011.
Intellect obtains pharmacokinetic data from OX1 Phase 1b trial for Alzheimer's disease
Intellect Neurosciences Files Orphan Drug Application in the United States for Its Clinical Candidate OX1 for the Treatment of Friedreich's Ataxia
Clinical proof of concept patient trials for OX1 in Friedreich's Ataxia
ViroPharma Licenses Rights From Intellect Neurosciences for Product Candidate for Friedreich's Ataxia
Has been previously proposed as a possible Alzheimer’s disease therapy, after, it is being investigated for other neurodegenerative diseases such HD, Friedreich's Ataxia, ataxia, ..., for its neuroprotective action. As usual, the major efforts are focused in AD, and most scientific "public" information is related to AD.
Curiously, it also has application in gardening, is an auxin (plant hormone), and it is used as a growth roots stimulator . :-)
References:
Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid. Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA. J Biol Chem. 1999
Development of indole-3-propionic acid (OXIGON) for Alzheimer's disease. Bendheim PE, Poeggeler B, Neria E, Ziv V, Pappolla MA, Chain DG. J Mol Neurosci. 2002
Indole-3-propionic acid attenuates neuronal damage and oxidative stress in the ischemic hippocampus. Hwang IK, Yoo KY, Li H, Park OK, Lee CH, Choi JH, Jeong YG, Lee YL, Kim YM, Kwon YG, Won MH. J Neurosci Res. 2009
A novel endogenous indole protects rodent mitochondria and extends rotifer lifespan. Poeggeler B, Sambamurti K, Siedlak SL, Perry G, Smith MA, Pappolla MA. PLoS One. 2010
Melatonin treatment restores mitochondrial function in Alzheimer's mice: a mitochondrial protective role of melatonin membrane receptor signaling. Dragicevic N, Copes N, O'Neal-Moffitt G, Jin J, Buzzeo R, Mamcarz M, Tan J, Cao C, Olcese JM, Arendash GW, Bradshaw PC. J Pineal Res. 2011.
Intellect obtains pharmacokinetic data from OX1 Phase 1b trial for Alzheimer's disease
Intellect Neurosciences Files Orphan Drug Application in the United States for Its Clinical Candidate OX1 for the Treatment of Friedreich's Ataxia
Clinical proof of concept patient trials for OX1 in Friedreich's Ataxia
ViroPharma Licenses Rights From Intellect Neurosciences for Product Candidate for Friedreich's Ataxia
Friday, September 30, 2011
ViroPharma Licenses Rights From Intellect Neurosciences for Product Candidate for Friedreich's Ataxia
EXTON, Pa., Sept. 30, 2011 /PRNewswire via COMTEX/ -- ViroPharma Incorporated (VPHM) today announced the license of worldwide rights from Intellect Neurosciences, Inc. (ILNS) to its clinical stage drug candidate, OX1, being developed for the treatment of Friedreich's Ataxia (FA), a rare, hereditary, progressive neurodegenerative disease. read more ...
Gene therapies advance towards finish line
Nature Reviews Drug Discovery 10, 719-720 (October 2011) | doi:10.1038/nrd3572
Asher Mullard
News and Analysis. Over a decade since gene therapy development came to a near standstill with the death of a clinical trial participant, the field is overcoming issues of immunogenicity, carcinogenicity, manufacturing and small patient populations.....
“I am certain that a gene therapy is going to cross the finish line within the next year or two, in either the United States or the European Union,” says Coté.
Asher Mullard
News and Analysis. Over a decade since gene therapy development came to a near standstill with the death of a clinical trial participant, the field is overcoming issues of immunogenicity, carcinogenicity, manufacturing and small patient populations.....
“I am certain that a gene therapy is going to cross the finish line within the next year or two, in either the United States or the European Union,” says Coté.
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