Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis

This study is currently recruiting participants.
Verified by National Institutes of Health Clinical Center (CC), July 2009
First Received: July 30, 2009

Objective: The goal of this study is to assess the safety, therapeutic efficacy and mechanism of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients

Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Scientists discover why we never forget how to ride a bicycle

PhysOrg.com, July 17th, 2009

Their research, published this month in Nature Neuroscience, has identified a key nerve cell in the brain that controls the formation of memories for motor skills such as riding a bicycle, skiing or eating with chop sticks.

Keywords: cerebellum, brain, co-ordinated movement, molecular layer interneuron, motor skill, brain-computer interfaces, prosthetic devices.

Structural basis for the mechanism of respiratory complex I.

J Biol Chem. 2009 Jul 27.

Berrisford JM, Sazanov LA.

Medical Research Council, United Kingdom.

Keywords: Cellular energy production, human neurodegenerative diseases, frataxin, Fe-S clusters, cysteines, Mitochondrial complex I, reactive oxygen species (ROS), iron-binding sites .

Stress signals link pre-existing sickness with susceptibility to bacterial infection

Bio-Medicine, Date:7/28/2009

Mitochondrial diseases disrupt the power generating machinery within cells and increase a person's susceptibility to bacterial infection, particularly in the lungs or respiratory tract.

The First Cellular Models Based on Frataxin Missense Mutations That Reproduce Spontaneously the Defects Associated with Friedreich Ataxia

Open-access -Creative Commons Attribution License
Full text

PLoS One. 2009; 4(7): e6379.
Published online 2009 July 24. doi: 10.1371/journal.pone.0006379.
The First Cellular Models Based on Frataxin Missense Mutations That Reproduce Spontaneously the Defects Associated with Friedreich Ataxia
Nadège Calmels,#1,4,5 Stéphane Schmucker,#1,4,5 Marie Wattenhofer-Donzé,1,5 Alain Martelli,1,5 Nadège Vaucamps,1 Laurence Reutenauer,1,3 Nadia Messaddeq,1,2 Cécile Bouton,6 Michel Koenig,1,2,3,4,5 and Hélène Puccio1,2,3,4,5*
1IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France
2Inserm, U596, Illkirch, France
3CNRS, UMR7104, Illkirch, France
4Université de Strasbourg, Strasbourg, France
5Collège de France, Chaire de génétique humaine, Illkirch, France
6Institut de Chimie des Substance Naturelles, CNRS, Gif-sur-Yvette, France
Ellen A. A. Nollen, Editor
University Medical Center Groningen, Netherlands
#Contributed equally.
* E-mail:hpuccio@igbmc.fr

Conceived and designed the experiments: NC SS HMP. Performed the experiments: NC SS MWD AM NV LR NM CB. Analyzed the data: NC SS HMP. Wrote the paper: NC SS AM MK HMP.
Received May 11, 2009; Accepted June 25, 2009.

ABSTRACT

Background
Friedreich ataxia (FRDA), the most common form of recessive ataxia, is due to reduced levels of frataxin, a highly conserved mitochondrial iron-chaperone involved in iron-sulfur cluster (ISC) biogenesis. Most patients are homozygous for a (GAA)n expansion within the first intron of the frataxin gene. A few patients, either with typical or atypical clinical presentation, are compound heterozygous for the GAA expansion and a micromutation.
Methodology
We have developed a new strategy to generate murine cellular models for FRDA: cell lines carrying a frataxin conditional allele were used in combination with an EGFP-Cre recombinase to create murine cellular models depleted for endogenous frataxin and expressing missense-mutated human frataxin. We showed that complete absence of murine frataxin in fibroblasts inhibits cell division and leads to cell death. This lethal phenotype was rescued through transgenic expression of human wild type as well as mutant (hFXNG130V and hFXNI154F) frataxin. Interestingly, cells expressing the mutated frataxin presented a FRDA-like biochemical phenotype. Though both mutations affected mitochondrial ISC enzymes activities and mitochondria ultrastructure, the hFXNI154F mutant presented a more severe phenotype with affected cytosolic and nuclear ISC enzyme activities, mitochondrial iron accumulation and an increased sensitivity to oxidative stress. The differential phenotype correlates with disease severity observed in FRDA patients.
Conclusions
These new cellular models, which are the first to spontaneously reproduce all the biochemical phenotypes associated with FRDA, are important tools to gain new insights into the in vivo consequences of pathological missense mutations as well as for large-scale pharmacological screening aimed at compensating frataxin deficiency.

Human ISD11 is essential for both iron–sulfur cluster assembly and maintenance of normal cellular iron homeostasis

Human Molecular Genetics Advance Access originally published online on May 18, 2009
Human Molecular Genetics 2009 18(16):3014-3025; doi:10.1093/hmg/ddp239
Published by Oxford University Press 2009

Yanbo Shi, Manik C. Ghosh, Wing-Hang Tong and Tracey A. Rouault^*

National Institute of Child Health and Human Development, Molecular Medicine Program, Bethesda, MD 20892, USA

^* To whom correspondence should be addressed. Tel: +1 301 496 6368; Fax: +1 301 402 0078; Email: trou@helix.nih.gov

Keywords: iron–sulfur (Fe–S) cluster biogenesis, Saccharomyces cerevisiae, cysteine desulfurase (ISCS), mitochondrial compartment, inactivated mitochondrial and cytosolic aconitases, iron regulatory protein 1, iron regulatory protein 2, punctate ferric iron accumulations in cells, iron homeostasis.

Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease (FAIR-PARK-I)

Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease (FAIR-PARK-I)
This study is not yet open for participant recruitment.
Verified by University Hospital, Lille, July 2009
First Received: July 20, 2009 Last Updated: July 21, 2009 History of Changes
Sponsored by:
University Hospital, Lille
Information provided by:
University Hospital, Lille
ClinicalTrials.gov Identifier:
NCT00943748

Transplanted Neurons Develop Disease-like Pathology In Huntington's Patients

ScienceDaily (July 20, 2009) — The results of a recent study published in the Proceedings of the National Academy of Sciences question the long-term effects of transplanted cells in the brains of patients suffering from Huntington's disease.

Other source: http://www.eurekalert.org/pub_releases/2009-07/ul-tnd071609.php

Original work which explains the test:

Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology

Thomas B. Freeman,^abcde Francesca Cicchetti,^df Robert A. Hauser,^bcg Terrence W. Deacon,^f Xiao-Jiang Li,^h Steven M. Hersch,ⁱ G. Michael Nauert,^j Paul R. Sanberg,^abc Jeffrey H. Kordower,^k Samuel Saporta,^acl and Ole Isacson^ef

^aDepartment of Neurosurgery,^bDepartment of Pharmacology and Experimental Therapeutics, and, ^cThe Neuroscience Program, University of South Florida, Tampa, FL 33606; Departments of, ^gNeurology and, ^lAnatomy,^jWomen's Center, Tampa, FL 33606;^kDepartment of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, IL 60612;^fNeuroregeneration Laboratory, McLean Hospital/MGH, Harvard Medical School, Belmont, MA 62478; and Departments of, ^hGenetics and, ⁱNeurology, Emory University, Atlanta, GA 30322

^dT.B.F. and F.C. contributed equally to this work.

^eTo whom reprint requests should be addressed: T.B.F. (phone: 813-259-0889; fax: 813-259-0944; E-mail: tfreeman@com1.med.usf.edu) or O.I. (E-mail: isacson@helix.mgh.harvard.edu).

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 12, 2000

Received July 13, 2000.

Penwest Announces Results of Phase Ib Trial of A0001

GlobeNewswire
Source: Penwest Pharmaceuticals Co.

In the Phase Ib trial, the drug was well tolerated by subjects, and no serious adverse events were reported. There was a dose-dependent increase in exposure approaching steady state within 2-4 days following repeat-dosing, and a maximum tolerated dose was established.

Plans to Advance A0001 Into Phase IIa Trials in Patients in Second Half of 2009

http://www.penw.com/

http://health.groups.yahoo.com/group/FA_babelFAmily/message/3058

UA Professors receive over $1.45 million in grants

Money to fund researching neurological diseases
The Crimson White, Published: Thursday, July 16, 2009
.../...
While they are researching different topics, both professors are focusing on certain proteins found in the body and their roles in neurological diseases. Busenlehner’s research focuses on a neurodegenerative disease called Friedreich’s ataxia, which is caused by decreased levels of the protein frataxin.
“What we are wanting to know is what is the exact function of this protein, frataxin, in the human body,” Busenlehner said.
.../...

Huntington's: Researchers Gain Insight Into Mechanism Underlying The Disease

Medical News Today , Article Date: 15 Jul 2009 - 0:00 PDT

Researchers at the University of Kentucky Markey Cancer Center and Graduate Center for Toxicology (GCT) have gained new insight into the genetic mechanisms underlying Huntington's disease and other neurodegenerative or neuromuscular disorders caused by trinucleotide repeats (or TNRs) in DNA.



This newspaper article is based on this research: http://friedreichscientificnews.blogspot.com/2009/07/incision-dependent-and-error-free.html

Incision-dependent and error-free repair of (CAG)(n)/(CTG)(n) hairpins in human cell extracts

Nat Struct Mol Biol. 2009 Jul 13

Hou C, Chan NL, Gu L, Li GM.
Graduate Center for Toxicology and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA.

Keywords: Expansion of CAG/CTG trinucleotide repeats, neurological disorders, Huntington's disease, proliferating cell nuclear antigen (PCNA), endonuclease activities, trinucleotide repeat instability.

[Diseases caused by triplet expansion.]

Rev Neurol. 2009 Jul 16-31;49(2):79-87

[Article in Spanish]
Rosales-Reynoso MA, Ochoa-Hernandez AB, Barros-Nunez P.
Centro de Investigacion Biomedica de Occidente IMSS (CIBO), Guadalajara, Mexico

Keywords: expansion of nucleotide triplets, meiosis, mitosis, CGG/ GCC, CAG/GTC, CTG/GAC, GAA/CTT, bulbospinal muscular atrophy, Huntington's diseas, spinocerebellar ataxias, fragile X syndrome, Friedreich's ataxia, myotonic dystrophy, cis-acting, trans-acting, pre-mutations, dynamic mutation processes.

Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of Cisplatin-induced neuropathy

OPEN ACCES

Min-Suk Yoon , Zaza Katsarava , Mark Obermann , Maria Schaefers , Bernd Liedert , Anna Dzagnidze , Andreas Kribben , Rupert Egensperger , Volker Limmroth , Hans Christoph-Diener and Juergen Thomale
BMC Neuroscience 2009, 10:77doi:10.1186/1471-2202-10-77
Published:
15 July 2009
Abstract (provisional)
Background
Cisplatin mediates its antineoplastic activity by formation of distinct DNA intrastrand cross links. The clinical efficacy and desirable dose escalations of cisplatin are restricted by the accumulation of DNA lesions in dorsal root ganglion (DRG) cells leading to sensory polyneuropathy (PNP). We investigated in a mouse model by which mechanism recombinant erythropoietin (rhEPO) protects the peripheral nervous system from structural and functional damage caused by cisplatin treatment with special emphasis on DNA damage burden.
Results
A cumulative dose of 16 mg cisplatin/kg resulted in clear electrophysiological signs of neuropathy, which were significantly attenuated by concomitant erythropoietin (cisplatin 32,48 m/s +/- 1,68 m/s; cisplatin + rhEPO 49,66 m/s +/- 1,26 m/s; control 55,01 m/s +/- 1,88 m/s; p < 0,001). The co-application of rhEPO, however, did not alter the level of unrepaired cisplatin-DNA lesions accumulating in DRG target cells. Micro-morphological analyses of the sciatic nerve from cisplatin-exposed mice showed damaged myelin sheaths and mitochondria. Co-administered rhEPO inhibited myelin sheaths from structural injuries and resulted in an increased number of intact mitochondria.
Conclusion
The protective effect of recombinant erythropoietin is not mediated by reducing the burden of DNA platination in the target cells, but it is likely to be due to a higher resistance of the target cells to the adverse effect of DNA damage. The increased frequency of intact mitochondria might also contribute to this protective role.

Full text: http://www.biomedcentral.com/content/pdf/1471-2202-10-77.pdf

Abnormal Left Atrial Contraction in Friedreich Ataxia—Relation with Both Alleles of the FXN Gene

Heart, Lung and Circulation
Volume 18, Supplement 3, 2009, Page S15
Abstracts for the Cardiac Society of Australia and New Zealand Annual Scientific Meeting and the International Society for Heart Research, Australasian Section, Annual Scientific Meeting

R.E. Peverill^1, , L. Donelan¹, J.S. Gelman¹, P.M. Mottram¹, L.A. Corben² and M.B. Delatycki²

¹Monash Cardiovascular Research Centre, MonashHEART and Monash University Department of Medicine (MMC), Australia

²Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia

The role of PGC-1{alpha} on mitochondrial function and apoptotic susceptibility in muscle

Peter J. Adhihetty,² Giulia Uguccioni,^1,3 Lotte Leick,⁴ Juan Hidalgo,⁵ Henriette Pilegaard,⁴ and David A. Hood^1,2,3

¹School of Kinesiology and Health Science, ²Department of Biology, and ³The Muscle Health Research Centre, York University, Toronto, Ontario, Canada; ⁴Copenhagen Muscle Research Centre and Centre of Inflammation and Metabolism, Department of Biology, University of Copenhagen, Denmark, and ⁵Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Autonomous University of Barcelona, Barcelona, Spain

Submitted 12 February 2009 ; accepted in final form 5 May 2009

Keywords: endurance training; exercise; mitochondrial biogenesis; reactive oxygen species, cytochrome-c oxidase activity, brain, liver, pancreas.

Mitochondrial Dysfunction Leads to Nuclear Genome Instability via an Iron-Sulfur Cluster Defect

Joshua R. Veatch1, 2, Michael A. McMurray1, 2, 3, Zara W. Nelson1 and Daniel E. Gottschling1, ,
1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA
2The Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA
3Present address: Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA
Received 14 September 2008; revised 30 January 2009; accepted 1 April 2009. Published: June 25, 2009. Available online 25 June 2009

Keywords; nuclear genome, genome instability, mitochondrial membrane potential, iron-sulfur cluster. a



Friedreich's Ataxia - Frataxin

Large-Scale Expansions of Friedreich's Ataxia GAA Repeats in Yeast

MolecularCell, Volume 35, Issue 1, 10 July 2009, Pages 82-92

Alexander A. Shishkin1, Irina Voineagu1, Robert Matera1, Nicole Cherng1, Brook T. Chernet1, Maria M. Krasilnikova2, Vidhya Narayanan3, Kirill S. Lobachev3 and Sergei M. Mirkin1, ,
1Department of Biology, Tufts University, Medford, MA 02155, USA
2Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
3School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
Received 22 August 2008; revised 7 January 2009; accepted 18 June 2009. Published: July 9, 2009. Available online 9 July 2009.

Keywords: DNA repeats , GAA repeats, Friedreich's ataxia, chimeric URA3 gene, rates of expansions of GAA repeats.

Of yeast and men: Unraveling the molecular mechanisms of Friedreich's ataxia

Public release date: 9-Jul-2009

EurekAlert¡

This news is in reference to this work: Large-Scale Expansions of Friedreich's Ataxia GAA Repeats in Yeast

Genome-wide analysis of interactions between ATP-dependent chromatin remodeling and histone modifications

OPEN ACCES

Zhiming Dai , Xianhua Dai , Qian Xiang , Jihua Feng , Jiang Wang , Yangyang Deng and Caisheng He
BMC Genomics 2009, 10:304doi:10.1186/1471-2164-10-304
Published: 8 July 2009

Background
ATP-dependent chromatin remodeling and the covalent modification of histones play central roles in determining chromatin structure and function. Although several specific interactions between these two activities have been elaborated, the global landscape remains to be elucidated.
Results
In this paper, we have developed a computational method to generate the first genome-wide landscape of interactions between ATP-dependent chromatin remodeling and the covalent modification of histones in Saccharomyces cerevisiae. Our method succeeds in identifying known interactions and uncovers many previously unknown interactions between these two activities. Analysis of the genome-wide picture revealed that transcription-related modifications tend to interact with more chromatin remodelers. Our results also demonstrate that most chromatin remodeling-modification interactions act via interactions of remodelers with both histone-modifying enzymes and histone residues. We also found that the co-occurrence of both modification and remodeling has significantly different influences on multiple gene features (e.g. nucleosome occupancy) compared with the presence of either one.
Conclusions
We gave the first genome-wide picture of ATP-dependent chromatin remodeling-histone modification interactions. We also revealed how these two activities work together to regulate chromatin structure and function. Our results suggest that distinct strategies for regulating chromatin activity are selectively employed by genes with different properties.

Full text: http://www.biomedcentral.com/content/pdf/1471-2164-10-304.pdf

[Peridural anaesthesia with ropivacaine for a patient with Friedrich's ataxia : Caesarean section after dorsal stabilisation of the spinal column (Th5

Anaesthesist. 2009 Jul 3

Hanusch P, Heyn J, Well H, Weninger E, Hasbargen U, Rehm M.

Klinik für Anästhesiologie und Intensivmedizin, Klinikum der Universität München, Marchioninistr. 15, 81377, München, Deutsc

Keywords: Friedreich's ataxia, increased sensitivity to muscle relaxants, special care during anaesthesia, peridural anaesthesia, ropivacaine, sufentanil, muscle weakness, scoliosis, cardiomyopathy, impaired glucose tolerance.

Novel swing-assist un-motorized exoskeletons for gait training

Kalyan Mankala , Sai Banala and Sunil Agrawal

Journal of NeuroEngineering and Rehabilitation 2009, 6:24doi:10.1186/1743-0003-6-24

Published:	3 July 2009

Abstract (provisional)

Robotics is emerging as a promising tool for functional training of human movement. Much of the research in this area over the last decade has focused on upper extremity orthotic devices. Some recent commercial designs proposed for the lower extremity are powered and expensive - hence, these are unaffordable by most clinics. In this paper, we present a novel un-motorized bilateral exoskeleton that can be used to assist in treadmill training of motor-impaired patients, such as with motor-incomplete spinal cord injury. The exoskeleton is designed such that the human leg will have a desirable swing motion, once it is strapped to the exoskeleton. Since this exoskeleton is un-motorized, it can be produced cheaply and also will have the potential to reduce the physical demand on therapists during treadmill training. The salient features of this swing-assist exoskeleton are: (i) The design uses torsional springs at the hip and the knee joints to assist the swing motion. The springs get charged by the treadmill during stance phase of the leg and provide propulsion forces to the leg during swing. (ii) The design of the exoskeleton uses simple dynamic models of sagittal plane walking, which are used to optimize the parameters of the springs so that the foot can clear the ground and have a desirable forward motion during walking. (iii) This design approach was used to construct a bilateral exoskeleton and was tested during treadmill walking for a range of walking speeds between 1.0 mph and 4.0 mph. Joint encoders and interface force-torque sensors mounted on the exoskeleton were used to evaluate the effectiveness of the exoskeleton in terms of the hip and knee joint torques applied by the human during treadmill walking.

Full text: provisional PDF

Ataxia with vitamin E deficiency in southeast Norway, case report.

Koht J, Bjørnarå KA, Jørum E, Tallaksen CM.
Faculty of Medicine, University of Oslo, Oslo, Norway.

Keywords: AVED, Friedreich's ataxia, Frataxin gene, unknown prevalence, Norway, preschool age, neurological examination, re-evaluation, re-examination, neuropathy. Vitamin E, heterozygous mutation, p.A120T, p.R134X, alpha-tocopherol transport protein gene, chromosome 8q13, treatment available,