Rare diseases: matching wheelchair users with rare metabolic, neuromuscular or neurological disorders to electric powered indoor/outdoor wheelchairs (EPIOCs)

Lorraine H. De Souza & Andrew O. Frank. Disabil Rehabil. 2015 Dec 30:1-10. [Epub ahead of print] DOI:10.3109/09638288.2015.1106599

The complex and diverse clinical problems of those with RDs present unique challenges to the multiprofessional wheelchair team to maintain successful independent mobility and community living. Powered mobility is a major therapeutic tool for those with rare diseases enhancing independence, participation, reducing pain and other clinical features. The challenge for rehabilitation professionals is reconciling the physical disabilities with the individual’s need for function and participation whilst allowing for disease progression and/or growth.

Identification of potential mitochondrial CLPXP protease interactors and substrates suggests its central role in energy metabolism

Fabian Fischer, Julian D. Langer & Heinz D. Osiewacz; (NATURE) Scientific Reports 5, Article number: 18375 (2015) doi:10.1038/srep18375

OPEN

Among the CLPP-associated pathologies is Friedreich’s Ataxia (FRDA), a neurodegenerative disease caused by failed assembly of Fe-S clusters due to defects in the mitochondrial iron chaperone frataxin31. In a FRDA mouse model, the proteolytic component CLPP is upregulated at mid-stage of the disease. This upregulation is concomitant with a loss of mitochondrial Fe-S proteins, indicating they are targets of CLPP in FRDA. Indeed, several proteins we identified in our study contain or bind to Fe-S clusters, e.g. aconitase, biotin synthase, and complex I components such as the NADH-ubiquinone oxidoreductase 75 kDa subunit. In addition, three of the proteins found as CLPXP interactors or substrates, the cysteine desulfurase NSF1, the chaperone HSPA9, and the glutaredoxin-related protein 5, are known to be essential for Fe-S cluster biogenesis in eukaryotic cells including those of mammals. Thus, our findings support the idea that CLPXP has a functional role in FRDA and might possibly be involved in regulating Fe-S cluster assembly and Fe-S cluster proteins.

The first therapeutics based on genome-editing tools will treat diseases caused by single genes, but many other factors dictate what is currently possible.

Virginia Gewin, Medicine: Expanding possibilities, Nature 528, S10–S11 (03 December 2015) doi:10.1038/528S10a Published online 02 December 2015

OPEN

 

Treatments for Syndromes of Progressive Ataxia and Weakness Disorders - PMR Market Insight Report to 2020

Persistence Market Research (PMR)

Stringent regulations and standard requires for approval process of new drugs impede growth of the treatments for syndromes of progressive ataxia and weakness disorders market. The approval process takes a very long time to approve a specific drug.

Burden of mitochondrial DNA variations in Friedreich's Ataxia (FRDA) patients and sharing of mitochondrial lineage with Caucasians

Inder singh, Sunil Sakhya, Madhuri Behari, M.V. Padma Srivastava, Garima Shukla, Vinay Goyal, Achal Kumar Srivastava, Mohd. Faruq, Parkinsonism & Related Disorders, Volume 22, Supplement 2, January 2016, Page e154, ISSN 1353-8020, doi: 10.1016/j.parkreldis.2015.10.360.

Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia

Charles A. Galea, Aamira Huq, Paul J. Lockhart, Geneieve Tai, Louise A. Corben, Eppie M. Yiu, Lyle C. Gurrin, David R. Lynch, Sarah Gelbard, Alexandra Durr, Francoise Pousset, Michael Parkinson, Robyn Labrum, Paola Giunti, Susan L. Perlman, Martin B. Delatycki and Marguerite V. Evans-Galea; Annals of Neurology Accepted manuscript online: 24 DEC 2015 DOI: 10.1002/ana.24595

This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provides a definitive resource for investigating disease pathogenesis in FRDA

Diagnosis and management of hypertrophic cardiomyopathy

Antonis Pantazis MD, Annina S Vischer MD, Maria Carrillo Perez-Tome MD and Silvia Castelletti MD;  Echo Res Pract. 2015 Mar 1;2(1):R45-53. doi: 10.1530/ERP-15-0007. Epub 2015 Mar 11.

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Friedreich Ataxia:  Histological features explain that the hypertrophy derives from a striking proliferation of mitochondria within the cardiomyocytes, and a marked loss of contractile fibres. The cardiac involvement is high (more than 60% of patient affected) and usually asymptomatic.

European medical research escapes stifling privacy laws

Alison Abbott. Nature, Breaking News. doi:10.1038/nature.2015.19054 16 December 2015

Proposed legislation had threatened the use of genomic and clinical data in medical studies.

Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia

Thiago J.R. Rezende Msc, Cynthia B. Silva MD, PhD, Clarissa L. Yassuda MD, PhD, Brunno M. Campos Msc, Anelyssa D'Abreu MD, PhD, Fernando Cendes MD, PhD, Iscia Lopes-Cendes MD PhD andMarcondes C. França Jr. MD, PhD; Mov Disord. 2015 Dec 21. doi: 10.1002/mds.26436. [Epub ahead of print]

Patients with Friedreich’s ataxia present more widespread gray and white matter damage than previously reported, including not only infratentorial areas, but also supratentorial structures.

The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation

Xiaobin Liu, Keith Ward, Christy Xavier, Jamieson Jann, Abbot F. Clark, Iok-Hou Pang, Hongli Wu, Redox Biology, Available online 19 December 2015, ISSN 2213-2317, doi:10.1016/j.redox.2015.12.005.

Study about RTA 408 for degenerative eye diseases. Currently there is an ongoing clinical trial for the FA. Although the work is focused on age-related macular degeneration, includes important insights on the action mechanism of RTA 408.

RTA 408 represents a novel class of therapeutics that has the potential to increase Nrf2 expression and thereby increase expression of antioxidant enzymes. RTA 408 is a member of the synthetic oleanane triterpenoid compounds. It is currently under clinical investigation for the prevention of cataract surgery-induced loss of corneal endothelial cells, prevention of radiation-induced dermatitis in breast cancer patients undergoing radiotherapy, treatment of solid tumors including melanoma and lung cancer, and treatment of Friedreich’s Ataxia and mitochondrial myopathies. The present study investigates the connection between RTA 408 and the Nrf2 pathway as well as multiple antioxidant enzymes in RPE cells. This will help determine whether RTA 408 may serve as a potent therapy for AMD and other degenerative eye diseases.

Functional and gait assessment in children with Friedreich ataxia: Comparison of quantitative and functional evaluation

G. Vasco, M. Petrarca, S. Gazzellini, M.L. Lispi, G. Della Bella, S. Carniel, M. Zazza, E. Castelli, E. Bertini; Gait & Posture, Volume 42, Supplement 3, December 2015, Pages S45-S46, ISSN 0966-6362, doi: 10.1016/j.gaitpost.2015.03.083.

The spatial and temporal parameters revealed to be the most sensitive quantitative indicators and have a good correlation with SARA.

Otoneurological findings prevalent in hereditary ataxias

Bianca Simone Zeigelboim, Helio Afonso Ghizoni Teive, Geslaine Santos, Maria Izabel Severiano, Vinicius Ribas Fonseca, João Henrique Faryniuk, Parkinsonism & Related Disorders, Volume 22, Supplement 2, January 2016, Page e152, ISSN 1353-8020, doi:10.1016/j.parkreldis.2015.10.356.

A retrospective cross-sectional study was conducted with 19 Friedreich's ataxia. The most evident neuro-otological symptoms were dizziness, lack of coordination of movement, and imbalance when walking.

Vitamin E therapy beyond cancer: tocopherol versus tocotrienol

Hong Yong Peh, W.S. Daniel Tan, Wupeng Liao, W.S. Fred Wong, Pharmacology & Therapeutics, Available online 17 December 2015, ISSN 0163-7258, doi:10.1016/j.pharmthera.2015.12.003.

Modifications to tocotrienols were performed as well: Vatiquinone (EPI-743), structurally similar to α-tocotrienol metabolite α-tocotrienol quinone, was developed for the treatment of Leigh syndrome and other inherited mitochondrial diseases by Edison Pharmaceuticals Inc. Currently, EPI-743 was approved by FDA (United States of America Food and Drug Administration) in July 2014 for the treatment of Leigh syndrome and an ongoing Phase-IIb clinical trial for Friedreich’s ataxia

[Memantine for optic nerve atrophy in Friedreich's Ataxia]- Memantin bei Optikusatrophie in Friedreich-Ataxie

S. Peter , K. Manousaridis, S. Boesch, S. Mennel; Der Ophthalmologe pp 1-4, [Article in German] DOI 10.1007/s00347-015-0191-7

Despite the limitations of this single and time limited case observational study, memantine should be discussed as an option for treatment of acute optic nerve atrophy in Friedreich’s ataxia.

Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin

Joseph F. Nabhan, Renea L. Gooch, Eugene L. Piatnitski Chekler, Betsy Pierce & Christine E. Bulawa; (Nature) Scientific Reports 5, Article number: 18251 (2015) doi:10.1038/srep18251

OPEN

 Interestingly, a number of treatments caused a change in total amount of FXN protein, without an effect on mature FXN. Our results imply that regulation of FXN protein levels is complex and that total amounts can be modulated chemically and genetically without altering the absolute amount of mature FXN protein.

Eye movements in neurodegenerative diseases.

MacAskill, Michael R.; Anderson, Tim J.; Current Opinion in Neurology, Published Ahead-of-Print. December 4, 2015 doi: 10.1097/WCO.0000000000000274

Epigenetic Biomarkers and Diagnostics

Edited by: José Luis García-Giménez (Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain; Medicine and Dentistry School; Biomedical Research Institute INCLIVA, University of Valencia, Spain). Academic Press, Boston, 2016, doi:10.1016/B978-0-12-801899-6.01001-9, Available online 8 December 2015

Chapter 3 - Epigenetic Mechanisms as Key Regulators in Disease: Clinical Implications, Abdelhalim Boukaba, Fabian Sanchis-Gomar and José Luis García-Giménez, doi:10.1016/B978-0-12-801899-6.00003-6
Alterations in the epigenetic machineries deregulate different epigenetic substrates, which in turn might be implemented as clinical epigenetic biomarkers for diagnosis, prognosis, and monitoring a wide variety of pathological conditions.

Chapter 20 – DNA Methylation in Neurodegenerative Diseases, Sahar Al-Mahdawi, Sara Anjomani Virmouni and Mark A. Pook, Pages doi:10.1016/B978-0-12-801899-6.00020-6.
This review focuses on our current understanding of the role of DNA methylation and its potential as a biomarker in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, fragile X-associated tremor/ataxia syndrome, Friedreich ataxia, and spinocerebellar ataxia type 7

Chapter 21 - The Histone Code and Disease: Posttranslational Modifications as Potential Prognostic Factors for Clinical Diagnosis, Nicolas G. Simonet, George Rasti and Alejandro Vaquero, 417-445, doi:10.1016/B978-0-12-801899-6.00021-8.
In this chapter, we summarize the current knowledge on the implications of histone PTMs in diverse human pathologies. We focus on the identified changes in histone modifications and associated enzymes in human diseases, as well as on their potential role in clinical diagnosis.

Disease-Associated Repeat Instability and Mismatch Repair

Monika H.M. Schmidt, Christopher E. Pearson, DNA Repair, Available online 12 December 2015, ISSN 1568-7864, doi: 10.1016/j.dnarep.2015.11.008.

The formation of other unusual DNA and R-loop structures is proposed to play a key role in MMR-mediated instability. A complex correlation is emerging between tissues showing varying amounts of repeat instability and MMR expression levels. Notably, naturally occurring polymorphic variants of DNA repair genes can have dramatic effects upon the levels of repeat instability, which may explain the variation in disease age-of-onset, progression and severity. An increasing grasp of these factors holds prognostic and therapeutic potential.

Pharmacology and Clinical Drug Candidates in Redox Medicine

V. Thao-Vi Dao, Ana I. Casas, Ghassan J. Maghzal, Tamara Seredenina, Nina Kaludercic, Natalia Robledinos-Anton, Fabio Di Lisa, Roland Stocker, Pietro Ghezzi, Vincent Jaquet, Antonio Cuadrado and Harald H.H.W. Schmidt; Antioxid Redox Signal. 2015 November 10; 23(14): 1113–1129. doi: 10.1089/ars.2015.6430

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Other lines of research have focused on targeting NRF2 in degenerative diseases where low-grade chronic inflammation is present. One very potent synthetic triterpenoid, CDDO-methyl ester, bardoxolone methyl, has been studied in great detail for treatment of diabetic nephropathy. The initial excitement about this compound was set back by a small yet significant increase in the risk of heart failure. Importantly though, this effect appears not to be related to NRF2 targeting, but rather to alteration of endothelin signaling, leading to reduction in urine volume and sodium excretion in some patients with advanced chronic kidney disease. Bardoxolone methyl is now being studied in new indications for pulmonary arterial hypertension, melanoma, and Friedreich's ataxia.

Regulating biobanking with children’s tissue: a legal analysis and the experts’ view

Elcke J Kranendonk, M Corrette Ploem and Raoul C M Hennekam; European Journal of Human Genetics (2016) 24, 30–36; doi:10.1038/ejhg.2015.59; published online 15 April 2015

The results of this analysis show that experts have no clear consensus about the appropriate rules for storage of and research with children’s material in biobanks. Development of a framework that provides a fair balance between fundamental paediatric research and privacy protection is necessary.

Antioxidants in Translational Medicine.

Harald H.H.W. Schmidt, Roland Stocker, Claudia Vollbracht, Gøran Paulsen, Dennis Riley, Andreas Daiber and Antonio Cuadrado; Antioxid Redox Signal. 2015 November 10; 23(14): 1130–1143.
doi: 10.1089/ars.2015.6393

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Friedreich Ataxia (Chapter 13)

Mary Kay Koenig, Chapter 13 - In Mitochondrial Case Studies, edited by Russell P. SanetoSumit ParikhBruce H. Cohen, Academic Press, Boston, 2016, Pages 103-112, ISBN 9780128008775, doi:10.1016/B978-0-12-800877-5.00013-9.

Diagnostic considerations, clinical presentation, pathophysiology, and treatment options are discussed.

Analyzing the Effects of a G137V Mutation in the FXN Gene

Nathalie Faggianelli, Rita Puglisi, Liana Veneziano, Silvia Romano, Marina Frontali, Tommaso Vannocci, Silvia Fortuni, Roberto Testi and Annalisa Pastore, Front. Mol. Neurosci., 25 November 2015 | doi:10.3389/fnmol.2015.00066

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This study analyze the effects of a point mutation G137V

IFN-γ for Friedreich ataxia: present evidence.

McKenzie Wells, Lauren Seyer, Kimberly Schadt & David R Lynch; Neurodegenerative Disease Management, Posted online on December 4, 2015, doi:10.2217/nmt.15.52

Systematic review and clinical recommendations for dosage of supported home-based standing programs for adults with stroke, spinal cord injury and other neurological conditions

Ginny Paleg and Roslyn Livingstone. BMC Musculoskelet Disord. 2015; 16: 358. Published online 2015 Nov 17. doi: 10.1186/s12891-015-0813-x

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GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients.

Christian Marcotulli, Silvia Fortuni, Gaetano Arcuri, Barbara Tomassini, Luca Leonardi, Francesco Pierelli, Roberto Testi, Carlo Casali; Neurological Sciences pp 1-4 First online: 30 November 2015, DOI: 10.1007/s10072-015-2427-3

IFNγ was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant.
Frataxin levels was mesured in peripheral blood multinuclear cells, this are a cell compartment easily accessible but not involved in the disease, In opinion of the researchers it's questionable if it's a real mirror of what happens in sensory neurons, additional and better biomarkers are needed.

Dr Evans–Galea, a leader in the field of gene therapy, talks about the challenges she has faced, but also the increasing visibility of female scientists in her field, and her professional mission: finding a cure for Friedrich ataxia

www.theguardian.com, interview by Brigid Delaney, Tuesday 1 December

The FXN gene was first discovered in the 90s, and there are potential treatments in development. Since then, it has become like a puzzle I couldn’t put down.

La phase de double appui : paramètre prédictif de la dégradation de la marche dans l’ataxie de Friedreich ?

B. Roche, R. Martin, I. Husson, Neurophysiologie Clinique/Clinical Neurophysiology, Volume 45, Issues 4–5, November 2015, Pages 403-404, ISSN 0987-7053, doi: 10.1016/j.neucli.2015.10.040

Alors que l’ICARS n’a pas saisi de dégradation significative, le tapis de marche GAITRite a révélé quant à lui une détérioration significative du double appui, paramètre représentatif, quand il augmente, d’une instabilité à la marche.

Gene-editing tool CRISPR opens a world of possibilities for rare genetic diseases

CRISPR gene-editing tool has scientists thrilled — but nervous. By Kelly Crowe, CBC News Posted: Nov 30, 2015 5:00 AM ET

The CRISPR system allows anyone with basic molecular biology training to edit the genome with a pinpoint precision not possible before, in addition CRISPR editing is relatively cheap once established.
Much remains to be done in scientific and legal aspects, would be able to eradicate human gene mutations from all future generations?. There is also a strong ethical concern, it could be used to cure genetic diseases or also for eugenic purposes.

Access to Orphan Drugs: A Comprehensive Review of Legislations, Regulations and Policies in 35 Countries

Gammie T, Lu CY, Babar ZU-D (2015), PLoS ONE 10(10): e0140002., doi:10.1371/journal.pone.0140002

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Access to orphan drugs depends on individual country’s pricing and reimbursement policies, which varied widely between countries. High prices and insufficient evidence often limit orphan drugs from meeting the traditional health technology assessment criteria, especially cost-effectiveness, which may influence access.
Overall many countries have implemented a combination of legislations, regulations and policies for orphan drugs in the last two decades. While these may enable the availability and access to orphan drugs, there are critical differences between countries in terms of range and types of legislations, regulations and policies implemented.

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Shao-Hua Yang, Wenjun Li, Nathalie Sumien, Michael Forster, James W. Simpkins, Ran Liu, Progress in Neurobiology, Available online 18 November 2015, ISSN 0301-0082, doi:10.1016/j.pneurobio.2015.10.005

There is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.

Retrotope announces opening of second clinical trial site for enrollment in Friedreich's ataxia clinical trial

LOS ALTOS, Calif., Nov. 20, 2015 /PRNewswire/ -- Retrotope announces the opening of second clinical trial site, the Collaborative Neuroscience Network, LLC. ("CNS") in Long Beach, California, for the ongoing 28-day, first-in-human randomized, double-blind, controlled, ascending dose study of orally dosed RT001 to evaluate the safety, tolerability, pharmacokinetics (PK), disease state, and exploratory endpoints in patients with Friedreich's ataxia (FA).

Frataxin expression in reticulocytes of non-splenectomized and splenectomized patients with HbE-β-thalassaemia

Yollada Suebpeng, Arunee Jetsrisuparb, Supan Fucharoen, Amporn Tripatara, Clinical Biochemistry, Available online 14 November 2015, ISSN 0009-9120, doi: 10.1016/j.clinbiochem.2015.11.008.

The relative FXN expression in the patients was found to be correlated with the levels of MDA and ferritin but not correlated with transferrin saturation. The elevation of FXN expression in the reticulocytes of these patients seems to be linked to oxidative stress and iron status. Findings also suggest that FXN expression is at least partially regulated by the mitochondrial demand for iron for haem synthesis.

Efficient attenuation of Friedreich's ataxia (FRDA) cardiomyopathy by modulation of iron homeostasis-human induced pluripotent stem cell (hiPSC) as a drug screening platform for FRDA,

Yee-Ki Lee, Yee-Man Lau, Kwong-Man Ng, Wing-Hon Lai, Shu-Leong Ho, Hung-Fat Tse, Chung-Wah Siu, Philip Wing-Lok Ho, International Journal of Cardiology, Available online 17 November 2015, ISSN 0167-5273, doi:10.1016/j.ijcard.2015.11.101.

Life without Fe-S clusters

Agostinho G. Rocha and Andrew Dancis, Molecular Microbiology 1365-2958, DOI - 10.1111/mmi.13273

Microcommentary on “Novel features of the ISC machinery revealed by characterization of Escherichia coli mutants that survive without iron-sulfur clusters” by Naoyuki Tanaka, Miaki Kanazawa, Keitaro Tonosaki, Nao Yokoyama, Tomohisa Kuzuyama, Yasuhiro Takahashi.

Développement d'un nouveau modèle cellulaire de l'ataxie de Friedreich : différenciation de cellules pluripotentes induites de patients en cardiomyocytes

Aurore Hick. (Theses) Rhumatologie et système ostéo-articulaire. Université de Strasbourg, 2014. Français.

Frataxin knockdown in Drosophila alters mitochondrial homeostasis and degradation in muscles and glia

Seminars: IGC - Instituto Gulbenkian de Ciência (Portugal), Speaker: Juan Navarro, Affiliation: Institut für Zoologie, Universität Regensburg, Germany, Date 13/11/2015

Normative Data for an Instrumental Assessment of the Upper-Limb Functionality

Marco Caimmi, Eleonora Guanziroli, Matteo Malosio, Nicola Pedrocchi, Federico Vicentini, Lorenzo Molinari Tosatti and Franco Molteni, BioMed Research International Volume 2015 (2015), Article ID 484131, 14 pages doi:10.1155/2015/484131


This work led to the creation of a reliable database of normative data of the Reaching and Hand-to-Mouth Evaluation Method. Its simplicity and brevity make the whole procedure widely applicable to the UL functional assessment.

Structural and Functional Magnetic Resonance Imaging of the Cerebellum: Considerations for Assessing Cerebellar Ataxias

Andreas Deistung , Maria R. Stefanescu, Thomas M. Ernst, Marc Schlamann, Mark E. Ladd, Jürgen R. Reichenbach, Dagmar Timmann, Review: The Cerebellum pp 1-5 First online: 31 October 2015 DOI 10.1007/s12311-015-0738-9

Data from initial fMRI studies are presented in three common forms of hereditary ataxias (Friedreich’s ataxia, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6).

Patent: METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT AND THE PREVENTION OF CARDIOMYOPATHY DUE TO FRIEDREICH ATAXIA

Inventor(s): PUCCIO HELENE MONIQUE [FR]; AUBOURG PATRICK [FR]; CRYSTAL RONALD G [US]; BOUGNERES PIERRE [FR]

Application number: US201514718696 20150521

A method for preventing or treating cardiomyopathy due to energy failure in a subject in need thereof is provided. The method comprises administering to the subject a therapeutically effective amount of a vector which comprises a nucleic acid sequence encoding a gene that can reverse energy failure. An exemplary cardiomyopathy is that which is associated with Friedreich ataxia and an exemplary nucleic acid sequence comprises a nucleic acid that encodes frataxin (FXN).

Management of Children with Mild, Moderate, and Moderately Severe Sensorineural Hearing Loss

Anne Marie Tharpe, Samantha Gustafson, Otolaryngologic Clinics of North America, Volume 48, Issue 6, December 2015, Pages 983-994, ISSN 0030-6665, doi:10.1016/j.otc.2015.07.005.

The roles of pediatricians and otolaryngologists in referring children for appropriate assessments and interventions, and encouraging families to comply with hearing technology use and therapeutic intervention are crucial to ensuring the best possible outcomes.

UAB researchers seek Friedreich’s ataxia biomarkers

UAB News, University of Alabama at Birmingham, November 04, 2015

“There is a high demand for biomarkers because of ongoing clinical trials with Friedreich’s ataxia patients,” said Marek Napierala, Ph.D., assistant professor in UAB Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute. “We need better measures of the progression of the disease and the therapeutic response.”

Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich's Ataxia Study

ClinicalTrials.gov Identifier: NCT02593773, First received: October 29, 2015

 The purpose of this phase 3 multi-center, open-label extension study is to evaluate the long-term safety of ACTIMMUNE (interferon-γ 1b) in subjects with Friedreich's Ataxia (FA).

Drug: Interferon γ-1b, Other Name: ACTIMMUNE

Approximately 90 subjects will receive subcutaneous (SC) doses of ACTIMMUNE three times a week (TIW) for a total of 26 weeks. The study drug dose is planned to be escalated on a weekly basis over the first 4 weeks of treatment (from 10 µg/m² to 25, 50, and 100 µg/m²). The dose may be reduced, interrupted, or held based on tolerability. By week 13, all subjects are to be on a stable tolerated dose of study drug in order to continue study participation; the dose may not be further increased after week 13, however, it may be reduced on a case-by-case basis to manage drug-related AEs.

Frataxin Is Localized to Both the Chloroplast and Mitochondrion and Is Involved in Chloroplast Fe-S Protein Function in Arabidopsis.

Turowski VR, Aknin C, Maliandi MV, Buchensky C, Leaden L, Peralta DA, Maria V. Busi, Alejandro Araya, Diego F. Gomez-Casati, PLoS ONE 10(10): e0141443. doi:10.1371/journal.pone.0141443

A personal perspective of orphan drug development for rare diseases: A golden opportunity or an unsustainable future?

Oo, C. and Rusch, L. M. Journal of Clinical Pharma. doi: 10.1002/jcph.599

Nevertheless, there is no better opportunity than the present to develop orphan drugs in order to accelerate the treatment and alleviate the suffering of patients with rare diseases.

Fronto-cerebellar dysfunction and dysconnectivity underlying cognition in friedreich ataxia: The IMAGE-FRDA study

Ian H. Harding1, Louise A. Corben, Elsdon Storey, Gary F. Egan, Monique R. Stagnitti, Govinda R. Poudel, Martin B. Delatycki and Nellie Georgiou-Karistianis. Hum. Brain Mapp.. doi: 10.1002/hbm.23034

These fronto-cerebellar disturbances provide a putative biological basis for the nonmotor symptoms observed in FRDA, and reflect the consequence of localized cerebellar pathology to distributed brain function underlying higher-order cognition

URINARY, BOWEL AND SEXUAL FUNCTION IN PATIENTS WITH FRIEDREICH'S ATAXIA

Meher Lad, Michael Parkinson, Myriam Rai, Massimo Pandolfo, Sinead Murphy, Anton Emmanuel, Jalesh Panicker, Paola Giunti; J Neurol Neurosurg Psychiatry 2015;86:e4 doi:10.1136/jnnp-2015-312379.74

Urinary and lower gastro-intestinal symptoms can have a severe impact on patients with FRDA although they are under-recognised.

Compassionate use of orphan drugs

Hanna I. Hyry, Jeremy Manuel, Timothy M. Cox and Jonathan C. P. Roos; Orphanet Journal of Rare Diseases 2015, 10:100 doi:10.1186/s13023-015-0306-x

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Compelling self-interested, legal and ethical arguments can be mounted to encourage manufacturers to offer therapies on a compassionate use basis and these are often equally applicable to provision on a humanitarian aid basis. The EU’s compassionate use programmes are instrumental in ensuring continuity of access to drugs until approval and reimbursement decisions are finalised. 

Patient-Funded Trials: Opportunity or Liability?

Danielle Marie Wenner, Jonathan Kimmelman, Alex John London, Patient-Funded Trials: Opportunity or Liability?, Cell Stem Cell, Volume 17, Issue 2, 6 August 2015, Pages 135-137, ISSN 1934-5909, doi:10.1016/j.stem.2015.07.016.

The goals of Patient-Funded Trials to empower patients, expand available research resources, and accelerate the pace of translation are worthy and important objectives. Because the current system lacks regulations or incentives that constructively channel the desires of patients, the ardor of investigators, and the profit motives of host clinics, this funding model harbors important liabilities for both patients and the broader clinical research enterprise.

Next generation partnerships in translational science and medicine

Hans‐Gustaf Ljunggren, Kenneth R Chien, EMBO reports (2015) 16, 1246-1249 DOI 10.15252/embr.201541065

Partnerships between academics, big pharma, biotech firms, philanthropists and patients look set to change the way science advances.

Interestingly, the focus of many of these partners is not so much to “translate” existing knowledge per se into medical progress, but more to foster “transcriptional medicine” by directly funding primary research and development at the early stages and by providing substantial resources to translate their own discoveries into cures for affected patient populations.

María Dolores Moltó: “La investigación en ataxia de Friedreich se dirige hacia la obtención de tratamientos efectivos”

Por GENÉTICA MÉDICA · 11 de octubre de 2015

¿Estamos más cerca de un tratamiento efectivo?

Si pensamos que cuando se identificó el gen no se tenía ninguna idea de cuál podría ser su función y que ahora ya se está evaluando el efecto terapéutico de un número importante de moléculas, mi respuesta es que sí. Pero también es cierto, que a pesar de los años de investigación todavía no se ha conseguido un tratamiento que sea realmente eficaz. No es nada fácil el tratamiento de las enfermedades genéticas, pero está claro que hoy conocemos qué les ocurre a las células sin frataxina y por lo tanto, se está en disposición de poder desarrollar estrategias que sean realmente útiles para el tratamiento de esta enfermedad. Leer mas....

A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency

Alexandra Seguin, Véronique Monnier, Amandine Palandri, Frédéric Bihel, Michael Rera, Martine Schmitt, Jean-Michel Camadro, Hervé Tricoire, and Emmanuel Lesuisse; Oxidative Medicine and Cellular Longevity, Volume 2015 (2015), Article ID 565140, 10 pages DOI: 10.1155/2015/565140

The unique complementarity of these two frataxin-deficient models, unicellular and multicellular, appears to be very efficient to select new compounds with improved selectivity, bringing significant perspectives towards improvements in FA therapy.

Acoustic Analyses of Prolonged Vowels in Young Adults With Friedreich Ataxia

Cecyle Carson, Jack Ryalls, Kaylea Hardin-Hollingsworth, Marie-Therese Le Normand, Bari Ruddy, Journal of Voice, Available online 9 October 2015, ISSN 0892-1997, doi:10.1016/j.jvoice.2015.05.008.

The purpose of this study was to determine which cepstral- and spectral-based measures extracted from prolonged vowels using Analysis of Dysphonia in Speech and Voice (ADSV) program discriminate between those who have FA and normal voice (NV) peers.

Joint preserving surgery versus arthrodesis in operative treatment of patients with neuromuscular polyneuropathy: questionnaire assessment

Marek Napiontek , Krzysztof Pietrzak; European Journal of Orthopaedic Surgery & Traumatology February 2015, Volume 25, Issue 2, pp 391-397 DOI 10.1007/s00590-014-1498-9

The purpose of the paper was to present the results of surgical treatment of foot deformities in peripheral neuropathies using bone procedures: both joint preserving and with joint arthrodesis. The study included patients presented Charcot–Marie–Tooth disease, Friedreich’s ataxia and peripheral motor and sensory neuropathies of undetermined nature. The results show that none of the surgical techniques used for correction of foot deformities in motor-sensory polyneuropathies seems to be preferable.

Pathology of Intercalated Discs in Friedreich Cardiomyopathy

R. Liane Ramirez, MS; Alyssa B. Becker, BA; Joseph E. Mazurkiewicz, PhD; Paul J. Feustel, PhD; Benjamin B. Gelman, MD, PhD; Arnulf H. Koeppen, MD, J Am Coll Cardiol. 2015;66(15):1739-1740. doi:10.1016/j.jacc.2015.06.1355

The underlying mutation in FA causes frataxin deficiency, which may adversely affect ICDs and GJs before the onset of heart disease and perhaps prenatally.

Cold Denaturation Unveiled: the Molecular Mechanism of Asymmetric Unfolding of Yeast Frataxin

Domenico Sanfelice, Edoardo Morandi, Annalisa Pastore, Neri Niccolai andPiero Andrea Temussi; ChemPhysChem 1439-7641 (2015), DOI 10.1002/cphc.201500765

A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia

Francoise Pousset, MD; Lise Legrand, MD; Marie-Lorraine Monin, MD; Claire Ewenczyk, MD; Perrine Charles, MD, PhD; Michel Komajda, MD; Alexis Brice, MD; Massimo Pandolfo, MD; Richard Isnard, MD, PhD; Sophie Tezenas du Montcel, MD, PhD; Alexandra Durr, MD, PhD. JAMA Neurol. Published online September 28, 2015. doi:10.1001/jamaneurol.2015.1855

Survival in FRDA is determined by cardiac complications, which are dependent on the mutation. The patients with the worse cardiac evolution had longer GAA repeats. Neurological impairment was not predictive of cardiac change over time. Patients with progressive decline of the left ventricular ejection fraction had a worse prognosis. This finding demonstrates that cardiac follow-up is important in FRDA to identify individuals at risk for further cardiac complications.

Monitoring Cardiac Function During Idebenone Therapy in Friedreich's Ataxia

Di Salvo Giovanni, Pergola Valeria, Fadel Bahaa and Al Fayyadh Majid, Current Pharmaceutical Design 21-4, Page: [479 - 483] DOI: 10.2174/138161282104141204142917

This drug has the potential to preserve and even improve mitochondrial function.Studies on Idebenone treatment showed rather conflicting results on FA cardiomyopathy. The present article reviews the clinical features of FA cardiomyopathy, imaging techniques used to diagnose, follow and monitor therapy which aimed to revert FA cardiomyopathy.

Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus

Yanjie Li, Yue Lu, Urszula Polak, Kevin Lin, Jianjun Shen, Jennifer Farmer, Lauren Seyer, Angela D. Bhalla, Natalia Rozwadowska, David R. Lynch, Jill Sergesketter Butler and Marek Napierala; Hum. Mol. Genet. (2015) doi: 10.1093/hmg/ddv397, First published online: September 23, 2015

The GAA-induced silencing effect does not influence expression of neighboring genes upstream or downstream of FXN. The results indicate that approaches aimed to reactivate frataxin expression should simultaneously address deficits in transcription initiation and elongation at the FXN locus.

FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia

Chutake YK, Costello WN, Lam CC, Parikh AC, Hughes TT, Michalopulos MG, Mark A. Pook, Sanjay I. Bidichandani. (2015) FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia. PLoS ONE 10(9): e0138437. doi:10.1371/journal.pone.0138437

OPEN ACCESS

Our results indicate that FXN transcriptional deficiency in the YG8sR humanized mouse model of FRDA is caused by deficient transcriptional initiation as a result of promoter silencing. While this mechanism has previously been noted in patient-derived lymphoblastoid cell lines, our present data provide supportive evidence for the existence of this mechanism of transcriptional deficiency in fibroblasts and in multiple tissues. Our data also suggest that the mechanism underlying FXN transcriptional deficiency in FRDA is unlikely to be tissue-specific.

Our data indicate that the YG8sR humanized mouse is a reasonable model for investigating the molecular mechanism(s) underlying repeat-mediated promoter silencing in FRDA. The YG8sR mouse model would also be useful for testing drugs that are designed to reverse the transcriptional initiation defect caused by promoter silencing in FRDA, such as the 2-aminobenzamide derived histone deacetylase inhibitors.

Staging of cardiomyopathy in Friedreich ataxia

Roger E. Peverill, International Journal of Cardiology, Available online 21 September 2015, ISSN 0167-5273, doi: 10.1016/j.ijcard.2015.09.047.


The combination of ECG, LGE and hsTnT with echocardiographic findings in the evaluation of these individuals is of considerable interest as it has suggested that absence of cardiac involvement in FRDA is uncommon. Whether there is any clinical significance of this finding is less certain, as it is not known whether those individuals with minor cardiac changes will ever develop cardiac symptoms or progressive cardiac disease. While the possibility of a staging system for cardiac involvement in FRDA remains of interest, the recent proposal may be considered premature given the limitations of our knowledge about the natural history of cardiac disease in FRDA.


Paper review:: The Cardiomyopathy in Friedreich’s Ataxia – New Biomarker for Staging Cardiac Involvement. Frank Weidemann, Dan Liu, Kai Hu, Cristiane Florescu, Markus Niemann, Sebastian Herrmann, Bastian Kramer, Stephan Klebe, Kathrin Doppler, Nurcan Üçeyler, Christian Oliver Ritter, Georg Ertl, Stefan Störk, International Journal of Cardiology, Available online 15 May 2015, ISSN 0167-5273, doi:10.1016/j.ijcard.2015.05.074.

Delayed-onset Friedreich's ataxia revisited

Lecocq, C., Charles, P., Azulay, J.-P., Meissner, W., Rai, M., N'Guyen, K., Péréon, Y., Fabre, N., Robin, E., Courtois, S., Guyant-Maréchal, L., Zagnoli, F., Rudolf, G., Renaud, M., Sévin-Allouet, M., Lesne, F., Alaerts, N., Goizet, C., Calvas, P., Eusebio, A., Guissart, C., Derkinderen, P., Tison, F., Brice, A., Koenig, M., Pandolfo, M., Tranchant, C., Dürr, A. and Anheim, M. (2015). Mov. Disord.. doi: 10.1002/mds.26382

Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as “delayed-onset Friedreich's ataxia.” 

Does tandem walking discriminate better than normal walking among children with DCD, ataxia and healthy controls? A preliminary analysis performed with IMUs on the trunk

D. Trojaniello, A. Mannini, D. Sival, H.J. Blok, A.M. Sabatini, U. Della Croce, Gait & Posture, Volume 42, Supplement 2, September 2015, Page S10, ISSN 0966-6362,doi: 10.1016/j.gaitpost.2015.07.028.

Significant differences were found between FRDA and H children and FRDA and DCD children for most of IMU-St and IMUSp variables. Variables extracted from both IMU-Sp and IMUSt during TW were able to discriminate between FRDA and DCD children and between FRDA and H children.

Friedreich Ataxia: From the Eye of a Molecular Biologist

Muthuswamy, Srinivasan MSc; Agarwal, Sarita PhD; Neurologist: September 2015 - Volume 20 - Issue 3 - p 51–55 doi: 10.1097/NRL.0000000000000054
Review Article

Protein replacement therapy for mitochondrial disorders

M. Rapoport, D. Marcus, A. Saada, T. Erlich, R. Hadad, H. Greif, M. Lichtenstein, H. Lorberboum-Galski, Mitochondrion, Volume 24, Supplement, September 2015, Page S35, ISSN 1567-7249, doi:10.1016/j.mito.2015.07.096.

The approach is to fuse the Mitochondrial targeting Sequence (MTS), with the delivery peptide TAT [HIV-transactivator of transcription (TAT) peptide]. This novel approach has been tested using different mitochondrial proteins implicated in mitochondrial human diseases: Lipoamide Dehydrogenase (LAB), C6ORF66 and Frataxin, and have been evaluated in vitro, in patients' cells and in vivo, in mouse models. In patient's cells and in mice tissues, including the brain, AT-MTS-Mitochondrial fusion proteins arrive at the cells and their mitochondria rapidly and efficiently, getting an improvement of the mitochondrial functions and life span in animal models.

Repurposing riluzole to treat hereditary cerebellar ataxia

Heather Wood; Nature Reviews Neurology (2015) doi:10.1038/nrneurol.2015.161 Published online 15 September 2015

Given the limited availability of new therapies for neurological disease, repurposing of existing drugs is an approach that is being increasingly explored. A randomized controlled trial, conducted in Italy provides evidence that this drug could also be beneficial in patients with hereditary cerebellar ataxia, spinocerebellar ataxia and Friedreich ataxia.

R loops: new modulators of genome dynamics and function

José M. Santos-Pereira & Andrés Aguilera, Nature Reviews Genetics (2015) doi:10.1038/nrg3961, Published online 15 September 2015

R loops are also a major threat to genome stability. For this reason, several DNA and RNA metabolism factors prevent R-loop formation in cells. Dysfunction of these factors causes R-loop accumulation, which leads to replication stress, genome instability, chromatin alterations or gene silencing. Importantly, Friedreich ataxia (FRDA) and fragile X syndrome (FXS) occur as a result of repeat expansions in the frataxin (FXN) and fragile X mental retardation 1 (FMR1) genes, respectively; this leads to gene silencing through H3K9me2 deposition on the expanded regions, which thus become fragile. Such expansions accumulate R loops, providing a new link among heterochromatin, R loops and replication-dependent fragility. 

Jones Tendon Transfer

Richard Derner, Jeffrey Holmes, Clinics in Podiatric Medicine and Surgery, Available online 12 September 2015, ISSN 0891-8422, http://dx.doi.org/10.1016/j.cpm.2015.06.004.

Charcot-Marie-Tooth (CMT), poliomyelitis, Roussy-Le´vy syndrome, and Friedreich ataxia are the most common lower motor neuron diseases causing disorders of the foot and lower extremities.

MRI Texture Analysis Reveals Bulbar Abnormalities in Friedreich Ataxia

T.A. Santos, C.E.B. Maistro, C.B. Silva, M.S. Oliveira, M.C. França Jr and G. Castellano; AJNR Am J Neuroradiol. Published online before print September 10, 2015, doi: 10.3174/ajnr.A4455

Gray level co-occurrence matrix–based texture analysis showed statistically significant differences for the medulla oblongata of patients with Friedreich ataxia compared with controls. These results highlight the medulla as an important site of damage in Friedreich ataxia. 

Characterisation of the retinal pigment epithelium in Friedreich ataxia

Duncan E. Crombie, Nicole Van Bergen, Kathryn C. Davidson, Sara Anjomani Virmouni, Penny A. Mckelvie, Vicki Chrysostomou, Alison Conquest, Louise A. Corben, Mark A. Pook, Tejal Kulkani, Ian Trounce, Martin F. Pera, Martin B. Delatycki, Alice Pébay; Biochemistry and Biophysics Reports, Available online 11 September 2015, ISSN 2405-5808, http://dx.doi.org/10.1016/j.bbrep.2015.09.003

OPEN ACCESS

Redox- and non-redox-metal-induced formation of free radicals and their role in human disease

Marian Valko , Klaudia Jomova, Christopher J. Rhodes, Kamil Kuča, Kamil Musílek; Archives of Toxicology, First online: 07 September 2015 DOI:10.1007/s00204-015-1579-5

Frataxin is a mitochondrial iron chaperone protein and plays a key role in the insertion of ferrous ions during the assembly of iron–sulfur clusters in the mitochondrial respiratory chain. The defect leads to the release of mitochondrial iron with in turn may catalyze hydroxyl radical formation via Fenton chemistry.

OUHSC professor, researcher gets $300,000 grant for research

The Oklahoma Daily; Wed Sep 9, 2015.

The three-year grant of $300,000 will fund research into promising therapies for a neuromuscular disease known as Friedreich's ataxia. Sanjay Bidichandani, is a professor of pediatrics at the OU College of Medicine and has worked at OU in the field of genetic research since 2000. Bidichandani’s research will evaluate the effectiveness of a new drug class known as HDAC inhibitors. 

Prospects of gene and cell therapy for managing cardiac complications in Friedreich ataxia

Charles J Isaacs, Julianna E Shinnick, Kimberly Schadt, David R Lynch & Kimberly Y Lin; Expert Opinion on Orphan Drugs, Published online: 02 Sep 2015 DOI: 10.1517/21678707.2015.1083854

The state of research into gene and cell therapy for cardiac issues in FRDA is one that deserves cautious optimism. As these therapies move closer to testing in humans, researchers will need to identify proper dosing and delivery methods based on the nature of the patient’s disease, as well as which patient groups are most likely to realize benefits from proposed treatments. Future studies must further assess risk in larger animals and plan ways to minimize risk in human trials.

Quantitative evaluation of gait ataxia by accelerometers

Shinichi Shirai, Ichiro Yabe, Masaaki Matsushima, Yoichi M. Ito, Mitsuru Yoneyama, Hidenao Sasaki, Journal of the Neurological Sciences, Available online 3 September 2015, ISSN 0022-510X, http://dx.doi.org/10.1016/j.jns.2015.09.004.

Effect of power-assisted hand-rim wheelchair propulsion on shoulder load in experienced wheelchair users: A pilot study with an instrumented wheelchair

Marieke G.M. Kloosterman, Jaap H. Buurke, Wiebe de Vries, Lucas H.V. Van der Woude, Johan S. Rietman, Medical Engineering & Physics, Available online 22 August 2015, ISSN 1350-4533, http://dx.doi.org/10.1016/j.medengphy.2015.07.004.

According to the guidelines, in order to create a better balance between mechanical loading and the work-capacity of the shoulder complex during propulsion, power-assisted propulsion on a treadmill is effective in reducing the majority of the potential risk factors of shoulder injury. Therefore, the use of power-assisted wheelchairs might be indicated for subjects prone to developing overuse injuries due to hand-rim propulsion or subjects with difficulties driving a hand-rim wheelchair primarily due to lack of upper-extremity power.

Friedreich ataxia in Norway – an epidemiological, molecular and clinical study

Iselin Marie Wedding, Mette Kroken, Sandra Pilar Henriksen, Kaja Kristine Selmer, Torunn Fiskerstrand, Per Morten Knappskog, Tone Berge and Chantal ME Tallaksen; Orphanet Journal of Rare Diseases 2015, 10:108 doi:10.1186/s13023-015-0328-4

OPEN ACCESS

Twenty-nine Friedreich ataxia patients were identified in Norway, of which 23 were ethnic Norwegian, corresponding to a prevalence of 1:176 000 and 1:191 000, respectively. The highest prevalence was seen in the north. Carrier frequency of 1:196 (95 % CI = [1:752–1:112]) was found.

Pilot Study of a 3d Motion Device- Feasibility Assessment in Patients with Parkinson’s Disease and Friedreich’s Ataxia

Disease Category: Friedreich's Ataxia
Location: University of South Florida- Mosani Center for Advnaced Healthcare, Tampa, FL 33612 United States

This study includes the use of a 3D motion device that measures movement in three directions. It is being used as part of this research study to find out if it accurately tracks motion so it can be used in other ataxia research trials in the future.

EUCHROMATIC REGION TARGETING METHODS FOR MODULATING GENE EXPRESSION

United States Patent Application 20150232858, Inventors: Ozsolak, Fatih (Boston, MA, US), RaNA Therapeutics, Inc. (Cambridge, MA, US). Publication Date: 08/20/2015


According to some aspects of the invention, methods and compositions are provided herein that are useful for increasing gene expression in a targeted and specific manner. Aspects of the invention are based on the identification of euchromatic regions of genes that overlap with sequences encoding antisense RNA transcripts. It has been found that oligonucleotides that are complementary to these particular euchromatic regions of target genes are useful for increasing expression of target genes when delivered to cells. In some embodiments, oligonucleotides are provided that are complementary with these euchromatic regions and that have chemistries suitable for delivery, hybridization and stability within cells. Furthermore, in some embodiments, oligonucleotide chemistries are provided that are useful for controlling the pharmacokinetics, biodistribution, bioavailability and/or efficacy of the oligonucleotides in vivo. Accordingly, in some embodiments, oligonucleotides provided herein are useful for the treatment of diseases or conditions associated with decreased levels of target genes.....

Friedreich's Ataxia Symposium, Date: Oct 12

Date: Oct 12, 7:30 a.m.-4:00 p.m. (ET). DoubleTree by Hilton Hotel Philadelphia – Valley Forge. 301 West DeKalb Pike, King of Prussia, PA 19406

The Friedreich’s Ataxia Center of Excellence at The Children’s Hospital of Philadelphia is pleased to present this one-day symposium providing patients and families with up-to-date clinical information on therapeutic approaches and current research being conducted in the field of Friedreich’s ataxia.

University of South Florida and Friedreich's Ataxia Research Alliance to host scientific symposium

EurekAlert. Pharma, biotech leaders to discuss new clinical studies testing drugs and gene therapy for FA. University of South Florida (USF Health)

Tampa, FL (Sept 1, 2015) -- The University of South Florida (USF) will again bring together leading researchers and patients searching for a treatment for Friedreich's ataxia and related disorders at the seventh annual scientific symposium "Understanding Energy for A Cure." The symposium will be held 5 to 8:30 p.m., Thursday, Sept. 17, at the USF Marshall Student Center Ballroom, USF Cedar Circle, Tampa, FL 33620.

An exploratory qualitative investigation of psychosocial determinants of parental decisions to support sport participation for youth with a mobility impairment

Celina H. Shirazipour, Amy E. Latimer-Cheung, Kelly P. Arbour-Nicitopoulos, Research in Developmental Disabilities, Volumes 45–46, October–November 2015, Pages 400-410, ISSN 0891-4222, http://dx.doi.org/10.1016/j.ridd.2015.08.001.

Compared to parents of non-athletes, parents of athletes identified different, more specific positive outcome expectations, including: being included and family networking. First, while parents of non-athletes viewed inclusion as a social benefit, half of parents of athletes stated that inclusion through sport and being part of the mainstream were important benefits in their own rights, providing distinct outcomes including a sense of normalcy. Second, half of the parents of athletes identified the family benefit of networking with other families. The family network developed within the sport organization provided opportunities to share their enjoyment of their children’s participation, discuss impairment concerns, and gain knowledge from others’ experiences.

Evidence for chromosome fragility at the frataxin locus in Friedreich ataxia

Daman Kumari, Bruce Hayward, Asako J. Nakamura, William M. Bonner, Karen Usdin,Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Available online 30 August 2015, ISSN 0027-5107, http://dx.doi.org/10.1016/j.mrfmmm.2015.08.007.

The region of chromosome 9 that contains the Frataxin (FXN) locus is prone to breakage and rearrangements.This chromosome fragility involves the generation of chromosome/chromatid gaps or breaks, or the high frequency loss of one or both copies of the affected gene when cells are grown under folate stress or as we showed previously, in the presence of an inhibitor of the ATM checkpoint kinase.

Investigation of mitochondrial DNA variations among Indian Friedreich's ataxia (FRDA) patients

Inder Singh, Mohammed Faruq, Madakasira Vasantha Padma, Vinay Goyal, Madhuri Behari, Ashoo Grover, Mitali Mukerji, Achal K. Srivastava, Mitochondrion, Available online 29 August 2015, ISSN 1567-7249, http://dx.doi.org/10.1016/j.mito.2015.08.003.

Overall, our study identifies the functionally important variations and mitochondrial lineage of Indian FRDA cases and, that underscores the importance of studying the role of mitochondrial genome variations in FRDA.

Stable isotopes and LC–MS for monitoring metabolic disturbances in Friedreich's ataxia platelets

Andrew J Worth, Sankha S Basu, Eric C Deutsch, Wei-Ting Hwang, Nathaniel W Snyder, David R Lynch, and Ian A Blair, Bioanalysis, Vol. 7, No. 15 , Pages 1843-1855 (doi: 10.4155/bio.15.118)

Platelets can be used as a surrogate tissue for in vivo biomarker studies to monitor new therapeutic approaches for the treatment of FRDA.

MDA Awards $10 million in new Research Grants

CHICAGO, Aug. 26, 2015 /PRNewswire/ -- Powered by its big-picture perspective to accelerate treatments and cures across the broad spectrum of neuromuscular diseases, MDA today announced the award of $10 million in new research grants to the world's brightest scientists conducting leading-edge discovery for muscular dystrophy, ALS and related muscle-debilitating diseases.

Among the new MDA research grants: Expanding therapeutic possibilities in Friedreich's ataxia (FA): Scientists at the University of Oklahoma Health Sciences Center will work to find the optimal HDAC inhibitor and dose for increasing production of the frataxin protein, which is deficient in FA and, in parallel, test an alternative HDAC inhibitor that may prove more effective than others tested to date.

Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial

Silvia Romano, Giulia Coarelli, Christian Marcotulli, Luca Leonardi, Francesca Piccolo, Maria Spadaro, Marina Frontali, Michela Ferraldeschi, Maria Chiara Vulpiani, Federica Ponzelli, Marco Salvetti, Francesco Orzi, Antonio Petrucci, Nicola Vanacore, Carlo Casali, Giovanni Ristori, The Lancet Neurology, Available online 25 August 2015, ISSN 1474-4422, http://dx.doi.org/10.1016/S1474-4422(15)00201-X.

Previous study in patients with cerebellar ataxias of different causes showed significant benefit of riluzole after 8 weeks. The study aimed to confirm these results in patients with spinocerebellar ataxia or Friedreich's ataxia in a 1-year trial.
This trial lends support to the idea that riluzole might be efficacious in the treatment of patients with cerebellar ataxia, in addition to its present indication for amyotrophic lateral sclerosis. The drug effect seems to be unaffected by adjustment for the different clinical forms of ataxia. The findings suggest that riluzole could eventually be used in clinical practice, but confirmatory studies on larger and disease-specific populations, for a longer observation period are needed.

Rare inherited diseases merit disease-specific trials

Alexandra Durr, The Lancet Neurology, Available online 25 August 2015, ISSN 1474-4422, http://dx.doi.org/10.1016/S1474-4422(15)00217-3.

Have Been recently presented the results the trial of riluzole, the study included patients with Friedreich's ataxia, SCA1, SCA2, SCA6, SCA8 and SCA10. Cerebellar ataxia, which include a multitude of different, rare genetic entities, are a difficult set of diseases for such studies.
The clinician eager to treat patients is left with some important questions about the design of trials for rare diseases. Is it appropriate to mix different forms of ataxias in a therapeutic trial?
To take into account the large variety of known and unknown confounding factors in disease progression and treatment response, trials in rare inherited diseases should: be disease-specific, and account for genetic forms of disease.

Compassionate use of orphan drugs

Hanna I. Hyry, Jeremy Manuel, Timothy M. Cox and Jonathan C. P. Roos. Orphanet Journal of Rare Diseases 2015, 10:100 doi:10.1186/s13023-015-0306-x

OPEN ACCESS

Compelling self-interested, legal and ethical arguments can be mounted to encourage manufacturers to offer therapies on a compassionate use basis and these are often equally applicable to provision on a humanitarian aid basis. The EU’s compassionate use programmes are instrumental in ensuring continuity of access to drugs until approval and reimbursement decisions are finalised. We propose the creation of a registry of drugs offered on a compassionate use basis; further transparency would allow such programmes to be evaluated and direct patients to sources of treatment. 

Atypical Presentation for Friedreich Ataxia in a Child

Caron, Elena MD; Burns, Dennis MD; Castro, Diana MD; Iannaccone, Susan T. MD, Journal of Clinical Neuromuscular Disease:
September 2015 - Volume 17 - Issue 1 - p 13–17, doi: 10.1097/CND.0000000000000086

Missense mutations are rare causes of Friedreich ataxia that can only be detected by sequencing of the FXN gene. Sequencing of the FXN gene is essential to make an early diagnosis when there is an atypical phenotype.

Effectiveness, safety and costs of orphan drugs: an evidence-based review

Effectiveness, safety and costs of orphan drugs: an evidence-based review Evidence based practice . Igho J Onakpoya, Elizabeth A Spencer, Matthew J Thompson, Carl J Heneghan; BMJ Open 2015;5:e007199 doi:10.1136/bmjopen-2014-007199

OPEN ACCESS

The available evidence suggests that there is inconsistency in the quality of evidence of approved orphan drugs, and there is no clear mechanism for determining their prices. In some cases, far cheaper generic agents appear to be available. A more robust, transparent and standard mechanism for determining annual costs is imperative

Targeting mitochondrial metal dyshomeostasis for the treatment of neurodegeneration

Jeffrey R Liddell, Neurodegenerative Disease Management, Posted online on August 21, 2015. (doi:10.2217/nmt.15.19)


Several trials indicate that redistributing iron may be an effective treatment for FRDA, but precise dosage control is required for optimal results.

Phenotypic Screening for Friedreich Ataxia Using Random shRNA Selection

M. Grazia Cotticelli, Fabio Acquaviva, Shujuan Xia, Avinash Kaur, Yongping Wang, Robert B. Wilson; J Biomol Screen August 18, 2015, doi: 10.1177/1087057115600433

The EuroBioBank Network: 10 years of hands-on experience of collaborative, transnational biobanking for rare diseases

Marina Mora, Corrado Angelini, Fabrizia Bignami, Anne-Mary Bodin, Marco Crimi, Jeanne- Hélène Di Donato, Alex Felice, Cécile Jaeger, Veronika Karcagi, Yann LeCam, Stephen Lynn, Marija Meznaric, Maurizio Moggio, Lucia Monaco, Luisa Politano, Manuel Posada de la Paz, Safaa Saker, Peter Schneiderat, Monica Ensini, Barbara Garavaglia, David Gurwitz, Diana Johnson, Francesco Muntoni, Jack Puymirat, Mojgan Reza, Thomas Voit, Chiara Baldo, Franca Dagna Bricarelli, Stefano Goldwurm, Giuseppe Merla, Elena Pegoraro, Alessandra Renieri, Kurt Zatlouka, Mirella Filocamo and Hanns Lochmüller; European Journal of Human Genetics (2015) 23, 1116–1123; doi:10.1038/ejhg.2014.272;

In the field of rare diseases (RDs) the number of available biospecimens is, in general, very limited. As a direct consequence of disease rarity, clinical trials are difficult to perform and so a limited number of treatments have been developed, whereas disease prognosis and natural history are poorly known, and patients with RDs do not receive the care and medical attention available to people with common diseases. Sharing material and data on RDs is essential for identifying disease-causing genes, studying pathological mechanisms, and developing treatments.

Mitochondrial dynamism and heart disease: changing shape and shaping change

Gerald W Dorn; EMBO Mol Med. 2015 July; 7(7): 865–877. doi: 10.15252/emmm.201404575

A example of heart disease provoked by primary genetic mitochondrial dysfunction is Friedreich's ataxia. This autosomal recessive neurodegenerative disease is caused by triplet nucleotide repeat expansions within the FXN gene, encoding the mitochondrial matrix iron chaperone protein frataxin. In addition to progressive dorsal sensory nerve degeneration and ataxia, hypertrophic cardiomyopathy is seen in a majority of patients; heart failure is the terminal diagnosis in approximately one-third of affected individuals. Cardiac mitochondria in Friedreich's ataxia undergo massive proliferation with decreased ATP production, consistent with functional compromise of the electron transport chain.

PGC-1 coactivators in β-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids

Daniel Oropeza, Nathalie Jouvet, Khalil Bouyakdan, Gabrielle Perron, Lea-Jeanne Ringuette, Louis H. Philipson, Robert S. Kiss, Vincent Poitout, Thierry Alquier, Jennifer L. Estall, Molecular Metabolism, Available online 14 August 2015, ISSN 2212-8778, http://dx.doi.org/10.1016/j.molmet.2015.08.001.

"These data highlight the importance of PGC-1s in coupling β-cell lipid metabolism to promote efficient insulin secretion."

PGC-1alpha Down-Regulation has been previously described as an important factor involved in many aspects of the pathogenesis of Friedreich's ataxia. Dr. Massimo Pandolfo (*) in a paper published in 2010 linked it to the deficiencies in the antioxidant response in Friedreich's ataxia.

It is widely known his involvement in many mitochondrial diseases, neurodegenerative diseases, diabetes, heart disease, etc.

Even though is not a specific AF study, this article is particularly interesting because it increases the knowledge about the effects of PGC-1 variations in very important aspects presents in FA, mitochondrial disturbances, diabetes, altered lipid metabolism, etc.

Currently FA researchers are showing that exists also an important component due to altered lipid metabolism in the disease, accumulation of lipid droplets in some cell types most affected by the low level of frataxin could cause problems with the lipid oxidation increasing the oxidative stress.


*PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's ataxia, PLoS ONE 5 (4): e10025 do:. 10.1371 / journal. pone. 0010025

Retrotope announces open enrollment for Friedreich's ataxia clinical trial

LOS ALTOS, Calif., Aug. 17, 2015 /PRNewswire/ -- Retrotope announces the opening of enrollment for a 28-day, first-in-human, randomized, double-blind, controlled, ascending dose study of orally dosed RT001 to evaluate the safety, tolerability, pharmacokinetics (PK), disease state, and exploratory endpoints in patients with Friedreich's ataxia (FA).

About RT001: Retrotope has discovered that a mechanism common to many degenerative diseases, namely, the free radical degradation of lipids in mitochondrial and cellular membranes, may actually cause disease. Free radicals attack and degrade the polyunsaturated fats (PUFAs) that are essential components of cellular membranes. We and others have shown that the degradation products of these fats are associated with many diseases of neurodegeneration and aging, and create further damage cascades that are toxic to cells. Retrotope's lead compound (RT001) is a patented, orally available, stabilized fatty-acid that shuts down this degradation and stabilizes ("fireproofs") cellular membranes against further attack.

The case of a missing QRS complex

Eric A. Meyerowitz, Ralph J. Verdino, The case of a missing QRS complex, Journal of Electrocardiology, Available online 8 August 2015, ISSN 0022-0736, http://dx.doi.org/10.1016/j.jelectrocard.2015.07.017.

A 26-year-old man with a history of Friedreich's ataxia, previously on no cardiac medications, presented to an outside hospital with new-onset systolic heart failure with an episode of chest pain and palpitations .....

Benefits of exercise in neurodegenerative diseases

By a lot of personal experiences explained by many affected by Friedreich's ataxia it is well known that exercise is beneficial to maintain the physical and psychological capabilities. These studies, in MS and in the early stages of Alzheimer's disease (AD), are pointing in the same direction in other neurodegenerative diseases.


Exercise May Reduce Disease Activity in Children With Multiple Sclerosis: DG News-Neurology, MINNEAPOLIS -- August 12, 2015 -- A study published in the online issue of the journal Neurology suggests children with multiple sclerosis (MS) who exercise regularly may have a less active disease.

“These findings add to the possibility that physical activity may have a beneficial effect on the health of the brain,” said Dr. Yeh. She noted that the study does not determine a cause-and-effect relationship between physical activity and disease activity in MS, but only shows an association between the two.

MRI Findings Show Neuroprotective Benefits of Aerobic Exercise in Patients With Early Alzheimer’s Disease: DocGuide Washington, DC -- July 22, 2015, by Brian Hoyle -- Aerobic exercise demonstrates neuroprotective benefits in the white matter connections of patients with early-stage Alzheimer’s disease (AD), according to results of a small, randomised study presented at the 2015 Alzheimer’s Association International Conference (AAIC).

Adherence to the exercise program was considered good in both the aerobic and nonaerobic groups (86.3% and 96.7%, respectively). These findings offer evidence-based support for the neuroprotective value of aerobic exercise. In particular, the researchers concluded, this patient population demonstrates that beneficial brain changes can occur even after the diagnosis of AD. The exercise was not overly taxing, Dr. Perea noted, and could be performed by many patients with AD, who would enjoy the other attendant benefits that exercise brings.

Idebenone Protects against Oxidized Low Density Lipoprotein Induced Mitochondrial Dysfunction in Vascular Endothelial Cells via GSK3β/β-catenin signaling pathways

Pengfei Lin, Junling Liu, Ming Ren, Kunqian Ji, Ling Li, Bin Zhang, Yaoqin Gong, Chuanzhu Yan, Idebenone Protects against Oxidized Low Density Lipoprotein Induced Mitochondrial Dysfunction in Vascular Endothelial Cells via GSK3β/β-catenin signaling pathways, Biochemical and Biophysical Research Communications, Available online 15 August 2015, ISSN 0006-291X, http://dx.doi.org/10.1016/j.bbrc.2015.08.058.

Intel just open sourced Stephen Hawking’s speech system and it’s a .NET 4.5 WinForms app that you can try for yourself

Mansib Rahman, Canadian Developer Connection. 14 Aug 2015

As we all know, the venerable physicist Professor Stephen Hawking is unable to talk as he is afflicted with ALS and thus relies on a computer system to communicate. In 2011, his condition was deteriorating so badly that he could best communicate at a rate of only 2 words per minute. He reached out to Alan Moore at Intel and asked if Intel could come up with new technology to help his plight.

Well, what are you waiting for? You can try all this out for yourself. Visit the software's Github release page to get the installer.

Nrf2—a therapeutic target for the treatment of neurodegenerative diseases

Nrf2—a therapeutic target for the treatment of neurodegenerative diseases. Delinda A. Johnson, Jeffrey A. Johnson, Free Radical Biology and Medicine, Available online 14 August 2015, Page FRBMD1500535, ISSN 0891-5849, http://dx.doi.org/10.1016/j.freeradbiomed.2015.07.147.

The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Recently, a clinical trial using RTA 408 was initiated for Friedreich’s ataxia, a neurodegenerative condition responsible for cerebellar ataxia due to impaired production of the protein frataxin leading to profound deficiencies in mitochondrial respiration (ClinicalTrials.gov Identifier NCT02255435).

PATENT: SMALL MOLECULE ACTIVATORS OF MITOCHONDRIAL FUNCTION

NEW PATENT: SMALL MOLECULE ACTIVATORS OF MITOCHONDRIAL FUNCTION.
Inventor(s): WILSON ROBERT B [US]; COTTICELLI MARIA GRAZIA [US]; BENEDETTI PHILLIP A [US]; SMITH AMOS [US]; MELVIN JASON E [US]; HURYN DONNA M [US]
Applicant(s): UNIV PENNSYLVANIA [US]
Original document: WO2010068767 (A1) ― 2010-06-17

Key Patent Granted For AAVLife’s Gene-Therapy Program to Treat Cardiomyopathy in Friedreich’s Ataxia

Key Patent Granted For AAVLife’s Gene-Therapy Program to Treat Cardiomyopathy in Friedreich’s Ataxia. BUSINESS WIRE, August 05, 2015

The patent broadly protects a promising method for treating cardiomyopathy by using an adeno-associated virus (AAV) vector to carry into cells a gene expressing the protein frataxin. The patent will run until 2033 or longer in the event of a successful application for an extension. Corresponding patent applications are pending in major markets globally. 

The quality of economic evaluations of ultra-orphan drugs in Europe – a systematic review

The quality of economic evaluations of ultra-orphan drugs in Europe – a systematic review. Y. Schuller, C. E. M. Hollak and M. Biegstraaten; Orphanet Journal of Rare Diseases 2015, 10:92 doi:10.1186/s13023-015-0305-y

OPEN ACCESS

In the European Union (EU), a disease is considered ‘orphan’ if it is a life-threatening or seriously debilitating disorder that affects fewer than 1 per 2 000. An orphan disease is defined in the EU as a disorder affecting less than 1 in 2 000 individuals. The concept of ultra-orphan has been proposed for diseases with a prevalence of less than 1:50 000. According to this classification Friedreich's Ataxia is within the group of the "orphan", although is close to the upper border of the "ultra-orphan", so share with the "ultra-orphan" many of the problems for the development of drugs and therapies.

Friedreich Ataxia in Classical Galactosaemia

Friedreich Ataxia in Classical Galactosaemia. Siobhán Neville, Siobhan O’Sullivan, Bronagh Sweeney, Bryan Lynch, Donncha Hanrahan, Ina Knerr, Sally Ann Lynch, Ellen Crushell; JIMD Reports, 29 Jul 2015, DOI 10.1007/8904_2015_477

Both conditions are known to occur with increased frequency amongst the Irish Traveller population. Neurological symptoms are easily attributed to an underlying diagnosis of galactosaemia. It is important to consider a diagnosis of Friedreich ataxia in a child from the Irish Traveller population with galactosaemia who presents with ataxia or cardiomyopathy.

Friedreich’s Ataxia Research Collaboration Announced

Friedreich’s Ataxia Research Collaboration Announced. Medical Sciences Division, University of Oxford, 30 July 2015.

A new collaborative drug discovery project in Friedreich’s Ataxia (FA) between the University of Oxford, Ataxia UK, Pfizer Inc, UCL and Imperial College London was recently announced.
The programme will initially run for three years and aims to develop a potential new medicine or therapy for Friedreich’s ataxia that, if successful, may be tested in clinical trials.

Les médicaments orphelins : des opportunités méconnues pour les développeurs en Europe

Les médicaments orphelins : des opportunités méconnues pour les développeurs en Europe. Orphan Drugs: Underrated Opportunities for The Developers in Europe. Yves Tillet et Anne-Catherine Maillols-Perroy; Thérapie 2015 Juillet-Août; 70 (4): 351–357

Key words: Orphan Drug Act / regulation 141/2000/EC / implementing regulation 847/2000 / Commission communication (2003/C 178/02) / orphan medical product / 10 year market exclusivity / similar medicinal product / significant benefit / clinical superiority / assumption of significant benefit

Mitigation of Myocardial Ischemia-Reperfusion Injury via HIF-1α-Frataxin Signalling.

Mitigation of Myocardial Ischemia-Reperfusion Injury via HIF-1α-Frataxin Signalling. Nelson Amaral, Darlington Okonko; American Journal of Physiology - Heart and Circulatory Physiology Published 25 July 2015 Vol. no. , DOI: 10.1152/ajpheart.00553.2015

Resources, challenges and way forward in rare mitochondrial diseases research.

Resources, challenges and way forward in rare mitochondrial diseases research. Rajput NK, Singh V and Bhardwaj A. [v1; ref status: indexed, http://f1000r.es/54x] F1000Research 2015, 4:70 (doi: 10.12688/f1000research.6208.1) OPEN ACCESS

Rare diseases affect over 300 million people globally, however the true burden of these diseases on human health remains to be determined. Rare genetic variants are disease causing and lead to a personalized disease manifestation. Thus, it is time to review the disease definition considering both the molecular mechanisms involved and environmental factors leading to differential phenotypes. This will allow for a better understanding of both rare and common diseases. On the other end, a paradigm shift in drug discovery and development is also needed to translate the effort in understanding disease mechanisms to identify potential therapeutic routes. Newer models and platforms that allow involvement of patient communities in research and development is also expected to offer solutions to patients suffering from rare diseases who may then benefit from appropriate treatment options. Community collaborative approaches for research and funding offer an unprecedented opportunity for making new discoveries and translating to therapeutic interventions.

L'atàxia de Friedreich: estudi del dèficit de frataxina en miòcits cardíacs

Friedreich's ataxia: a study of frataxin deficiency in cardiac myocytes. Author: Èlia Obis Monné, Director: Jordi Tamarit Sumalla, Joaquim Ros Salvador; Thesis, date of defense:2014-12-10, Universitat de Lleida. Departament de Ciències Mèdiques Bàsiques. Tesis Doctorals en Xarxa (Universitat de Lleida)

Full text files in this thesis will be available from 2015-12-10



Frataxin deficiency in cardiac myocytes causes an alteration of the mitochondrial network and oxidative stress. Furthermore, cardiac myocytes undergo a change in the metabolic profile and accumulate large amounts of fatty acids in lipid droplets.

More information.....

RNA-based drugs, very promising research (RaNA Therapeutics)

RNA-based drugs, very promising research (RaNA Therapeutics). EXOME News, Ben Fidler July 23rd, 2015 and The Boston Globe (Bussines)  by Jack Newsham Globe Correspondent  July 23, 2015

RaNA Therapeutics, a Cambridge-based drug startup, announced today will help fund the preclinical work needed to get at least two programs into human trials in 2017. So far the company has touted potential therapies for spinal muscular atrophy and Friedreich’s Ataxia. These therapies are RNA-based drugs meant to switch back on genes that are silenced in certain diseases, and thus don’t produce critical proteins (like spinal motor neuron in the case of people with SMA, and frataxin for those with Friedreich’s). (EXOME)


The company said Thursday that it raised the funds from a group of new and existing investors led by MRL Ventures, an arm of the drug giant Merck, and the Baupost Group. RaNA plans to have one or two treatments for spinal muscular atrophy and Friedreich’s ataxia in clinical trials by 2017. (The Boston Globe)


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A study of up to 12 years of follow-up of Friedreich ataxia utilising four measurement tools

A study of up to 12 years of follow-up of Friedreich ataxia utilising four measurement tools. Geneieve Tai, Louise A Corben, Lyle Gurrin, Eppie M Yiu1, Andrew Churchyard, Michael Fahey, Brian Hoare, Sharon Downie, Martin B Delatycki;
J Neurol Neurosurg Psychiatry 2015;86:660-666 doi:10.1136/jnnp-2014-308022

Individuals with larger GAA1 repeat sizes and earlier ages of disease onset were shown to deteriorate at a faster rate and were associated with greater FARS and ICARS scores and lower FIM and MBI scores, which are indicative of greater disease severity.

Haptic wearables as sensory replacement, sensory augmentation and trainer – a review

Haptic wearables as sensory replacement, sensory augmentation and trainer – a review. Peter B. Shull and Dana D. Damian; Journal of NeuroEngineering and Rehabilitation 2015, 12:59 doi:10.1186/s12984-015-0055-z
OPEN ACCESS

Sensory impairments decrease quality of life and can slow or hinder rehabilitation. Small, computationally powerful electronics have enabled the recent development of wearable systems aimed to improve function for individuals with sensory impairments. The purpose of this review is to synthesize current haptic wearable research for clinical applications involving sensory impairments. This review found that wearable haptic devices improved function for a variety of clinical applications including: rehabilitation, prosthetics, vestibular loss, osteoarthritis, vision loss and hearing loss

Specialized Cortex Glial Cells Accumulate Lipid Droplets in Drosophila melanogaster.

Specialized Cortex Glial Cells Accumulate Lipid Droplets in Drosophila melanogaster. Viktor Kis,* Benjámin Barti, Mónika Lippai, and Miklós Sass; PLoS One. 2015; 10(7): e0131250.
Published online 2015 July 6. doi: 10.1371/journal.pone.0131250 OPEN ACCESS

While a large portion of the Drosophila neurodegeneration mutants (bubblegum, swiss cheese, loechrig, ApoD, frataxin, sicily) [19–23] affect lipid metabolism and disturb LD homeostasis, neither the cellular, nor the spatio-temporal distribution of LDs has been described to date in Drosophila. In this paper, we used the brain of the fruitfly to study lipid droplet anatomy in the larval nervous system.

Oxidative Stress and the Homeodynamics of Iron Metabolism

Oxidative Stress and the Homeodynamics of Iron Metabolism. Nikolaus Bresgen and Peter M. Eckl; Biomolecules 2015, 5(2), 808-847; doi:10.3390/biom5020808

In conclusion, cellular iron homeodynamics is based on a well-orchestrated interaction of iron uptake, intracellular transport, iron storage, usage and export, which is embedded in cellular metabolic and surveillance control. Under stress conditions, this orchestration changes in order to maintain homeodynamics and protect the cell from severe destabilization.

Gene Expression Profile in Peripheral Blood Cells of Friedreich Ataxia Patients

Gene Expression Profile in Peripheral Blood Cells of Friedreich Ataxia Patients. Agessandro Abrahao, Jose Luiz Pedroso, Patricia de Carvalho Aguiar and Orlando Barsottini; Neurology April 6, 2015 vol. 84 no. 14 Supplement P2.122

We found a robust downregulation of FXN, but no statistically significant differences were found between FRDA and controls for the remaining genes. Except for FXN, our study did not find a differential gene expression profile in PBCs of FRDA patients and a reliable gene expression profile biomarker obtained from an easily accessible tissue remains unclear.

Clinical Trial: Biomarkers in Friedreich's Ataxia

Clinical Trial: Biomarkers in Friedreich's Ataxia ClinicalTrials.gov Identifier: NCT02497534. First received: July 7, 2015

Sponsor: University of Florida

The purpose of this project is to characterize measures of cardiac performance and neuromuscular physiology in FA patients using novel techniques, including echocardiography and magnetic resonance imaging (MRI), metabolic exercise testing, and neurophysiological outcomes.

This study is not yet open for participant recruitment.

Regional Cerebral Disease Progression in Friedreich's Ataxia: A Longitudinal Diffusion Tensor Imaging Study

Regional Cerebral Disease Progression in Friedreich's Ataxia: A Longitudinal Diffusion Tensor Imaging Study. Mascalchi, M., Toschi, N., Giannelli, M., Ginestroni, A., Della Nave, R., Tessa, C., Piacentini, S., Dotti, M. T., Aiello, M., Nicolai, E., Soricelli, A., Salvi, F. and Diciotti, S., Journal of Neuroimaging.(2015) doi: 10.1111/jon.12270

DTI can track brain microstructural changes in FRDA and can be considered a potential biomarker of disease progression.

Science Heroes: Annalisa Pastore: A love story with the double helix that started at 17

Science Heroes: Annalisa Pastore: A love story with the double helix that started at 17. Frontiers Blog, Posted on July 14, 2015

This led her to—at least partially— identify the role of the protein, resulting from the expression of frataxin, in the disease mechanism. These findings could ultimately open the door to designing a new strategy to treat Friedreich’s ataxia, and other neurodegenerative diseases.

Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism.

Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism. Rikke K. J. Olsen, Nanna Cornelius, and Niels Gregersen; J Inherit Metab Dis. 2015; 38(4): 703–719.
Published online 2015 May 30. doi: 10.1007/s10545-015-9861-5

Springer OPEN Choice

Based on our own and other’s studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism, by production of pathological amounts of ROS, may cause disturbed redox signalling and induce chronic cell stress with non-resolving or compromised cell repair responses and increased susceptibility to cell stress induced cell death.

TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia

TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia. Pablo Calap-Quintana, Sirena Soriano, José Vicente Llorens, Ismael Al-Ramahi, Juan Botas, María Dolores Moltó, María José Martínez-Sebastián; PLoS ONE 10(7): e0132376. doi:10.1371/journal.pone.0132376

OPEN ACCESS

We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment.

Familial segmental spinal myoclonus: a rare clinical feature of Friedreich’s ataxia

Familial segmental spinal myoclonus: a rare clinical feature of Friedreich’s ataxia. Rajendra Singh Jain, Sunil Kumar and Shankar Tejwani, SpringerPlus 2015, 4:330 doi:10.1186/s40064-015-1121-5

OPEN ACCESS


Spinal segmental myoclonus (SSM) is a unique and rare manifestation of FRDA. This might be the first case report of SSM in FRDA patient.

Dynamics in the sense of dignity over the course of illness: A longitudinal study into the perspectives of seriously ill patients

Dynamics in the sense of dignity over the course of illness: A longitudinal study into the perspectives of seriously ill patients. Isis E. van Gennip, H. Roeline W. Pasman, Mariska G. Oosterveld-Vlug, Dick L. Willems, Bregje D. Onwuteaka-Philipsen; International Journal of Nursing Studies, Available online 27 June 2015, ISSN 0020-7489, http://dx.doi.org/10.1016/j.ijnurstu.2015.06.010.

Single-molecule spectroscopy of protein conformational dynamics in live eukaryotic cells

Single-molecule spectroscopy of protein conformational dynamics in live eukaryotic cells. Iwo König, Arash Zarrine-Afsar, Mikayel Aznauryan, Andrea Soranno, Bengt Wunderlich, Fabian Dingfelder, Jakob C Stüber, Andreas Plückthun, Daniel Nettels & Benjamin Schuler; Nature Methods (2015)doi:10.1038/nmeth.3475 Published online 06 July 2015

Advances in methodology are making it gradually more feasible to investigate biomolecular processes in their native cellular environment. The ultimate goal is to reach quantitative molecular understanding with the same rigor as in test-tube experiments.The results on protein GB1 and frataxin indicated a remarkable robustness in the conformational stabilities and even folding kinetics of these proteins in cells compared to in simple buffered solutions. We therefore expect that single-molecule spectroscopy will play an important role in bridging the gap between our quantitative understanding of biomolecules in vitro and in vivo.


Source: Single-molecule spectroscopy of protein conformational dynamics in live eukaryotic cells

Ultra-structural hair alterations in Friedreich's ataxia: A scanning electron microscopic investigation

Ultra-structural hair alterations in Friedreich's ataxia: A scanning electron microscopic investigation. Turkmenoglu, F. P., Kasirga, U. B. and Celik, H. H., Microsc. Res. Tech.. Article first published online: 3 JUL 2015 doi: 10.1002/jemt.22531

«SARAgrama»: una propuesta de representación gráfica en la evolución de las ataxias

«SARAgrama»: una propuesta de representación gráfica en la evolución de las ataxias. « SARAgraph»: A proposed graphic system for representing ataxia progression . I. Pulido-Valdeolivas, D. Gómez-Andrés, I. Sanz-Gallego, J. Arpa-Gutiérrez, Neurología (English Edition), Available online 11 June 2015,

MRI abnormalities of the cerebellar cortex and nuclei in SCA3, SCA6, and Friedreich’s ataxia

MRI abnormalities of the cerebellar cortex and nuclei in SCA3, SCA6, and Friedreich’s ataxia. M.R. Stefanescu, M. Dohnalek, S. Maderwald, M. Thürling, M. Minnerop, A. Beck, M. Schlamann, J. Diedrichsen, M.E. Ladd, D. Timmann, Clinical Neurophysiology, Volume 126, Issue 8, August 2015, Page e73, ISSN 1388-2457, http://dx.doi.org/10.1016/j.clinph.2015.04.094

Do large purine repeat sequences play a role in transcriptional regulation of genes associated with neurological disorders?

Do large purine repeat sequences play a role in transcriptional regulation of genes associated with neurological disorders?. Himanshu Narayan Singh, Moganty R. Rajeswari, Gene, Available online 3 July 2015, ISSN 0378-1119, http://dx.doi.org/10.1016/j.gene.2015.07.007.

Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans

Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans. Alfonso Schiavi, Silvia Maglioni, Konstantinos Palikaras, Anjumara Shaik, Flavie Strapazzon, Vanessa Brinkmann, Alessandro Torgovnick, Natascha Castelein, Sasha De Henau, Bart P. Braeckman, Francesco Cecconi, Nektarios Tavernarakis, Natascia Ventura; Current Biology, Available online 2 July 2015, ISSN 0960-9822, http://dx.doi.org/10.1016/j.cub.2015.05.059.

Mitochondrial autophagy is an evolutionarily conserved response to frataxin silencing, mitophagy is activated in response to mitochondrial stress. Mitophagy induction is part of an adaptive iron starvation response induced as a protective mechanism against mitochondrial stress, thus suggesting novel potential therapeutic strategies for the treatment of mitochondrial disorders.

Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia

Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia. Rosella Abeti, Ebru Uzun, Indhushri Renganathan, Tadashi Honda, Mark A. Pook, Paola Giunti, Pharmacological Research, Available online 2 July 2015, ISSN 1043-6618, http://dx.doi.org/10.1016/j.phrs.2015.05.015.

Two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger Nrf2 antioxidant pathway.

Keep the fire burning: Current avenues in the quest of treating mitochondrial disorders

Keep the fire burning: Current avenues in the quest of treating mitochondrial disorders. Christin Tischner, Tina Wenz, Mitochondrion, Available online 30 June 2015, ISSN 1567-7249, http://dx.doi.org/10.1016/j.mito.2015.06.002.

Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells

Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells. Shira Yanovsky-Dagan, Hagar Mor-Shaked and Rachel Eiges, World J Stem Cells 2015 June 26; 7(5): 823-838

Frataxin levels in peripheral tissue in Friedreich ataxia

Frataxin levels in peripheral tissue in Friedreich ataxia. Lazaropolous, M., Dong, Y., Clark, E., Greeley, N. R., Seyer, L. A., Brigatti, K. W., Christie, C., Perlman, S. L., Wilmot, G. R., Gomez, C. M., Mathews, K. D., Yoon, G., Zesiewicz, T., Hoyle, C., Subramony, S. H., Brocht, A. F., Farmer, J. M., Wilson, R. B., Deutsch, E. C. and Lynch, D. R.; Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.225

Breaking bad: R-loops and genome integrity

Breaking bad: R-loops and genome integrity. Julie Sollier, Karlene A. Cimprich, Trends in Cell Biology, Available online 1 June 2015, ISSN 0962-8924, http://dx.doi.org/10.1016/j.tcb.2015.05.003.

How a patient advocacy group developed the first proposed draft guidance document for industry for submission to the U.S. Food and Drug Administration

How a patient advocacy group developed the first proposed draft guidance document for industry for submission to the U.S. Food and Drug Administration. Pat Furlong, John F. P. Bridges, Lawrence Charnas, Justin R. Fallon, Ryan Fischer, Kevin M. Flanigan, Timothy R. Franson, Neera Gulati, Craig McDonald, Holly Peay and H. Lee Sweeney; Orphanet Journal of Rare Diseases 2015, 10:82 doi:10.1186/s13023-015-0281-2 Published: 24 June 2015

OPEN ACCESS, FULL TEXT PDF

Transcription blockage by stable H-DNA analogs in vitro

Transcription blockage by stable H-DNA analogs in vitro. Shristi Pandey, Anna M. Ogloblina, Boris P. Belotserkovskii, Nina G. Dolinnaya, Marianna G. Yakubovskaya, Sergei M. Mirkin and Philip C. Hanawalt, Nucl. Acids Res. (2015) doi: 10.1093/nar/gkv622 First published online: June 22, 2015

Open Access, full text pdf



Formation of H-DNA has been implicated in transcription blockage by expanded (GAA)n repeats responsible for the human genetic disease Friedreich's ataxia

TAT-MTS-FXN Protein as Replacement Therapy for Friedreich’s Ataxia

TAT-MTS-FXN Protein as Replacement Therapy for Friedreich’s Ataxia, Dalia Megiddo, MD, Chief Development Officer, Hagar Greif, PhD, Senior Director of Pre Clinical Studies.

Cumulative data highly support TAT-MTS(cs)-Frataxin as Protein Replacement Therapeutic Candidatefor Friedreich’s Ataxia