Researchers Develop Hybrid Protein Tools For Gene Cutting And Editing

MedicalNews Today, Article Date: 31 Aug 2010

An Iowa State University team of researchers has developed a type of hybrid proteins that can make double-strand DNA breaks at specific sites in living cells, possibly leading to better gene replacement and gene editing therapies. Read more

[Distribution of frataxin in eye retina of normal mice and of transgenic R7E mice with retinal degeneration]

Zh Evol Biokhim Fiziol. 2010 Jul-Aug;46(4):347-9.

[Article in Russian]

Development of a potential therapy for Friedreich ataxia based on transduction of the frataxin protein in the mitochondria

Canadian Association for Familial Ataxias - Claude St-Jean Foundation
August 25, 2010,

CAFA IS LAUNCHING A MAJOR RESEARCH PROJECT

This research project’s goal is to develop a therapy for Friedreich ataxia by targeting the actual cause of the illness, the reduction of frataxin. The project will therefore aim to administer the frataxin protein intravenously. However, as this protein does not spontaneously penetrate cells, it will be encapsulated with peptides (fragments of other proteins), in nanoparticles. Alternatively, the frataxin protein itself will be modified by adding peptides which will allow the proteins to penetrate not only the interior of cells, but also the interior of the mitochondria.

Symposium participants optimistic about finding first treatment for Friedreich's ataxia

USF Health News, August 30, 2010 @ 4:58 pm

"With all the significant scientific advancements presented, at the end of the symposium it was the people with Friedreich’s ataxia who gave the research meaning and value"

Proteomic Analysis of Protein-Protein Interactions within the CSD Fe-S Cluster Biogenesis System

J. Proteome Res., Just Accepted Manuscript, Publication Date (Web): August 24, 2010

Heather May Bolstad , Danielle J Botelho and Matthew James Wood

Keygen: Fe-S cluster biogenesis, cysteine desulfurase CsdA, sulfur acceptor protein CsdE, E1-like protein CsdL. Fe-S cluster assembly (ErpA, glutaredoxin-3, glutaredoxin-4), sulfur trafficking (CsdL, YchN) proteins, two-pathway model.

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Lipid Peroxides: More Sophisticated Than Their Reputation

ScienceDaily (Aug. 24, 2010) — Accumulation of lipid peroxides in the cell are associated with diseases and cellular stress. In the current issue of Proceedings of the National Academy of Sciences, researchers at Helmholtz Zentrum München and the Swedish medical university Karolinska Institutet show that lipid peroxides also play an important, yet-unrecognized role in the regulation of receptor tyrosine kinases.

Reference scientific paper:
12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases.
M. Conrad, A. Sandin, H. Forster, A. Seiler, J. Frijhoff, M. Dagnell, G. W. Bornkamm, O. Radmark, R. Hooft van Huijsduijnen, P. Aspenstrom, F. Bohmer, A. Ostman. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1007909107

The Monash University are seeking healthy participants for the control group, Understanding Motor Deficits in Friedreich's Ataxia

The aim of this study is to investigate the extent of motor overflow in people with Friedreich's ataxia. Motor overflow refers to involuntary movement which occurs on the opposite side of the body when voluntary movement takes place on one side.

Defects in Mitochondrial Axonal Transport and Membrane Potential without Increased Reactive Oxygen Species Production in a Drosophila Model of Friedreich Ataxia

The Journal of Neuroscience, August 25, 2010, 30(34):11369-11378; doi:10.1523/JNEUROSCI.0529-10.2010

Yujiro Shidara {dagger} and Peter J. Hollenbeck
Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907

KEYWORDS: Friedreich ataxia, frataxin deficiency, oxidative stress, cellular neuropathology, mitochondrial axonal transport, membrane potential (MMP), reactive oxygen species (ROS), neuromuscular junctions (NMJs), antimycin A.

Long-term effects of coordinative training in degenerative cerebellar disease†

Movement Disorders, Article first published online: 24 AUG 2010, DOI: 10.1002/mds.23222

Winfried Ilg PhD1, Doris Brötz PT2, 3. Susanne Burkard PT3, Martin A. Giese PhD1, Ludger Schöls MD4,*, Matthis Synofzik MD4.

Prospects for the Use of Artificial Chromosomes and Minichromosome-Like Episomes in Gene Therapy

Journal of Biomedicine and Biotechnology, Volume 2010 (2010), Article ID 642804, 16 pages, doi:10.1155/2010/642804

Sara Pérez-Luz1,2,3 and Javier Díaz-Nido1,2,3

1Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
2Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), C/Nicolás Cabrera 1, Universidad Autónoma de Madrid, 28049 Madrid, Spain
3U-748, Area de Neurogenética, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain

OPEN ACCESS

Abstract

Artificial chromosomes and minichromosome-like episomes are large DNA molecules capable of containing whole genomic loci, and be maintained as nonintegrating, replicating molecules in proliferating human somatic cells. Authentic human artificial chromosomes are very difficult to engineer because of the difficulties associated with centromere structure, so they are not widely used for gene-therapy applications. However, OriP/EBNA1-based episomes, which they lack true centromeres, can be maintained stably in dividing cells as they bind to mitotic chromosomes and segregate into daughter cells. These episomes are more easily engineered than true human artificial chromosomes and can carry entire genes along with all their regulatory sequences. Thus, these constructs may facilitate the long-term persistence and physiological regulation of the expression of therapeutic genes, which is crucial for some gene therapy applications. In particular, they are promising vectors for gene therapy in inherited diseases that are caused by recessive mutations, for example haemophilia A and Friedreich's ataxia. Interestingly, the episome carrying the frataxin gene (deficient in Friedreich's ataxia) has been demonstrated to rescue the susceptibility to oxidative stress which is typical of fibroblasts from Friedreich's ataxia patients. This provides evidence of their potential to treat genetic diseases linked to recessive mutations through gene therapy.

Section: "4.4. Gene Therapy for Friedreich’s Ataxia"

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Mitochondrial protein import: from proteomics to functional mechanisms

Nature Reviews Molecular Cell Biology 11, 655–667 (1 September 2010) | doi:10.1038/nrm2959

Oliver Schmidt , Nikolaus Pfanner & Chris Meisinger

Keywords: Mitochondria, proteins, cytosol, import pathways, protein translocases.

Cytosolic Iron-Sulfur Cluster Assembly (CIA) System: Factors, Mechanism, and Relevance to Cellular Iron Regulation

J. Biol. Chem. 2010 285: 26745-26751. doi:10.1074/jbc.R110.122218

Anil K Sharma, Leif J Pallesen, Robert J Spang and William E Walden*

University of Illinois at Chicago, United States

KEYWORDS: Iron sulfur (FeS) cluster biogenesis, cellular iron homeostasis.

Expression of Human Frataxin Is Regulated by Transcription Factors SRF and TFAP2

Li K, Singh A, Crooks DR, Dai X, Cong Z, et al. 2010 . PLoS ONE 5(8): e12286. doi:10.1371/journal.pone.0012286

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Abstract
Background

Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by reduced expression levels of the frataxin gene (FXN) due to expansion of triplet nucleotide GAA repeats in the first intron of FXN. Augmentation of frataxin expression levels in affected Friedreich ataxia patient tissues might substantially slow disease progression.
Methodology/Principal Findings

We utilized bioinformatic tools in conjunction with chromatin immunoprecipitation and electrophoretic mobility shift assays to identify transcription factors that influence transcription of the FXN gene. We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. SRF and TFAP2 binding sequences in the FXN promoter enhanced transcription from luciferase constructs, while mutagenesis of the predicted SRF or TFAP2 binding sites significantly decreased FXN promoter activity. Further analysis demonstrated that robust SRF- and TFAP2-mediated transcriptional activity was dependent on a regulatory element, located immediately downstream of the first FXN exon. Finally, over-expression of either SRF or TFAP2 significantly increased frataxin mRNA and protein levels in HEK293 cells, and frataxin mRNA levels were also elevated in SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts transfected with SRF or TFAP2.
Conclusions/Significance

We identified two transcription factors, SRF and TFAP2, as well as an intronic element encompassing EGR3-like sequence, that work together to regulate expression of the FXN gene. By providing new mechanistic insights into the molecular factors influencing frataxin expression, our results should aid in the discovery of new therapeutic targets for the treatment of Friedreich ataxia.

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H MR Spectroscopy in Friedreich's Ataxia and Ataxia with Oculomotor Apraxia Type 2.

Brain Res. 2010 Aug 13. [Epub ahead of print]

Iltis I, Hutter D, Bushara KO, Clark HB, Gross M, Eberly LE, Gomez CM, Oz G.
Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, U.S.A.

Keywords: Friedreich's ataxia (FRDA, ataxia with oculomotor apraxia type 2 (AOA2), brain metabolism, biomarker of the disease progression, Friedreich's Ataxia Rating Scale (FARS), monitor disease progression.

First half report 2010 - Lundbeck

Lu AA24493 is in clinical phase II in the treatment of Friedreich's ataxia and
in clinical phase I in the treatment of acute ischaemic stroke. Ongoing studies
in both programmes are expected to be concluded in the second half of 2010.

Santhera Obtains European Patent for Use of Catena®/Sovrima®

Liestal, Switzerland, August 13, 2010 - Santhera Pharmaceuticals (SIX: SANN)
announced today that the European Patent Office granted patent protection for
the use of idebenone (brand name Catena®/Sovrima®) in the treatment of Duchenne
Muscular Dystrophy and other muscular dystrophies.

Friedreich’s Ataxia Induced Pluripotent Stem Cells Recapitulate GAA•TTC Triplet-Repeat Instability

NCBI, Public on Jul 02, 2010

Experiment type: Expression profiling by array

Keywords: Friedreich’s ataxia (FRDA), GAA•TTC trinucleotide repeats, FXN gene, induced pluripotent stem cells (iPSCs), fibroblasts, retroviral transduction, Msh2, repeat instability.

A Phase 3, Double-blind, Placebo-Controlled Trial of Idebenone in Friedreich Ataxia

Arch Neurol. 2010;67(8):941-947. doi:10.1001/archneurol.2010.168

David R. Lynch, MD, PhD; Susan L. Perlman, MD; Thomas Meier, PhD  

 

Automated quantitative gait analysis in animal models of movement disorders

BMC Neuroscience 2010, 11:92doi:10.1186/1471-2202-11-92

Caroline Vandeputte, Jean-Marc Taymans, Cindy Casteels, Frea Coun, Yicheng Ni, Koen Van Laere and Veerle Baekelandt.

OPEN ACCESS

Conclusion

The automated quantitative gait analysis test may be a useful tool to study both motor impairment and recovery associated with various neurological motor disorders.

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Erythropoiesis and iron sulfur cluster biogenesis

Advances in Hematology, Received 1 March 2010; Revised 4 June 2010; Accepted 2 August 2010

Hong Ye and Tracey A. Rouault

OPEN ACCES

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Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production.

Neurobiol Aging. 2010 Jul 29.

Wu Z, Du Y, Xue H, Wu Y, Zhou B.
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.

I would like to emphasize: .../... "suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity".../...

A rapid, noninvasive immunoassay for frataxin: Utility in assessment of Friedreich ataxia.

Mol Genet Metab. 2010 Jul 8. [Epub ahead of print]

Deutsch EC, Santani AB, Perlman SL, Farmer JM, Stolle CA, Marusich MF, Lynch DR.
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Keywords: Friedreich ataxia (FRDA), frataxin, Western blot analysis, fibroblasts, lymphocytes, , muscle biopsies, lateral flow immunoassay, buccal cells.