Evaluation of Myocardial Motion in Friedreich Ataxia Patients and Healthy Volunteers by High Temporal and Spatial Resolution MRI Tissue Phase-mapping Imaging

RSNA Meeting, November 25-30, McCormick Place, Chicago, Illinois
Scientific Informal (Poster) Presentations

Author List: Karsten Kortuem | Christian Oliver Ritter MD | Frank Weidemann | Herbert Koestler PhD | Dietbert Hahn MD | Meinrad Johannes Beer MD

Oligomerization propensity and flexibility of yeast frataxin studied by X-ray crystallography and small-angle X-ray scattering

Journal of Molecular Biology, In Press, Accepted Manuscript, doi:10.1016/j.jmb.2011.10.034

Christopher A.G. Söderberg a, [1], Alexander V. Shkumatov b, 2, Sreekanth Rajan a, Oleksandr Gakh c, Dmitri I. Svergun b, Grazia Isaya c,, Salam Al-Karadaghi a.
a Center for Molecular Protein Science, Institute for Chemistry and Chemical Engineering, Lund University, PO Box 124, SE-221 00 Lund, Sweden
b EMBL, Hamburg Outstation, Notkestraße 85, D-22603 Hamburg, Germany
c Department of Pediatric and Adolescent Medicine and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA

Keywords: Protein oligomerization; Protein flexibility; metal chaperone; Friedreich's ataxia; Neurodegenerative diseases

The cerebellar cognitive profile

Brain (2011) first published online October 27, 2011 doi:10.1093/brain/awr266

Anna M. Tedesco, Francesca R. Chiricozzi, Silvia Clausi, Michela Lupo, Marco Molinari, and Maria G. Leggio

Keywords: cerebellar role in non-motor functions, cerebellar cognitive affective syndrome, cerebellar damage, ataxia, cerebellum, cognition.

Pioglitazone and bladder cancer

In France, is currently running Friedreich's Ataxia clinical trial with Pioglitazone

The Lancet, Volume 378, Issue 9802, Pages 1543 - 1544, 29 October 2011

Dominique Hillaire-Buys a bEmail Address, Jean-Luc Faillie b c, Jean-Louis Montastruc d e

a CHRU Montpellier, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital, 34295 Montpellier, France
b Faculty of Medicine, University of Montpellier 1, Montpellier, France
c CHU Nîmes, Department of Epidemiology and Clinical Research, Nîmes University Hospital, Nîmes, France
d CHRU Toulouse, Department of Clinical Pharmacology, Toulouse University Hospital, Toulouse, France
e Department of Pharmacoepidemiology INSERM U1027, Faculty of Medicine, University of Toulouse, Toulouse, France

Keywords: Pioglitazone, peroxisome-proliferator-activated receptor (PPAR)agonist, oral hypoglycaemic drug, bladder cancer, US Food and Drug Administration (FDA), FDA Adverse Event Reporting System, European Medicines Agency.

Pioglitazone and bladder cancer

The Lancet, Volume 378, Issue 9802, Page 1544, 29 October 2011, doi:10.1016/S0140-6736(11)61663-2

Robert Elford Ryder
Department of Diabetes and Endocrinology, City Hospital, Birmingham B18 7QH, UK

Keywords: French and German regulatory bodies, risk of bladder cancer, European Medicines Agency (EMA), increased fractures, heart failure, type 2 diabetes, cardiovascular benefit.

"Despite the EMA's conclusion over bladder cancer risk, the overall risk—benefit balance remains strongly in favour of continued use of pioglitazone, especially in patients with ischaemic heart disease (but without heart failure) or stroke"

Pioglitazone and bladder cancer — Authors' reply

Erland Erdmann a, John A Dormandy b, Massimo Massi-Benedetti c, Robert Spanheimer

­Genes en lugar de fármacos

Interesting TV report on gene therapy (Spanish language)

Hidden Administration of Drugs

Clinical Pharmacology & Therapeutics 90, 651-661 (November 2011) | doi:10.1038/clpt.2011.206

F Benedetti, E Carlino and A Pollo

Keywords: placebo-controlled trials, dummy treatment (placebo), psychological component, psychology and pharmacodynamics.

An unusual atrial tachycardia in a patient with Friedreich ataxia

Europace (2011) 13 (11): 1660-1661. doi: 10.1093/europace/eur156

Justin M.S. Lee1,*, Ian Turner1, Ajit Agarwal2 and Simon P. Fynn1
1Department of Cardiology, Papworth Hospital, Cambridge CB23 3RE, UK
2Department of Cardiology, West Suffolk Hospital, Bury St Edmunds, IP33 2QZ, UK

Keywords: atrial tachycardia, Friedreich ataxia, arrhythmi, linear ablation.

Anaesthesia for a patient with Friedreich's ataxia.

Indian J Anaesth. 2011 Jul;55(4):418-20.

Ganesan I.

Department of Anaesthesiology, SRM Medical College Hospital and Research Centre, Chennai, Tamil Nadu, India.

NO ABSTRAC

Inactivation of mitochondrial aspartate aminotransferase contributes to the respiratory deficit of yeast frataxin-deficient cells

Biochem. J. (2011) Immediate Publication, doi:10.1042/BJ20111574
Dominika Sliwa, Julien Dairou, Jean-Michel Camadro and Renata Santos
Institut Jacques Monod, Paris, France

Keywords: Friedreich ataxia, frataxin, iron homeostasis, hypersensitivity to oxidants, NAD+ and NADH, malate-aspartate NADH shuttle, mitochondrial aspartate aminotransferase (Aat1), mitochondrial acetylated proteins, post-translational modification.

FULL TEXT PDF

Physiological oxygen level is critical for modeling neuronal metabolism in vitro

Zhu, J., Aja, S., Kim, E.-K., Park, M. J., Ramamurthy, S., Jia, J., Hu, X., Geng, P. and Ronnett, G. V. (2011), Journal of Neuroscience Research. doi: 10.1002/jnr.22765

KEYWORDS: In vitro models, nonphysiological conditions, ambient (21%) oxygen levels, physiological oxygen level (5% O2), glucose uptake, glycolysis, glucose oxidation , fatty acid oxidation, AMPK activity, intracellular ATP level,

"Oxygen level is an important parameter to consider when modeling neuronal responses to stress in vitro".

Un score pour évaluer la stabilité au cours de la marche : méthodologie et validation chez le patient atteint d’ataxie de Friedreich

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

FULL TEXT PDF

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

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

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

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.

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.

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