(WO/2010/083327) MEASURING LEVELS OF FRATAXIN

PATENT, WO/2010/083327, PCT/US2010/021067

MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH (US), OGLESBEE, Devin; (US),
MATERN, Dietrich; (US), ISAYA, Grazia; (US).

A method for assessing levels of a frataxin polypeptide in a mammal.

This document relates to methods and materials involved in measuring levels of a frataxin polypeptide present in a biological sample. For example, methods and materials related to the use of anti-frataxin antibody-bound microspheres and biotinylated anti-frataxin antibodies to measure the levels of a frataxin polypeptide in a biological sample from a mammal (e.g., a newborn human) are provided.

Co-precipitation of phosphate and iron limits mitochondrial phosphate availability in Saccharomyces cerevisiae lacking the yeast frataxin homologue (YFH1)

J. Biol. Chem. jbc.M110.163253First Published on December 28, 2010, doi:10.1074/jbc.M110.163253

Alexandra Seguin, Renata Santos, Debkumar Pain, Andrew Dancis, Jean-Michel Camadro, Emmanuel Lesuisse

Institut Jacques Monod, France; University of Medicine and Dentistry of New Jersey, United States; University of Pennsylvania, United States

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Enfermedad cardiovascular en pacientes cubanos afectados por Ataxia de Friedreich.

Cardiovascular disease in Cuban patients affected by Friedreich's ataxia. (full text in Spanish)

Revista Electrónica "Ciencias Holguín", Año XVI, No. 4, Mes Diciembre 2010, ISSN 1027-2127.

Dra. Tania Cruz Mariño. Dra. Ana Luz Portelles Caminero. Dr. William Áreas Zalazar. Dr. Luis Velázquez Pérez.

ABSTRACT

In describing the Friedreich's ataxia, Nicholaus referred to cardiac disease. This autosomal recessive disease is due to dynamic mutation in the FRDA gene, encoding the protein frataxin deficiency, leading to oxidative stress and cardiac cell death. This research was conducted in order to describe the cardiovascular abnormalities present in Cuban patients affected by Friedreich's ataxia. Individuals with confirmatory molecular diagnosis of the disease underwent electrocardiogram, echocardiogram, and clinical assessment by internationally validated scales: ICARS and SARA. Ventricular re-polarization disorders diffuse intra-atrial conduction disturbances and disorders of diastolic function were common findings. The restrictive pattern appreciated provides live evidence that the disease leads to left ventricular diastolic dysfunction. The occurrence of a silent acute myocardial infarction indicates the importance of identifying emerging forms of myocardial involvement.

KEY WORDS: FRIEDREICH'S ATAXIA; HEREDITARY ATAXIA; CARDIOMYOPATHY; MYOCARDIAL INFARCTION.

Generation of Induced Pluripotent Stem Cell Lines from Friedreich Ataxia Patients.

Stem Cell Rev. 2010 Dec 22.

Liu J, Verma PJ, Evans-Galea MV, Delatycki MB, Michalska A, Leung J, Crombie D, Sarsero JP, Williamson R, Dottori M, Pébay A.

Centre for Reproduction and Development, Monash Institute of Medical Research, Monash University, Melbourne, Australia,

Keywords: Friedreich ataxia (FRDA), neurodegeneration, cardiomyopathy, trinucleotide (GAA) repeat expansion, FXN gene, frataxin, induced pluripotent stem (iPS) cell lines, skin fibroblasts, pluripotent, peripheral neurons, cardiomyocytes, models, human BAC, immunocompatible cells, transplantation therapy.

PREIMPLANTATION GENETIC DIAGNOSIS (PGD)

Important Info: Although it is a private center information, explains very well the technique, in layman's language ,I do not try in any way publicize the medical center.

PREIMPLANTATION GENETIC DIAGNOSIS (PGD) Patient Information

Some couples are at risk of transmitting an inherited disease to their children. One of the couple may be affected by this disease, or they each may carry a mutation, which if both were inherited by a child would cause the disease. Preimplantation genetic diagnosis (PGD) is a way of detecting a specific disease-causing genetic mutation within an embryo before it is transferred to the womb and forms a pregnancy.

Rare diseases, orphan drugs and their regulation: questions and misconceptions

Nature Reviews Drug Discovery 9, 921-929 (December 2010) | doi:10.1038/nrd3275

Erik Tambuyzer

Sustained advocacy efforts driven by patients' organizations to make rare diseases a health priority have led to regulatory and economic incentives for .....

Iron-dependent functions of mitochondria-relation to neurodegeneration.

J Neural Transm. 2010 Dec 15.
Gille G, Reichmann H.
Klinik und Poliklinik für Neurologie, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany

Keywords: neurodegenerative diseases, iron dyshomeostasis, mitochondrial dysfunction, physiological role of iron in mitochondria, Friedreich ataxia (FRDA),idiopathic Parkinson disease (PD), respiratory chain, iron-sulphur clusters, cytochromes, aconitase, frataxin gene, frataxin, reactive oxygen species.

Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome.

Eur Heart J. 2010 Dec 14. [Epub ahead of print]

Raman SV, Phatak K, Hoyle JC, Pennell ML, McCarthy B, Tran T, Prior TW, Olesik JW, Lutton A, Rankin C, Kissel JT, Al-Dahhak R.
The Ohio State University, 473 W. 12th Ave, Suite 200, Columbus, OH 43210, USA.

Keywords: Cardiomyopathy, Friedreich ataxia (FA), fibrosis, cardiac magnetic resonance with adenosine, precontrast imaging, myocardial iron estimation, myocardial perfusion reserve index (MPRI), left ventricular (LV) mass, left ventricular ejection fraction.

Connecting Variability in Global Transcription Rate to Mitochondrial Variability

PLOS Biology, Dec 14, 2010 (publication date)

Ricardo Pires das Neves1,2,3, Nick S. Jones4, Lorena Andreu1, Rajeev Gupta1, Tariq Enver1, Francisco J. Iborra1,5*

1 Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom, 2 Biocant Center of Innovation and Biotechnology, Cantanhede, Portugal, 3 Center for Neuroscience and Cell Biology University of Coimbra, Coimbra, Portugal, 4 Department of Physics and Biochemistry, Oxford Centre for Integrative Systems Biology, CABDyN Complexity Centre, Oxford, United Kingdom, 5 Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain

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A Decrementing Form of Plasticity Apparent in Cerebellar Learning

The Journal of Neuroscience, December 15, 2010, 30(50):16993-17003; doi:10.1523/JNEUROSCI.2455-10.2010

Tatsuya Ohyama,1 Horatiu Voicu,3 Brian Kalmbach,1 and Michael D. Mauk1,2

1Center for Learning and Memory and 2Section of Neurobiology, The University of Texas at Austin, Austin, Texas 78712-0805, and 3Department of Neurobiology and Anatomy, The University of Texas-Houston Health Science Center, Houston, Texas 77030

" These results demonstrate the utility of eyelid conditioning as a means to identify and characterize the rules that govern input to output transformations in the cerebellum."

The value of Arabidopsis research in understanding human disease states.

Curr Opin Biotechnol. 2010 Dec 6.

Xu XM, Møller SG.
Centre for Organelle Research, Faculty of Science and Technology, University of Stavanger, Norway.

Keywords: Arabidopsis thaliana, understand molecular mechanisms, human disease, neurodegenerative disorders, Alzheimer's, Parkinson's, Friedreich Ataxia.

Blood cells from Friedreich ataxia patients harbor frataxin deficiency without a loss of mitochondrial function

Mitochondrion, Article in Press, Accepted Manuscript, doi:10.1016/j.mito.2010.12.003

Mary A. Selak a, Elise Lyver b, Elizabeth Micklow b, Eric C. Deutsch c, Ozlem Onder d, Nur Selamoglu d, Claire Yager a, Simon Knight b, Martin Carroll b, Fevzi Daldal d, Andrew Dancis b, David R. Lynch c and Jean-Emmanuel Sarry b,

a Children's Hospital of Philadelphia Research Institute, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA
b Division of Hematology/Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
c Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, and Children's Hospital of Philadelphia, Philadelphia, PA, USA
d Department of Biology, University of Pennsylvania, Philadelphia, PA, USA

KEYWORDS: Friedreich ataxia (FRDA), frataxin, neurons, cardiomyocytes, platelets, peripheral blood mononuclear cells, mitochondria, biomarkers.

Restless legs syndrome in Friedreich ataxia: A polysomnographic study

Movement Disorders, n/a. doi: 10.1002/mds.22769 (Early View (Articles online in advance of print)
Frauscher, B., Hering, S., Högl, B., Gschliesser, V., Ulmer, H., Poewe, W. and Boesch, S. M.

Keywords: sleep disturbance, restless legs syndrome, Friedreich ataxia, Frataxin, ferritin, periodic leg movements, polysomnography.

US reviews human trial participant protections

The Lancet, Volume 376, Issue 9757, Pages 1975 - 1976, 11 December 2010, doi:10.1016/S0140-6736(10)62247-7

Nellie Bristol

Commission Chair Amy Gutmann, President of the University of Pennsylvania stated. “We have an ethical obligation to protect the health and well-being of all research participants.”

Electrophysiology of Respiratory Chain Complexes and the ADP-ATP Exchanger in Native Mitochondrial Membranes.

Biochemistry. 2010 Dec 7;49(48):10308-18. Epub 2010 Nov 11.

Watzke N, Diekert K, Obrdlik P.
IonGate Biosciences GmbH, Industriepark Hoechst, D528, 65926 Frankfurt am Main, Germany.

Keywords: mitochondrial membranes, proton-pumping respiratory chain complexes, mitochondrial secondary active solute transport proteins, solid-supported membrane (SSM) technology, respiratory chain complexes CI, CII, CIII, and CIV, the F(O)F(1)-ATPase/synthase (CV), the adenine nucleotide translocase (ANT), oxidative phosphorylation (OXPHOS), uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), IC(50), Coenzyme Q (CoQ), decylubiquinone (DBQ), idebenone (Ide).

Axial diffusivity is increased in the degenerating superior cerebellar peduncles of Friedreich's ataxia.

Neuroradiology. 2010 Dec 3. [Epub ahead of print]

Della Nave R, Ginestroni A, Diciotti S, Salvatore E, Soricelli A, Mascalchi M., S. Giuseppe Hospital, Radiodiagnostic Section, Empoli, Italy.

Keywords: Decreased fractional anisotropy (FA), diffusion tensor MR imaging (DTI), white matter (WM), radial diffusivity, axial diffusivity, Friedreich's ataxia (FRDA), selective neuronal loss, dentate nuclei, cerebellar peduncles (SCPs), TBSS analysis.

Large-scale in silico modeling of metabolic interactions between cell types in the human brain

Nature Biotechnology, Year published:(2010), DOI: doi:10.1038/nbt.1711

Nathan E Lewis, Gunnar Schramm, Aarash Bordbar, Jan Schellenberger, Michael P Andersen, Jeffrey K Cheng, Nilam Patel, Alex Yee, Randall A Lewis, Roland Eils, Rainer König, Bernhard Ø Palsson.

Keywords: Metabolic interactions, gene expression data, proteomics data, literature-based manual curation, model human metabolism, metabolites, interstitial fluid, models of brain energy metabolism, astrocytes, Alzheimer's disease, regions of the brain.

Simplest explanation: Metabolism Models May Explain Why Alzheimer's Disease Kills Some Neuron Types First (ScienceDaily (Dec. 6, 2010)

Taking the lottery out of gene therapy

NEW SCIENTIST HEALTH ,Magazine issue 2789

GENE therapy should become a more exact science thanks to the discovery that it is possible to predict where a transferred gene is likely to be inserted into the recipient's DNA.

"Peter Cherepanov at Imperial College London, who was not part of the team, says now that the probability of an undesirable insertion can be estimated, it will become easier to balance the chance of success with the risk of side effects."

ORIGINAL PAPER: Deciphering the Code for Retroviral Integration Target Site Selection

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Catalysis and Mechanistic Insights into Sirtuin Activation.

Chembiochem. 2010 Nov 9. [Epub ahead of print]

 Dittenhafer-Reed KE, Feldman JL, Denu JM.

Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison.

Keywords:  SIRT1, resveratrol,  SRT1720, mechanism by which they activate remains poorly defined,  type II diabetes, neurodegeneration, diseases associated with aging.

Repeat expansion affects both transcription initiation and elongation in friedreich ataxia cells

J Biol Chem. 2010 Dec 2. [Epub ahead of print]

Kumari D, Biacsi RE, Usdin K., NIH, United States.

Keywords: Expansion of a GAA·TTC-repeat, first intron, frataxin (FXN) gene, mRNA deficit, Friedreich ataxia (FRDA), DNA methylation, histone modifications, chromatin immuno-precipitation, chromatin, RNA polymerase II, histone H3 trimethylated on lysine 4, trimethylated H3K36.

Accelerating orphan drug development

Nature Reviews Drug Discovery 9, 901-902 (December 2010) | doi:10.1038/nrd3340

Timothy R. Coté, Kui Xu & Anne R. Pariser

"Given the limited resources available for rare disease R&D, it is imperative that all knowledge gained is used to maximum benefit at each phase.
The FDA is committed to accelerating orphan drug development through a regulatory system built on integrity, consistency and transparency; a system that has delivered benefits to people who desperately need them and promises to deliver much more."

The Neuropathology of Late-Onset Friedreich's Ataxia.

Cerebellum. 2010 Dec 4. [Epub ahead of print]

Koeppen AH, Morral JA, McComb RD, Feustel PJ.
Research Service (151), VA Medical Center, 113 Holland Ave, Albany, NY, 12208, USA.

Keywords: Friedreich's ataxia (FRDA), very young persons, routine laboratory test, cardiomyopathy, late-onset, neurological disability, dorsal root ganglia, atrophy of the dentate nucleus, Frataxin levels.

Mitochondrial Fe-S cluster biogenesis, frataxin and the modulation of susceptibility to drug-induced cardiomyopathy

Aging (Albany NY). 2010 Nov 27.
Michael N. Sack
NHLBI Center for Molecular Medicine, National Institutes of Health, Bethesda, MD 20892, USA
Commentary on: Schulz et al. Activation of mitochondrial energy metabolism protects against cardiac failure. Aging 2010; 2: this issue

OPEN ACCESS

An intriguing new finding, by Shultz et al is published in AGING regarding the induction of frataxin. Mutations in frataxin result in the development of Friedreich's Ataxia, an inherited neurodegenerative disease associated with the development of severe cardiomyopathy. Frataxin, itself is involved in mitochondrial iron-sulphur cluster biogenesis which functions, in part, to incorporate appropriate amounts of iron into mitochondrial proteins including aconitase and succinate dehydrogenase [13]. Whether frataxin functions as an iron-chaperone protein or plays a regulatory role in controlling iron and sulphur flux within mitochondria is not yet completely characterized. Nevertheless, the study by Shultz and colleagues [14] shows that increased cardiac frataxin enhances tricarboxylic acid cycle function resulting in increased cardiac ATP, NADH, NADPH and reduced glutathione levels. This array of features is consistent with an enhanced bioenergetic capacity and increased antioxidant defenses. The authors go on to demonstrate that overexpression of frataxin is cardioprotective against doxorubicin-induced cardiomyopathy. This intriguing study shows that the modulation of the mitochondria at the fundamental level of integrating cofactors required for protein functional integrity have beneficial effects in disease processes that are exacerbated by mitochondrial dysfunction. This study further highlights the complexity of mitochondrial function and adds a new level of regulation operational in the pathophysiology of heart failure that may be amenable to therapeutic modulation.

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