Clinical trials: To catch a crook, you might try statistics

Gary R. Cutter; Nature Reviews Neurology 13, 9–10 (2017) doi:10.1038/nrneurol.2016.194 Published online 16 December 2016

To reduce research fraud, we need to understand more deeply why professional researchers and clinicians commit fraud. Certainly, personal interest is a major factor. Review boards thoroughly assess conflicts of interest to protect authors from gaining excess monetary gains via publications, but we have little to protect against advancing one’s personal interests — indeed, we reward it. Promotions, grants and grant renewals all depend on publications. Moreover, researchers might commit fraud for more egotistic reasons than mere survival in their chosen career, such as for money or to get a product on the market, to boost the market value of their start‑up company, or perhaps even to deliberately sabotage competitors.
Making trial and other experimental data publicly available have been suggested as one
strategy to reduce fraud, as any interested individual could search for evidence, thereby making fraud less tempting. However, the consequences of the false positives should be kept in mind: do we wish to impugn even one honest researcher in our attempts to catch dishonest ones?.

Single Protein May Hold Secret to Treating Parkinson’s Disease and More

By Dana G. Smith, PhD / Gladstone News / December 26, 2016.

“Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now,” explained first author Gaia Skibinski, PhD, a staff research scientist at Gladstone. “Overexpressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”

The scientists say that Nrf2 itself may be difficult to target with a drug because it is involved in so many cellular processes, so they are now focusing on some of its downstream effects. They hope to identify other players in the protein regulation pathway that interact with Nrf2 to improve cell health and that may be easier to drug.

Synthetic genome readers target clustered binding sites across diverse chromatin states

Graham S. Erwin, Matthew P. Grieshop, Devesh Bhimsaria, Truman J. Do, José A. Rodríguez-Martínez, Charu Mehta, Kanika Khanna, Scott A. Swanson, Ron Stewart, James A. Thomson, Parameswaran Ramanathan, and Aseem Z. Ansari, PNAS 2016 ; published ahead of print November 8, 2016, doi: 10.1073/pnas.1604847113

Nucleosomal DNA, even in heterochromatin, may thus be partially preorganized to accommodate polyamide binding in the minor groove. The linear polyamide (3) studied here was designed to bind to GAA repeats in the first intron of frataxin to alleviate transcriptional repression, a locus that appears to be situated within heterochromatin marked by H3K9me3. Taken together, the ability of polyamides to access heterochromatin (a major barrier to binding to natural and artificial DNA-binding factors) opens unique opportunities to deploy this class of synthetic genome readers to regulate gene networks that direct cellular fate and function.

Correction of the frataxin gene using CRISPR

Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich Ataxia. D L Ouellet, K Cherif, J Rousseau and J-P Tremblay; Gene Therapy, accepted article preview 26 December 2016; doi: 10.1038/gt.2016.89.

Short title: Correction of the frataxin gene using CRISPR

Here, we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo.
All experiments present in this article help to identify the most suitable mouse model for gene editing in vivo, hoping this will quickly lead to human clinical trials in Friedreich ataxia patients. However, as any kind of therapy, the side effects of a treatment must be clearly defined and known before going further with the massive treatment of patients.

DNA repair in the trinucleotide repeat disorders

Lesley Jones, Henry Houlden, Sarah J Tabrizi; The Lancet Neurology, Volume 16, Issue 1, January 2017, Pages 88-96, ISSN 1474-4422, doi:10.1016/S1474-4422(16)30350-7


Some pathogenic mechanisms are common to multiple diseases. For instance, a repeat that prevents gene expression is seen in fragile X syndrome and Friedreich’s ataxia. Mechanisms related to DNA repair have been implicated as modulators of somatic expansion of the disease-associated repeated sequences in mouse modelsof Huntington’s disease, myotonic dystrophy, fragile X syndrome, and Friedreich’s ataxia.

Where next?: To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.

Mitochondrial capacity, muscle endurance & low energy in friedreich ataxia

Hannah. M. Bossie M.S., T. Bradley. Willingham M.S., Robbi. A. Van Schoick M.S., Patrick. J. O'Connor Ph.D. andKevin. K. McCully Ph.D., Muscle & Nerve (Accepted Article) DOI: 10.1002/mus.25524
RESULTS: Groups did not differ in mitochondrial capacity (FRDA and AB: 1.8 ± 0.3 1/min). The difference in muscle endurance at 6 Hz was lower by 19.2% in the FRDA (group affect: P < 0.001). Feelings of physical energy were 34% lower in FRDA. In FDRA muscle, endurance was positively related to mitochondrial capacity (r=0.59, P=0.03), and disease severity was negatively related to mitochondrial capacity (r=-0.55, P=0.04) and muscle endurance (r=-0.60, P=0.01). DISCUSSION: Non-invasive measures of skeletal muscle mitochondrial capacity and muscle specific endurance are useful in monitoring FRDA.

Cytokine therapy-mediated neuroprotection in a Friedreich's ataxia mouse model

Kevin C Kemp MSc, PhD, Nadia Cerminara BSc, PhD, Kelly Hares BSc, PhD, Juliana Redondo BSc, PhD, Amelia J Cook, Harry R Haynes BSc, MBChB, Bronwen R Burton BSc, PhD, Mark Pook BSc, PhD, Richard Apps PhD, Neil J Scolding FRCP, PhD and Alastair Wilkins FRCP, PhD; Annals of Neurology, Accepted Article DOI: 10.1002/ana.24846

Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological and behavioural deficits associated with Friedreich's ataxia. These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying and neuroprotective treatment for Friedreich's ataxia.

Profitability and Market Value of Orphan Drug Companies: A Retrospective, Propensity-Matched Case-Control Study

Hughes DA, Poletti-Hughes J (2016), PLoS ONE 11(10): e0164681. doi:10.1371/journal.pone.0164681

OPEN ACCESS

The small markets associated with rare diseases, however, necessitate high prices for returns to be made on investments, and orphan drugs are generally more expensive than non-orphan drugs. Each one of the world’s 10 most expensive drugs is an orphan, with alipogene tiparvovec (gene therapy approved in Europe for inherited lipoprotein lipase deficiency) ranked highest at about US$1.4m per patient over a year. The revenue-generating potential of orphan drugs is consequently as great as for non-orphan drugs with almost a third being US$1bn blockbuster products in terms of global annual sales.
Orphan drugs also command a higher profit margin, owing to shorter clinical development time, incentives related to research and development, reduced marketing costs and premium pricing. However, it is unclear whether this necessarily translates to higher company profits. One cross-sectional analysis of a small sample of specialised orphan drug companies concluded that they had not performed as strongly as other companies. This observation is not supported by the evidence of the rapid and extensive diversification into the orphan drugs market by large pharmaceutical companies, some of which have established dedicated rare disease units, and acquired or partnered biotech companies already in the rare disease sector.
Concerns have been expressed meanwhile that orphan drug policies are being exploited by companies as treatments initially approved for rare diseases are later used more broadly. Rituximab, as one example, was initially approved as an orphan drug by the FDA for the treatment of follicular non-Hodgkin’s lymphoma. It is now used to treat a wide variety of conditions making it the fourth best-selling drug in the world in 2014.

We hypothesise that companies with orphan drug market authorization are more profitable and are more attractive investment opportunities than non-orphan drug companies. We aimed to test whether the financial performance of publicly listed European and US orphan drug companies is better than matched non-orphan drug companies in terms of their market value and profitability.

Christmas 2016

I wish you peace and prosperity to all of you.

Juan-Carlos Baiges

Evaluation of oligonucleotides for therapy of Friedreich ataxia

Brunel University London. 22/12/2016. Principal Investigator: Dr Mark Pook, Funding body: RaNA Therapeutics.

The aim of this project is firstly to characterise a novel transgenic mouse model of the multi-system autosomal inherited genetic disorder, Friedreich ataxia (FRDA). This mouse model, designated YG8LR, contains the human frataxin transgene together with an inserted 410 GAA repeat expansion mutation. Our studies aim to characterise the FRDA mouse model at molecular, biochemical, histopathological and behavioural levels. Once characterised, the FRDA mouse model will then be used in preclinical studies to investigate the potential of specific frataxin oligonucleotides generated by RaNA Therapeutics to stabilize frataxin mRNA and hence increase frataxin expression.

Using Social Finance to Fund Generic Drug Repurposing for Rare Diseases: A Social Impact Bond Proof of Concept

RS Thompson, J Potter, A Griffiths, S Eljamel, F Raffai, NT Sireau, Value in Health, Volume 19, Issue 7, November 2016, Pages A505-A506, ISSN 1098-3015, doi:10.1016/j.jval.2016.09.923.

Repurposing existing generic pharmaceuticals to treat rare diseases with an unmet medical need has a number of clear benefits; reducing the investment required in drug discovery, and leveraging known information on drug behaviour and safety often in multiple patient populations. Findacure, a  charitable organisation, have completed a proof of concept study into the use of social finance to fund generic drug repurposing research. The proof of concept involved the development of health economic models for congenital hyperinsulinism, Wolfram syndrome, and Friedreich’s ataxia. This study has demonstrated that generic drug repurposing has the potential to save the healthcare system quantities of money sufficient to repay investment in a clinical trial, and build an investable and sustainable financial proposition. Crucially this model would deliver much needed new treatments to rare disease patients, treatments which would otherwise be considered financially inviable.

Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders

Md. Torequl Islam, Neurological Research Vol. 0 , Iss. 0,0, Pages 1-10 doi:10.1080/01616412.2016.1251711

Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich’s ataxia, Huntington’s disease, Multiple sclerosis, and Parkinson’s diseases.
In Friedreich’s ataxia, iron accumulates in the mitochondria and results mitochondrial Fe–S cluster containing proteins (e.g. aconitase) and abnormality in respiratory chain electron transporters on complex I–III, thereby leading to oxidative stress and free radical accumulation. In addition, to heart, the highest concentration of frataxin is found in the spinal cord (SC) and dorsal root ganglia. The frataxin is evident to regulate iron handling in mitochondria, thus prevents iron-induced oxidative stress. The depletion of frataxin in the mitochondria is a consequence in FRDA.

Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms

Rawan Eid, Nagla T.T. Arab, Michael T. Greenwood, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 2, February 2017, Pages 399-430, ISSN 0167-4889, doi:10.1016/j.bbamcr.2016.12.002.

Friedreich's ataxia is another example of a recessive mutation, the mutation results in a dramatic reduction in the expression of frataxin. Frataxin is thought to store iron and to promote Fe-S cluster assembly. In yeast, the overexpression the iron binding prosurvival ferritin serve to increase the viability of cells lacking frataxin while iron chelators are shown to protect cultured cell and animal models of Friedreich's ataxia. In spite of what appears to be iron overload mediated cell death iron chelator have very little therapeutic value. More likely the lack of frataxin is leading to stress, and increase in redox active iron and the induction of PCD. Thus the overexpression of genes encoding proteins with pro-survival or anti-oxidant functions, including ferritin, as well as anti-oxidants may protect from the decrease in frataxin levels.

Dissociating oral motor capabilities: Evidence from patients with movement disorders

Anja Staiger, Theresa Schölderle, Bettina Brendel, Wolfram Ziegler; Neuropsychologia, Available online 8 December 2016, ISSN 0028-3932, doi:10.1016/j.neuropsychologia.2016.12.010.

The objective of the present study was to expand our knowledge of the relationship between speech movements, on the one hand, and speech-like and nonspeech oral motor behaviors, on the other, by using a rate paradigm. 130 patients with neurological movement disorders of different origins and 130 neurologically healthy subjects participated in the study.

UNDERLYING GENETIC CAUSE IN CEREBELLAR ATAXIAS: EVALUATION OF AN IRISH COHORT

Petya Bogdanova-Mihaylova, Raymond PJ Murphy, Richard A Walsh1, Sinéad M Murphy; J Neurol Neurosurg Psychiatry 2016;87:e1 doi:10.1136/jnnp-2016-315106.203

At the National Ataxia Clinic, Tallaght Hospital, from December 2014–April 2016, 137 patients with inherited ataxias were assessed. In December 2014, 53% of 133 patients had a genetically confirmed diagnosis. The commonest in the autosomal-recessive (AR) group were Friedreich's ataxia, Ataxia-telangiectasia (AT), Ataxia with oculomotor apraxia 1&2 (AOA1&2) and, in the autosomal-dominant group, SCA2, SCA3 and SCA14.

Paradoxical Abnormalities of Intra and Postoperative Neuroelectrical Recording of a Scoliotic Child with Friedreich’s Ataxia

Ahmed B. Bayoumi, Zafer Orkun Toktas, Baran Yılmaz, Orkun Koban, Murat Sakir Eksi, Hulya Aydin Gungor and Deniz Konya; EC Neurology 3.2 (2016): 350-353.

Scoliotic patients with Friedrich’s ataxia may show no response during the intra operative neuromonitoring by using MEP or SEP. A wake-up test setting must be planned with anesthesiology team to be done intra operatively for this subset of population to ensure the safety of the spinal procedure. To overcome such circumstances further and to plan the surgery in that fashion, pre-operative baseline neuromonitoring should be obtained in such neuromuscular scoliosis cases.

Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients

M Hadjivassiliou, J Martindale, P Shanmugarajah, R A Grünewald, P G Sarrigiannis, N Beauchamp, K Garrard, R Warburton, D S Sanders, D Friend, S Duty, J Taylor, N Hoggard; J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2016-314863

A total of 1500 patients were assessed over 20 years. Twenty per cent had a family history, the remaining having sporadic ataxia. The commonest cause of sporadic ataxia was gluten ataxia (25%). A genetic cause was identified in 156 (13%) of sporadic cases with other causes being alcohol excess (12%) and cerebellar variant of multiple system atrophy (11%). Using NGS, positive results were obtained in 32% of 146 patients tested. The commonest ataxia identified was EA2. A genetic diagnosis was achieved in 57% of all familial ataxias. The commonest genetic ataxias were Friedreich's ataxia (22%), SCA6 (14%), EA2 (13%), SPG7 (10%) and mitochondrial disease (10%). The diagnostic yield following attendance at the Sheffield Ataxia Centre was 63%.

Mitochondria and Iron: current questions

Bibbin T. Paul, David H. Manz, Frank M. Torti, and Suzy V. Torti; Expert Review of Hematology Vol. 0 , Iss. 0,0 doi:10.1080/17474086.2016.1268047

Several genetic diseases can result in disrupted iron-sulfur cluster biogenesis and severe mitochondrial iron overload. For example, point mutations or homozygous unstable GAA trinucleotide expansion in the FXN gene can result in Friedreich's ataxia (FRDA), an autosomal recessive disease characterized by severe neurodegeneration and cardiomyopathy. These manifestations of FRDA are caused by an accumulation of intra-mitochondrial iron, which decreases mitochondrial function and increases sensitivity to oxidative stress.
Mitochondria serve a key role in the synthesis and assembly of heme and Fe-S clusters, and are therefore essential for the delivery of iron to client proteins. Appropriate levels of iron, however, are also important for the proper function of the mitochondria. Conditions of iron deficiency or excess disrupt a myriad of mitochondrial functions. This interdependence between iron and mitochondria is best demonstrated by diseases that simultaneously disrupt mitochondrial iron and mitochondrial function, such as Frederich’s Ataxia, infantile mitochondrial complex II/III deficiency, neonatal oxidative phosphorylation deficiency, and sideroblastic anemia.
To develop effective treatment for pathologies leading to localized mitochondrial iron overload or deficiency, we will first need to develop a more detailed understanding of mitochondrial iron regulation. We anticipate substantial progress towards this goal in the next five years.

Amélioration des paramètres spatiotemporels de la marche par des chaussures orthopédiques dans l’ataxie de Friedreich

Bastien Roche, Isabelle Husson, Neurophysiologie Clinique/Clinical Neurophysiology, Volume 46, Issues 4–5, November 2016, Pages 276-277, ISSN 0987-7053, doi:10.1016/j.neucli.2016.09.098

Alors que l’évolution de l’ataxie s’oriente vers une instabilité plus importante, puis une perte de la marche, l’utilisation des chaussures orthopédiques permet d’améliorer, comparativement à la marche pieds nus, la stabilité et la fonctionnalité de la marche.

Paediatric spinal conditions

Tomlinson JE, Gummerson NW, Surgery (2016), doi:10.1016/j.mpsur.2016.10.013

Achieving an upright posture, and balancing the 24 mobile segments of the spine in a vertical column, is clearly no easy task. The neuromuscular control of the spine involves brain, nerve and muscle (including feedback pathways). Problems anywhere in this pathway may lead to a neuromuscular scoliosis. Causes include cerebral palsy, Friedreich’s ataxia, syringomyelia, tumour, trauma, myelodysplasia, spinal muscular atrophy, poliomyelitis, Duchenne muscular dystrophy and arthrogryposis.
The treatment goals in this group of patients are to prevention of significant cardiorespiratory compromise, and maintain function. Function may often be maintenance of sitting balance, use of the upper limbs, the use of a wheelchair, or ease of hygiene and pressure area care rather than walking. Scoliosis surgery in neuromuscular conditions is a significant undertaking and other adaptations such as moulded seating should be considered, with surgery playing a role when other options have been exhausted. Surgery is usually a long posterior instrumented fusion, but unlike idiopathic curves, fixation is often to the pelvis.

Gradually Progressive Spastic Ataxia in a Young Man: Steadily Unsteady

Divyanshu Dubey, MD; Pravin Khemani, MD; Eric Remster, MD; Jeffrey L. Elliott, MD; JAMA Neurol. Published online December 12, 2016. doi:10.1001/jamaneurol.2016.1581

The final diagnosis was adult-onset FA. An atypical presentation of a more common condition such as FA, should always be considered as more likely than a common presentation of an extraordinarily rare disorder. It is now recognized that up to 25%of patients with FA may be considered atypical according to classical diagnostic criteria.
Patients with atypical FA may present with retained reflexes, spasticity, mild or absent limb ataxia, lack of dysarthria, and no cardiomyopathy. Among them, spastic ataxia with almost no sensory neuropathy has been associated with a limited GAA expansion. It is thought that GAA expansion size significantly affects the degree of involvement of the central somatosensory pathway and peripheral sensory axons, along with the overall severity of disease, as the clinical course of disease and neuropathology can be variable based on the degree of repeat expansion or heterozygosity of GAA mutation.

Automatic classification of gait in children with Early-Onset Ataxia or Developmental Coordination Disorder and controls using inertial sensors

Andrea Mannini, Octavio Martinez-Manzanera, Tjitske F. Lawerman, Diana Trojaniello, Ugo Della Croce, Deborah A. Sival, Natasha M. Maurits, Angelo Maria Sabatini; Gait & Posture, Available online 2 December 2016, ISSN 0966-6362, doi:10.1016/j.gaitpost.2016.12.002.

Early-Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) are two conditions that affect coordination in children. Phenotypic identification of impaired coordination plays an important role in their diagnosis. Gait is one of the tests included in rating scales that can be used to assess motor coordination. A practical problem is that the resemblance between EOA and DCD symptoms can hamper their diagnosis. In this study we employed inertial sensors and a supervised classifier to obtain an automatic classification of the condition of participants.
In absence of reliable distinctive biomarkers, the Scale for Assessment and Rating of Ataxia (SARA), is often used as an additional, supportive biomarker to indicate ataxia severity. Despite the high reliability of the scale, we have shown that pediatric SARA is confounded by other factors than ataxia, as well. Nevertheless, we have shown that the relative SARA gait subscore can support the recognition of an indisputable EOA phenotype in mildly affected participants. Presently available quantitative gait parameters [14] are still not ubiquitously implemented as a clinical tool. Based on the remarks reported above, we reasoned that clinically simple and reproducible quantitative gait analysis could be worthwhile for reliable EOA and DCD recognition.
In the present paper, we evaluate a method for the automatic and objective assessment of pediatric gait as compared to a clinical diagnosis in a similar way to what was previously done for other pathological conditions. Additionally, the accuracy of phenotypic assessments is estimated. Both methods classify patients into three groups (EOA, DCD and CTRL). To be effective, the automatic assessment is expected to guarantee both a limited increase of the complexity of the evaluation and a minimal impact on the gait patterns under evaluation. Hopefully, this study provides a first step towards incorporating a clinically objective and viable biomarker for uniform identification of EOA and DCD.

Vestibular findings in autosomal recessive ataxia

Bianca Simone Zeigelboim, Helio Afonso Ghizoni, Teive Hugo Amilton Santos de Carvalho, Edna Marcia da Silva Abdulmassih, Jair Mendes Marques and Rafaella Cristyne Cardoso. International Tinnitus Journal. 2013;18(2):156-162.

The most evident neurotological symptoms were dizziness, lack of coordination of movement, and imbalance when walking. Alterations in vestibular examinations occurred in 89.5% of patients, mostly in the caloric test, with a predominance of deficient central vestibular system dysfunction. This underscores the importance of the contribution of topodiagnostic labyrinthine evaluations for neurodegenerative diseases.

Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich’s Ataxia Transgenic Mice

Calatrava-Ferreras, L.; Gonzalo-Gobernado, R.; Reimers, D.; Herranz, A.S.; Casarejos, M.J.; Jiménez-Escrig, A.; Regadera, J.; Velasco-Martín, J.; Vallejo-Muñoz, M.; Díaz-Gil, J.J.; Bazán. Int. J. Mol. Sci. 2016, 17, 2066. doi:10.3390/ijms17122066 (registering DOI)

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We intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 μg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA.

Horizon slumps after phase 3 Friedreich's ataxia trial flops

FierceBiotech. by Nick Paul Taylor | Dec 8, 2016 9:40am. Horizon Pharma’s Actimmune has missed the primary endpoint in a phase 3 trial, sparking a 20% drop in its stock price. The study set out to show that interferon gamma-1b could improve outcomes in patients with the rare neurodegenerative movement disorder Friedreich's ataxia, but the drug failed to move the needle.

RareDR (Rare Disease Report).Andrew Black Published Online: Thursday, Dec 08, 2016
Horizon Pharma’s Phase 3 study assessing actimmune for the treatment of Friedreich’s ataxia did not meet its primary endpoint of displaying significant change in the modified Friedreich's Ataxia Rating Scale (FARS‐mNeuro) during a 26-week time period.

Globe Newswire. 8th December 2016. Today announced that the Phase 3 trial, STEADFAST (Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich’s Ataxia study), evaluating ACTIMMUNE® (interferon gamma-1b) for the treatment of Friedreich’s ataxia (FA) did not meet its primary endpoint of a statistically significant change from baseline in the modified Friedreich’s Ataxia Rating Scale (FARS‐mNeuro) at 26 weeks versus treatment with placebo. FARS‐mNeuro is an exam-based rating scale that measures disease progression based on functional parameters such as speech, ability to swallow, upper and lower limb coordination, gait and posture. In addition, the secondary endpoints did not meet statistical significance. No new safety findings were identified on initial review of data other than those already noted in the ACTIMMUNE prescribing information for approved indications.

REUTERS. Dec 8 Horizon Pharma Plc.
* Horizon Pharma Plc announces topline results from phase 3 study of ACTIMMUNE (interferon gamma-1b) in Friedreich's Ataxia
* Horizon Pharma Plc says ACTIMMUNE for treatment of Friedreich's Ataxia (FA) did not meet its primary endpoint
* Horizon Pharma Plc says secondary endpoints did not meet statistical significance
* Horizon Pharma Plc says company believes it is well-positioned for growth in 2017 and beyond based on its existing portfolio of medicines
* Horizon Pharma Plc says announcement does not impact Horizon Pharma's full-year 2016 adjusted net sales or adjusted EBITDA guidance Source text for Eikon: Further company coverage.

UNITED STATES, SECURITIES AND EXCHANGE COMMISSION, WASHINGTON, D.C. 20549. CURRENT REPORT: Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934. Date of Report (Date of earliest event reported): December 8, 2016.
On December 8, 2016, Horizon Pharma announced that the Phase 3 trial, STEADFAST (Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich’s Ataxia study), evaluating ACTIMMUNE® (interferon gamma-1b) for the treatment of Friedreich’s ataxia (FA) did not meet its primary endpoint of a statistically significant change from baseline in the modified Friedreich’s Ataxia Rating Scale (FARS-mNeuro) at 26 weeks versus treatment with placebo. In addition, the secondary endpoints did not meet statistical significance. No new safety findings were identified on initial review of data other than those already noted in the ACTIMMUNE prescribing information for approved indications. The Company, in conjunction with the independent Data Safety Monitoring Board, the principal investigator and the Friedreich’s Ataxia Research Alliance (FARA) Collaborative Clinical Research Network (CCRN) in FA, has determined that, based on the trial results, the FA development program will be discontinued, including the 26-week extension study and the long-term safety study.

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Horizon Pharma plc Announces Topline Results from Phase 3 Study of ACTIMMUNE® (interferon gamma-1b) in Friedreich's Ataxia

DUBLIN, Ireland, Dec. 08, 2016 (GLOBE NEWSWIRE) -- Horizon Pharma plc (NASDAQ:HZNP), today announced that the Phase 3 trial, STEADFAST (Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich's Ataxia study), evaluating ACTIMMUNE® (interferon gamma-1b) for the treatment of Friedreich's ataxia (FA) did not meet its primary endpoint of a statistically significant change from baseline in the modified Friedreich's Ataxia Rating Scale (FARS‐mNeuro) at 26 weeks versus treatment with placebo. FARS‐mNeuro is an exam-based rating scale that measures disease progression based on functional parameters such as speech, ability to swallow, upper and lower limb coordination, gait and posture.
In addition, the secondary endpoints did not meet statistical significance. No new safety findings were identified on initial review of data other than those already noted in the ACTIMMUNE prescribing information for approved indications. The Company, in conjunction with the independent Data Safety Monitoring Board, the principal investigator and the Friedreich's Ataxia Research Alliance (FARA) Collaborative Clinical Research Network (CCRN) in FA, has determined that, based on the trial results, the FA development program will be discontinued, including the 26-week extension study and the long-term safety study.

Researchers uncover possible source of genetic error causing multiple diseases

Phys.org, Tufts University, December 5, 2016.

Tufts University researchers have discovered a possible explanation for the occurrence of a genetic error that causes over a dozen neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy and forms of spinocerebellar ataxia.

More information: The role of break-induced replication in large-scale expansions of (CAG)n∙(CTG)n repeats, Jane C Kim, Samantha T Harris, Teresa Dinter, Kartik A Shah & Sergei M Mirkin, Nature Structural & Molecular Biology, Published online 05 December 2016 doi:10.1038/nsmb.3334

Protective role of frataxin against myocardial ischemia reperfusion injury

Abdullah Al Asmari; Global Summit on Heart Diseases and Therapeutics, October 20-21, 2016 Chicago, USA. Posters & Accepted Abstracts: J Clin Exp Cardiolog DOI: 10.4172/2155-9880.C1.051

In this study, we hypothesized that FXN protects cardiomyocytes against IR injury by preventing the dysregulation of myocardial bioenergetics. We identified that FXN expression is increased in response to IR injury and that increase is mediated by hypoxia inducible factor (HIF-1α) which results in regulation of mitochondrial iron homeostasis and the ensuing mitochondrial ROS formation. Most surprisingly, we observed that enhanced FXN expression displayed elevated levels of glutathione (GSH) and superoxide dismutase (SOD). Furthermore, these findings were supported in our FXN over-expressing and knock down cells under the same IR condition. Together, these results demonstrate that increased expression of FXN is cardioprotective against IR injury through its anti-oxidant effect and by improving mitochondrial energetics.

Antibióticos y trastornos de la marcha [Antibiotics and gait disorders]

Gómez-Porro P, Vinagre-Aragón A, Zabala-Goiburu JA. Rev Neurol 2016; 63: 501-9. [Article in Spanish]

Revisión

La toxicidad neurológica de muchos antibióticos se ha documentado en numerosos artículos y notas clínicas. En esta revisión se clasifican los antibióticos en función del mecanismo fisiopatogénico por el que pueden provocar un trastorno de la marcha.El principal objetivo era agrupar todos los fármacos que pueden provocar un trastorno de la marcha, para facilitar la sospecha clínica y, en consecuencia, el tratamiento de los pacientes.

The neurological toxicity of many antibiotics has been reported in a number of articles and clinical notes. In this review antibiotics are classified according to the physiopathogenic mechanism that can give rise to a gait disorder. The main aim was to group all the drugs that can give rise to a gait disorder, in order to facilitate the clinical suspicion and, consequently, the management of patients.

Loss of Frataxin activates the iron/sphingolipid/PDK1/Mef2 pathway in mammals

Kuchuan Chen, Tammy Szu-Yu Ho, Guang Lin, Kai Li Tan, Matthew N Rasband, Hugo J Bellen; eLife Tue, 29 Nov 2016 DOI:10.7554/eLife.20732
Here, we show that loss of Fxn in the nervous system in mice also activates an iron/sphingolipid/PDK1/Mef2 pathway, indicating that the mechanism is evolutionarily conserved. Furthermore, sphingolipid levels and PDK1 activity are also increased in hearts of FRDA patients, suggesting that a similar pathway is affected in FRDA.

Negotiating prices of drugs for rare diseases

Séverine Henrard & Francis Arickx, Bulletin of the World Health Organization 2016;94:779-781. doi:10.2471/BLT.15.163519

Due to the increasing number of treatments for rare diseases that have been approved and are under development, and hence the rising costs for countries’ health systems, there is an ongoing debate about health policies for rare diseases and particularly about reimbursement of rare disease drugs

Number of applications for orphan designation for medicinal products to the European Medicines Agency over the years 2000–2015

A Cost of Illness Study Evaluating The Healthcare And Societal Burden of Friedreich’s Ataxia In The United Kingdom

K Hanman, A Griffiths, A Bobrowska, J Vallortigara, J Greenfield, RS Thompson, Value in Health, Volume 19, Issue 7, November 2016, Pages A584-A585, ISSN 1098-3015, doi:10.1016/j.jval.2016.09.1372

Overall, the total COI of FRDA patients to the NHS was £8,038,645 per year, with a mean annual cost per patient of £3,556. The development and delivery of new treatment options, particularly to address the loss of mobility and cardiac abnormalities experienced by FRDA patients, will substantially reduce the economic burden of this rare and devastating disease.

Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

Cinzia Cinesi, Lorène Aeschbach, Bin Yang & Vincent Dion. Nature Communications 7, Article number: 13272 (2016) doi:10.1038/ncomms13272

Excising expanded GAA/TTC repeats in Friedreich Ataxia fibroblasts reactivated the expression of frataxin, improved the activity of the Fe-S-containing Aconitase, and increased cellular ATP levels. Together with our results, these studies offer great hope that Cas9 nickase-mediated shrinkage of expanded repeat tracts in somatic tissues may alleviate disease symptoms in patients.

Launches of First Therapies Approved for Spinal Muscular Atrophy and Friedreich's Ataxia Will Revolutionize Treatment and Drive Growth of These Rare Disease Markets

BURLINGTON, Mass., Oct. 25, 2016 /PRNewswire/ -- Decision Resources Group finds that the anticipated launches of the first therapies for the treatment of spinal muscular atrophy (SMA) or Friedreich's ataxia (FA) will transform treatment of these diseases and lead to their markets expanding dramatically.
Following the anticipated label expansion of Horizon Pharma's Actimmune (interferon gamma-1b), the FA market is forecasted to grow significantly over the next ten years. However, interviewed neurologists' perceived limitations of Actimmune, including its unclear mechanism of action, variable effect on frataxin protein levels, and modest preservation of neurological function, could constrain its uptake and allow competitors to challenge Actimmune's position.
According to interviewed experts, gene therapy will also transform the FA treatment landscape, possibly negating the need for drug treatment. However, gene therapies being developed by Agilis Biotherapeutics, Pfizer, and RaNA Therapeutics are in preclinical testing and unlikely to launch during the study period.
"Despite the lack of competing brands entering the market in the near term, Actimmune's high U.S. cost may be an obstacle for its rapid adoption among patients with FA. If Actimmune can show that it delays disease progression or improves neurological function over a year or more, prescribers, patients, and payers are likely to accept its very high price."

Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA)n Repeats by PNA or LNA Targeting

Helen Bergquist, Cristina S. J. Rocha, Rubén Álvarez-Asencio, Chi-Hung Nguyen, Mark. W. Rutland, C. I. Edvard Smith, Liam Good, Peter E. Nielsen, Rula Zain; PLoS ONE 11(11): e0165788. doi:10.1371/journal.pone.0165788

Chemical and structural probing of GAA repeats provides evidence for pyrimidine triplex (H-DNA) formation and the presence of different structures at the pathological repeats. Furthermore, we find that PNA and LNA sequence-specific targeting of Friedreich’s ataxia GAA repeat expansions can alter and resolve higher order DNA structures. BQQ-OP mediated triplex-specific cleavage of double strand DNA and chloroacetaldehyde chemical modification of single strand DNA regions at (GAA)n repeats demonstrate that GAA-PNA binding result in a duplex invasion complex, that completely dissociates all detectable triplex containing higher order structures at this site, whereas this is not the case for CTT-PNA. Additionally, we obtained a similar pattern using LNA based ONs. Furthermore, a significant change in plasmid morphology in the presence of GAA-LNA was detected using atomic force microscopy. Our results suggest that DNA targeting by modified GAA-oligomers at expanded (GAA)n repeats can be employed to examine the possible role of non-canonical DNA structures in FXN gene silencing and potentially applied to develop new nucleic acids-based therapeutic strategies in Friedreich’s ataxia disease.

Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia

A. Benussi, V. Dell’Era, M.S. Cotelli, M. Turla, C. Casali, A. Padovani, B. Borroni, Brain Stimulation, Available online 3 November 2016, ISSN 1935-861X, doi:10.1016/j.brs.2016.11.001.

We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia (SCA2, SCA38, SCA14, with Friedreich’s ataxia, AOA type 2, MSA-C, FXTAS and SOAO). A two-weeks’ treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia.

Doubts About Therapy for Neurological Diseases With Antisense Oligonucleotides

Satyakam Bhagavati, MD, JAMA Neurol. Published online October 31, 2016. doi:10.1001/jamaneurol.2016.4332

The review by Corey1 and the accompanying editorial paint a very positive picture about the potential of antisense oligonucleotides (ASOs) to treat neurological diseases such as Friedrich ataxia,2 spinal muscular atrophy,3 and Duchenne muscular dystrophy. Although the principle on which ASO-based treatment is based is promising, a review of the literature, however, reveals critical lacunae in the data that have been used to claim efficacy.

Related Articles:
Clinical Implications of Basic Neuroscience Research, Synthetic Nucleic Acids and Treatment of Neurological Diseases David R. Corey, PhD

Antisense Oligonucleotides for Treating Neurological Diseases, David R. Corey, PhD

Challenges ahead for trials in Friedreich’s ataxia

David R Lynch, Elizabeth Kichula, The Lancet Neurology, Volume 15, Issue 13, December 2016, Pages 1300-1301, ISSN 1474-4422, doi:10.1016/S1474-4422(16)30281-2.

Nevertheless, although natural history studies such as EFACTS identify the problems in progressing with therapeutic trials in Friedreich’s ataxia, they also identify one mechanism for keeping trials small: stratification.
In all of the natural history studies of Friedreich’s ataxia including the EFACTS, individuals with longer GAA repeat lengths had faster progression.

Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study

Kathrin Reetz, Imis Dogan, Ralf-Dieter Hilgers, Paola Giunti, Caterina Mariotti, Alexandra Durr, Sylvia Boesch, Thomas Klopstock, Francisco Javier Rodriguez de Rivera, Ludger Schöls, Thomas Klockgether, Katrin Bürk, Myriam Rai, Massimo Pandolfo, Jörg B Schulz, The Lancet Neurology, Volume 15, Issue 13, December 2016, Pages 1346-1354, ISSN 1474-4422, http://dx.doi.org/10.1016/S1474-4422(16)30287-3.

"To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial."

In conclusion, our results of the 2 year analysis of the EFACTS cohort allowed substantiation of the suitability of the SARA and ADL as robust outcome measures for future therapeutic trials, which should be designed with an observational period of at least 2 years.

The future of epigenetic drugs

BioMed Central, Sarah Dowie 8 Sep 2016. Insights and opinion from BioMed Central on the latest biology research and developments in the field.

In the light of increasing knowledge on the role epigenetic factors play in disease, it is now becoming apparent that epigenetics could be ideal therapeutic targets - particularly taking into consideration that many of these epigenetic factors are reversible. Epigenetic drugs are incredibly potent and can help reverse abnormal gene expression that can result in various diseases.

Heterologous mitochondrial targeting sequences can deliver functional proteins into mitochondria

Dana Marcus, Michal Lichtenstein, Natali Cohen, Rita Hadad, Tal Erlich-Hadad, Hagar Greif, Haya Lorberboum-Galski, The International Journal of Biochemistry & Cell Biology, Available online 19 October 2016, ISSN 1357-2725, doi:10.1016/j.biocel.2016.10.013.

We chose the FXN protein to examine whether nuclear-encoded mitochondrial proteins can efficiently be targeted via a heterologous MTS (hMTS) and deliver a functional protein into mitochondria.
hMTSs delivered a functional FXN protein into the mitochondria even more efficiently than the native MTSfxn, as evidenced by the rescue of FA patients’ cells from oxidative stress; demonstrating a 18%-54% increase in cell survival; and a 13%-33% increase in ATP levels, as compared to the fusion protein carrying the native MTS.

Cellular thiamine status is coupled to function of mitochondrial 2-oxoglutarate dehydrogenase

G. Mkrtchyan, A. Graf, L. Bettendorff, V. Bunik, Neurochemistry International, Available online 20 October 2016, ISSN 0197-0186, doi:10.1016/j.neuint.2016.10.009.

Our study points to cell-specific regulation of the thiamine-dependent metabolic network, which includes significant coupling between the OGDH reaction, often the TCA cycle “bottle neck”, and thiamine influx in normal rat brain and astrocytes. In the brain with decreased thiamine levels and/or impaired OGDH, which have been observed in aging and/or neurodegenerative diseases, such coupling may require thiamine levels exceeding those known to saturate the ThDPdependent enzymes under normal conditions. The findings may justify therapeutic application of high doses of thiamine in patients with neurodegenerative diseases.

Iron related hemochromatosis (HFE) gene mutations in Friedreich Ataxia patients

Inder Singh, Sunil Shakya, Rakesh Kumar Singh, Istaq Ahmad, Vinay Goyal, Garima Shukla, Madakasira Vasantha Padma Srivastava, Mohammed Faruq, Achal Kumar Srivastava, Parkinsonism & Related Disorders, Available online 19 October 2016, ISSN 1353-8020, doi:10.1016/j.parkreldis.2016.10.015.

This is the first case-control study analyzing HFE mutations as a modifier of FRDA phenotypes and its severity. Our study suggests that the presence of p.H63D may be the risk factor for the occurrence of peripheral neuropathy in FRDA patients.

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Polak Urszula, Li Yanjie, Butler Jill Sergesketter, and Napierala Marek. Stem Cells and Development. October 2016, ahead of print. doi:10.1089/scd.2016.0147.

Taken together, these results demonstrate that transcriptional repression caused by long GAA repeat tracts can be partially or transiently reversed by altering particular epigenetic modifications, thus revealing possibilities for detailed analyses of silencing mechanism and development of new therapeutic approaches for FRDA.

AN AYURVEDIC PERSPECTIVE OF FRIEDREICH’S ATAXIA

Dr. Archana Mogili, Dr. Mrudula Sankaramanchi, Dr. C H.Sadanandam. International Ayurvedic medical Journal, Volume 4; Issue 10; October- 2016

The Ayurveda approach to Friedreich’s ataxia is aimed at controlling the symptoms, treating the degeneration of nervous system and preventing long term complications by considering it as PRANA AVRUTA VYANA UDANA VATA VYADHI.

In FRDA which as no direct reference from the classics, the treatment protocol can be planned by understanding the underlying pathology of the disease in Ayurveda perspective. Here it can be interpreted FRDA has prana avruta vyana, udana vata vyadhi and avarana chikitsa in general and specific to particular avarana can be adopted.

NOTE: Ayurvedic medicine (also called Ayurveda) is one of the world’s oldest medical systems. It originated in India more than 3,000 years ago and remains one of the country’s traditional health care systems. Its concepts about health and disease promote the use of herbal compounds, special diets, and other unique health practices. India’s government and other institutes throughout the world support clinical and laboratory research on Ayurvedic medicine, within the context of the Eastern belief system. But Ayurvedic medicine isn’t widely studied as part of conventional (Western) medicine. This fact sheet provides a general overview of Ayurvedic medicine and suggests sources for additional information. (Recommended reading: Ayurvedic Medicine: In Dept, see the links clicking on the title)

Human neuron-astrocyte 3D co-culture-based assay for evaluation of neuroprotective compounds

Ana Paula Terrasso, Ana Carina Silva, Augusto Filipe, Pedro Pedroso, Ana Lúcia Ferreira, Paula Marques Alves, Catarina Brito, Journal of Pharmacological and Toxicological Methods, Available online 11 October 2016, ISSN 1056-8719, doi: 10.1016/j.vascn.2016.10.001.

Central nervous system drug development has registered high attrition rates, mainly due to the lack of efficacy of drug candidates, highlighting the low reliability of the models used in early-stage drug development and the need for new in vitro human cell-based models and assays to accurately identify and validate drug candidates.

For the assay validation, we have used Idebenone, an antioxidant benzoquinone, shortchain analogue of coenzyme Q10 ; and positive control for neuroprotection over the tBHP insult. It has been widely investigated for the treatment of Friedreich’s ataxia. The Idebenone treatment led to a reduction in oxidative stress markers (Jaber & Polster, 2015). Consistently with its antioxidant activity, Idebenone prevents lipid peroxidation in isolated brain mitochondria, synaptosomes and human hepatic cells (Erb et al., 2012). It was also shown to protect against ROS-induced damage in several in vitro cultures, as primary cortical neurons and immortalized neural cells. We observed a dose-dependent neuroprotective effect over tBHP insult when Idebenone is administrated in pre-incubation.

The specificity of the neuroprotective effect observed for Idebenone over tBHP insult was evaluated using a non-oxidative lesion induced by chloramphenicol. Idebenone did not confer a neuroprotective effect over the chloramphenicol insult indicating that the neuroprotection observed for tBHP is specific and not an assay artefact.

Applications of CRISPR/Cas9 for Gene Editing in Hereditary Movement Disorders

Wooseok Im, Jangsup Moon, Manho Kim; Review Article, J Mov Disord 2016; 9(3): 136-143. Published online: September 21, 2016 DOI:10.14802/jmd.16029

Genome editing using CRISPR/Cas9 is possible in various cell lines, including human induced pluripotent stem cells, which can be utilized as a valuable in vitro tool for the investigation of specific mutations in the pathogenesis of various disorders. For example, Vannocci et al. developed a novel cellular model of Friedreich’s ataxia, which is an autosomal recessive ataxia caused by reduced levels of frataxin, using CRISPR/Cas9 to stably introduce the disease frataxin gene into cells.

hiPSC Disease Modeling of Rare Hereditary Cerebellar Ataxias Opportunities and Future Challenges

Dunja Lukovic, Victoria Moreno-Manzano, Francisco Javier Rodriguez-Jimenez, Angel Vilches, Eva Sykova, Pavla Jendelova, Miodrag Stojkovic, Slaven Erceg; Neuroscientist 1073858416672652, first published on October 6, 2016 DOI:10.1177/1073858416672652

This work, for the first time, bridges the preclinical drug evaluation in FRDA-specific patient neurons derived from hiPSC and clearly shows the advantages of using hiPSC differentiated cells compared with other widely used cellular models, such as immortalized cell lines and those tested on rodent cells. Although these studies have provided insights into the pathogenesis of FRDA in cardiomyocytes and neurons, additional work is required to elucidate the role of frataxin deficits in other affected cell types, such as the cerebellar neurons.

New Reasons to Pursue the Therapeutic Potential of Synthetic Nucleic Acids for Neurological Diseases

Jill Sergesketter Butler, PhD; Marek Napierala, PhD; Editorial. JAMA Neurol. 2016;73(10):1175-1177. doi:10.1001/jamaneurol.2016.2571

Findings published by Corey’s group demonstrate a novel use for synthetic nucleic acids in restoring frataxin (FXN) levels in cell line models derived from patients with FRDA.The mechanism of increased expression does not rely merely on activating transcription at the FXN locus, nor is the RNA interference pathway required. Instead, data from either approach indicate that the ability of the engineered nucleic acids to specifically bind the mutant FXN pre–messenger RNA and block its interaction with the genomic locus is sufficient to restore FXN messenger RNA and protein levels. Thus, in addition to relieving transcription inhibition, elimination of detrimental R-loops might also result in stabilization of the expanded repeat sequences and prevention of somatic instability. Extensive data related to dosing, toxicity, and biodistribution, to name a few, have already been collected and can be used to pave the way for moving R-loop specific nucleic acids to the clinic much more quickly.

Synthetic Nucleic Acids and Treatment of Neurological Diseases

David R. Corey, PhD; JAMA Neurol. 2016;73(10):1238-1242. doi:10.1001/jamaneurol.2016.2089

Emerging Target: Frataxin/Friedreich’s Ataxia: We reasoned that oligonucleotides that blocked the expanded repeat could prevent R-loop formation and release the break on transcription We designed duplex RNAs or ASOs to be complementary to the AAG repeat. Both approaches led to increased expression of RNA and protein. Levels of FXN protein were similar to those observed in wild-type cells. Our data suggest that the mechanism of action of either the ASOs or the duplex RNAs involves binding to the expanded repeat and physically preventing it from associating chromosomal DNA to form the critical R-loop structure. Antisense oligonucleotides efficiently inhibit gene expression in liver and the central nervous system.Using them to treat the broad range of tissues necessary to fully treat Friedreich’s ataxia will require more potent compounds and more effective strategies for delivering oligonucleotides in to all tissues that are affected.

Modeling and correction of structural variations in patient-derived iPSCs using CRISPR/Cas9

Chul-Yong Park, Jin Jea Sung, Sang-Hwi Choi, Dongjin R Lee, In-Hyun Park & Dong-Wook Kim; Nature Protocols 11, 2154–2169 (2016) doi:10.1038/nprot.2016.129 Published online 06 October 2016

This protocol enables the correction of large inverted segments and short nucleotide repeat expansions in diseases such as hemophilia A, fragile X syndrome, Hunter syndrome, and Friedreich's ataxia.

The rare and undiagnosed diseases diagnostic service – application of massively parallel sequencing in a state-wide clinical service

Gareth Baynam, Nicholas Pachter, Fiona McKenzie, Sharon Townshend, Jennie Slee, Cathy Kiraly-Borri, Anand Vasudevan, Anne Hawkins, Stephanie Broley, Lyn Schofield, Hedwig Verhoef, Caroline E. Walker, Caron Molster, Jenefer M. Blackwell, Sarra Jamieson, Dave Tang, Timo Lassmann, Kym Mina, John Beilby, Mark Davis, Nigel Laing, Lesley Murphy, Tarun Weeramanthri, Hugh Dawkins and Jack Goldblatt. Orphanet Journal of Rare Diseases 201611:77 DOI: 10.1186/s13023-016-0462-7

OPEN ACCESS
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License

We describe an iteratively improving diagnostic platform provided within a public health service that is aligned to the unmet needs of people living with rare and undiagnosed diseases, by supporting equitable state-wide diagnostic health care provision for the world’s geographically largest public health jurisdiction. It is largely been performed within existing budgets through a patient-centric approach and clinically informed re-alignment of existing resources.

Systematic review on the evaluation criteria of orphan medicines in Central and Eastern European countries

Tamás Zelei, Mária J. Molnár, Márta Szegedi and Zoltán Kaló. Orphanet Journal of Rare Diseases 201611:72 DOI:10.1186/s13023-016-0455-6 Published: 4 June 2016

Open Access.
Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)

NRF2 in neurodegenerative diseases

 Antonio Cuadrado, Current Opinion in Toxicology, Available online 3 October 2016, ISSN 2468-2020, doi:10.1016/j.cotox.2016.09.004.

Neurodegenerative diseases, and degenerative disorders as a whole, share in common the deviation from homeostatic responses related to the control of proteostasis and low-grade chronic oxidative, inflammatory, and metabolic stress. These are all crucial events where transcription factor Nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a very important defensive role. In this paper, biochemical and genetic evidence connecting NRF2 with neurodegenerative diseases will be discussed, mainly in the context of preclinical mouse models and in patients with Alzheimer’s and Parkinson’s disease. NRF2 can be targeted pharmacologically and the most successful drugs to endorse a neuroprotective therapy will be commented, including dimethyl fumarate.

Mitochondrial Lon Protease in Human Disease and Aging: Including an etiologic classification of Lon-related diseases and disorders

Daniela A. Bota, Kelvin J.A. Davies, Free Radical Biology and Medicine, Available online 5 July 2016, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.06.031.

Friedreich ataxia (FRDA)show a clear progressive increase in Lon protein levels. Lon upregulation is also accompanied by an increase in proteolytic activity, and by decreased levels of mitochondrial Fe–S proteins. The effect of Lon upregulation on loss of mitochondrial Fe-S proteins during the progression of the disease suggests that Fe-S proteins may be targets of Lon in FRDA.

A neurodegenerative perspective on mitochondrial optic neuropathies

Patrick Yu-Wai-Man , Marcela Votruba, Florence Burté, Chiara La Morgia, Piero Barboni, Valerio Carelli; Review: Acta Neuropathologica pp 1-18 First online: 30 September 2016 doi:10.​1007/​s00401-016-1625-2

Open Access

Friedreich Ataxia (FRDA) is the most common form of hereditary ataxia and it is due to recessive mutations in the FXN gene, which encodes for a mitochondrial protein involved in the biosynthetic pathways of iron-sulphur clusters. The latter are essential components of aconitase and the mitochondrial respiratory chain complexes I, II and III, and their combined dysfunction probably contributes to the development of optic neuropathy, which is now a well-recognised feature of FRDA.

Use of CRISPR/Cas9 system to correct mutations responsible for Duchenne Muscular Dystrophy and Friedreich ataxia.

(1888PressRelease) October 01, 2016 - MarketsandMarkets Conferences. Dr. Jacques P. Tremblay from University of Laval, Quebec joins the speaker panel for the 2nd Annual Genome Editing & Engineering Conference

Dr. Tremblay will be presenting at the conference on use of CRISPR/Cas9 system to correct mutations responsible for Duchenne Muscular Dystrophy and Friedreich ataxia. Joining Dr. Tremblay on the panel will be experts representing organizations such as University of Utah School of Medicine, Massachusetts Institute of Technology, J. Craig Venter Institute, University of Nebraska Medical Center, University of California, University of Washington, University of Southern California, University of Rochester, National Institutes of Health, University of Texas, University of Minnesota, Hiroshima University and Wellcome Trust Sanger Institute.

Late-Onset Friedreich’s Ataxia (LOFA) Mimicking Charcot–Marie–Tooth Disease Type 2: What Is Similar and What Is Different?

Rubens Paulo A. Salomão, Maria Thereza Drumond Gama, Flávio Moura Rezende Filho, Fernanda Maggi, José Luiz Pedroso , Orlando G. P. Barsottini; Short Report, The Cerebellum pp 1-3 First online: 29 September 2016 doi:10.​1007/​s12311-016-0822-9

Herein, we report a patient that presented with late-onset progressive steppage gait, neuropathy and pes cavus, suggesting Charcot–Marie–Tooth (CMT) disease. Subsequent genetic investigation confirmed Friedreich’s ataxia (FRDA). We suggest that late-onset forms of hereditary neuropathies should be carefully evaluated, since LOFA may be a CMT mimicker.

Congenital and Hereditary Diseases of the Spinal Cord, Seminars in Ultrasound, CT and MRI

Lily L. Wang, Karin S. Bierbrauer, Available online 14 July 2016, ISSN 0887-2171, doi:10.1053/j.sult.2016.07.002.

Friedreich’s ataxia is a hereditary autosomal recessive movement disorder usually beginning in childhood and progresses with age. The cerebellum and the spinal cord are involved. The autonomic system can be involved as the disease progresses. Cardiac disease, diabetes, scoliosis are common associations. Genetic testing offers a conclusive diagnosis in patients with a compatible history and clinical examination. Imaging in Friedreich’s ataxia has been mostly focused in the brain. Spinal findings are non-specific on conventional MRI with cervical cord atrophy.

A longitudinal study of the SF-36 version 2 in Friedreich ataxia

G. Tai, L. A. Corben, E. M. Yiu and M. B. Delatycki; Acta Neurologica Scandinavica, Version of Record online: 28 SEP 2016 DOI: 10.1111/ane.12693

This study aimed to examine the relationship between SF-36 version 2 (SF-36V2) summary scores and Friedreich ataxia (FRDA) clinical characteristics, and to investigate the responsiveness of the scale, in comparison with the Friedreich Ataxia Rating Scale (FARS), over 1, 2 and 3 years.

Our findings suggest that despite physical decline, individuals with FRDA have relatively stable mental well-being. This study demonstrates that the SF-36V2 is unlikely to be a useful tool for identifying clinical change in FRDA therapeutic trials.

Atypical Features in a Large Turkish Family Affected with Friedreich Ataxia

Semiha Kurt, Betul Cevik, Durdane Aksoy, E. Irmak Sahbaz, Aslı Gundogdu Eken, and A. Nazli Basak. Case Reports in Neurological Medicine Volume 2016 (2016), Article ID 4515938, 7 pages doi:10.1155/2016/4515938

Open access article distributed under the Creative Commons Attribution License

Other movement disorders

Silverdale MA, Medicine (2016), doi:10.1016/j.mpmed.2016.06.010

Structural problems usually show on cranial magnetic resonance imaging. The age of onset often helps to reach a diagnosis in chronic cerebellar disorders. Many genetic conditions present at a younger age, whereas other conditions such as multiple system atrophy present at an older age. Cranial imaging can help in chronic cerebellar disorders: some conditions cause cerebellar atrophy (e.g. ataxia telangiectasia) whereas others usually do not (e.g. Friedreich’s ataxia).

Mitochondrial dysfunction and diabetic retinopathy

Toke Bek, Chair, Mitochondrion, Available online 22 July 2016, ISSN 1567-7249, doi:10.1016/j.mito.2016.07.011

Friedreich's spinal ataxia, Diabetes mellitus in this condition is due to a loss of pancreatic beta cell function secondary to the mitochondrial dysfunction (Kersten et al 2014). One patient followed in the author's clinic had no registered diabetic retinopathy after five years of diabetes duration but had no light perception because of the neurological deficits of the disease.

The physiological basis of therapies for cerebellar ataxias

Hiroshi Mitoma and Mario Manto; Therapeutic Advances in Neurological Disorders September 2016 9: 396-413, doi:10.1177/1756285616648940

In conclusion, the understanding of the physiological basis of the various therapies is a critical step for clinicians dealing with CAs. We suggest that some degree of reversibility can be achieved if the therapies of CAs are administered as early as possible and take into account the pathogenesis behind the disorder. Novel therapies should take into account the mechanisms of the cerebellar circuitry in order to be effective

Studying the pathophysiologic connection between cardiovascular and nervous systems using stem cells.

Coskun, V. and Lombardo, D. M. (2016), J. Neurosci. Res.. doi: 10.1002/jnr.23924

Analysis of the hearts of patients with FA shows detectable iron accumulation, supporting the idea of iron overload as the disease mechanism. The innervation pattern of the heart by parasympathetic, sympathetic, and sensory neurons, as well as their interaction with the cardiac conduction system, is critical for the homeostatic operation of the cardiovascular system. In situations such as exercise, traumatic injury, or blood loss, a compensatory increase in cardiac output is achieved by a corresponding increase in adrenergic activity.

Emerging therapies for mitochondrial disorder

Helen Nightingale, Gerald Pfeffer, David Bargiela, Rita Horvath, Patrick F. Chinnery. Brain, 1633-1648 First published online: 3 May 2016 DOI:10.1093/brain/aww081

Open Access, (Creative Commons Attribution License)

From a clinical perspective, nuclear-genetic enzyme defects show the greatest promise. Stem cell therapy is already being used in specific contexts, and its efficacy and safety being evaluated, and gene therapy trials in mouse models show clear benefits. Unfortunately, each one of these rare genetic diseases may require their own proprietary approach, and the impact needs to be evaluated long-term. Small molecules are attractive because they have the potential to provide a more generic solution applicable across the mitochondrial disease spectrum, and a greater understanding of cell signalling pathways opens up several unexpected disease targets. For some of these drugs, clinical evaluation is imminent, particularly for those being repurposed or repositioned drugs such as bezafibrate. It is critical at this stage that laboratory and clinical scientists work closely with patient organizations to ensure that the ultimate aims of therapy will actually tackle issues that are important to patients. Given limited resources, this will ensure that new treatments improve quality of life—a prerequisite if these treatments are going to be adopted by healthcare systems worldwide.

Population-based preconception carrier screening: how potential users from the general population view a test for 50 serious diseases

Mirjam Plantinga, Erwin Birnie, Kristin M Abbott, Richard J Sinke, Anneke M Lucassen, Juliette Schuurmans, Seyma Kaplan, Marian A Verkerk, Adelita V Ranchor and Irene M van Langen; European Journal of Human Genetics (2016) 24, 1417–1423; doi:10.1038/ejhg.2016.43

OPEN ACCESS

‘You should at least ask’. The expectations, hopes and fears of rare disease patients on large-scale data and biomaterial sharing for genomics research

Pauline McCormack, Anna Kole, Sabina Gainotti, Deborah Mascalzoni, Caron Molster, Hanns Lochmüller and Simon Woods; European Journal of Human Genetics (2016) 24, 1403–1408; doi:10.1038/ejhg.2016.30

One of the means of doing this is to ensure that patient organisations are represented in ongoing governance of a global platform such as RD-Connect as part of ensuring that participants feel they have an equivalent level of protection and control in these global interactions as they do in their local relationships with researchers.

Longitudinal study of gait lower limb coordination and rehabilitative indications in patients affected by Ataxia of Friedreich (FRDA)

M. Petrarca, G. Vasco, S. Gazzellini, S. Carniel, A. Pisano, E. Bertini, E. Castelli, Gait & Posture, Volume 49, Supplement 1, September 2016, Pages S2-S3, ISSN 0966-6362, doi:10.1016/j.gaitpost.2016.07.025.

The resulting walking pattern is the product of a complex interaction between cerebellar dysfunction and sensory loss,compromising both balance control and multi-joint coordination. It is possible to speculate on the reduction of sensibility and of selective muscular control which produces increased exploitation of the body biomechanical properties.

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Merav Darash-Yahanaa, Yair Pozniakb, Mingyang Luc, Yang-Sung Sohn, Ola Karmi, Sagi Tamir, Fang Bai, Luhua Song, Patricia A. Jennings, Eli Pikarsky, Tamar Geiger, José N. Onuchic, Ron Mittler and Rachel Nechushtai, PNAS early/2016/09/07, DOI:10.1073/pnas.1612736113

Freely available online through the PNAS open access option.

Disrupted expression of frataxin, another protein involved in Fe-S biogenesis, in hepatocytes of transgenic mice similarly led to impaired mitochondrial function, oxidative stress, and the development of multiple hepatic tumors. Moreover, ISCU and frataxin are regulated at the transcriptional level by p53 controlling the levels of ROS in cells

Retrotope Announces Phase I/II Clinical Trial Results of RT001 in Treatment of Friedreich's Ataxia

LOS ALTOS, CA--(Marketwired - Sep 16, 2016) - Dr. Theresa Zesiewicz, principal investigator in Retrotope's first-in-human clinical trial of RT001 in Friedreich's ataxia (FA), today presented early results from Retrotope's Phase I/II trial conducted at the University of South Florida Ataxia Research Center and the Collaborative NeuroSciences Network in Long Beach, CA. The trial, a randomized, double-blind, comparator controlled, two-dose study of RT001 in 18 FA patients for 28 days, met all of its primary safety, tolerability and pharmacokinetic (PK) goals. While biological activity was not a primary goal of the study, a number of clinically important activity measures were tested, found to be highly correlated to well-studied disease severity scales and showed multiple, unexpected, robust signals of drug effect at one or more doses.

Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control

Michela Guaraldo, Paolo Santambrogio, Elisabetta Rovelli, Augusta Di Savino, Giuseppe Saglio, Davide Cittaro, Antonella Roetto & Sonia Levi; Scientific Reports 6, Article number: 33432 (2016) doi:10.1038/srep33432

The reagents Aza and NaB make the DNA accessible to transcription factors and activate FTMT expression. Our findings sustain that the moderate induction of FTMT expression by epigenetic therapy could be useful in disease characterized by oxidative stress, as FRDA.

UF and the Advocacy Group GoFAR Announce Gene Therapy program for Friedreich’s Ataxia

Press release: Gainesville - FL, Torino - IT, Sept.13, 2016

USF Health and FARA to host patient-focused scientific symposium Sept. 15

USF Health and FARA to host patient-focused scientific symposium Sept. 15 [Video], Written by Anne DeLotto Baier · September 12, 2016

International experts from academia and industry will gather to discuss advances in Friedreich’s ataxia from the laboratory to the clinic.

 Tampa, FL (Sept. 12, 2016) — The University of South Florida (USF) will bring together leading researchers and patients searching for a treatment for Friedreich’s ataxia (FA) and related disorders at the eighth annual scientific symposium “Understanding Energy for A Cure.” The symposium will be held 5 to 8:30 p.m., Thursday, Sept. 15, at the USF Sam and Martha Gibbons Alumni Center, 11810 USF Alumni Drive, Tampa, FL 33620.

Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

Maya Kuperberg, Dorit Lev, Lubov Blumkin, Ayelet Zerem, Mira Ginsberg, Ilan Linder, Nirit Carmi, Sarah Kivity, Tally Lerman-Sagie, Esther Leshinsky-Silver; August 29, 2016, doi: 10.1177/0883073816664836

When a patient arrives with a suspected monogenic disease the authors first take detailed history, perform a full clinical exam, and create a family tree. If a specific genetic disease is suspected based on this data, direct traditional tests are to be performed. Only if the patient remains undiagnosed should the authors turn to whole exome sequencing. The authors were able to diagnose patients exhibiting nonspecific, atypical, or overlapping symptoms.

Over 300 genetic conditions are known to cause ataxia, and without additional specific symptoms achieving a diagnosis is very difficult. Whole exome sequencing studies on cerebellar ataxia have achieved a success rate of 18%-64%. The authors report a high success rate of 57.1% for patients with ataxia.

The Application of Human Spinal Cord Magnetic Resonance Spectroscopy to Clinical Studies: A Review, Seminars in Ultrasound, CT and MRI

Patrik Oliver Wyss, Andreas Hock, Spyros Kollias, Available online 12 July 2016, ISSN 0887-2171, doi:10.1053/j.sult.2016.07.005.

Friedreich’s ataxia (FRDA) is an autosomal recessive degenerative disorder affecting the nervous system and the heart. Spectroscopic measurements in the brain showed decreased NAA in the vermis and the cerebellar hemispheres and increased myo-Inositol in the vermis. The total amount of Cr in the cerebellar hemispheres and Glu in the vermis was higher suggesting an alteration in the glutamatergic neurotransmission system. Findings in the spinal cord were in accordance with those of the brain showing a reduction of NAA by 40% and an increase of mI by 46% reflecting neuronal damage and gliosis.

Introduction to Special Issue on Mitochondrial Redox Signaling in Health and Disease

Juan P. Bolaños, Enrique Cadenas, Michael R. Duchen, Mark B. Hampton, Giovanni E. Mann, Michael P. Murphy, Free Radical Biology and Medicine, Available online 5 August 2016, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.08.004.

The genetic deficiency of the mitochondrial protein frataxin is the cause of Friedreich ataxia. Frataxin deficiency is not associated with cognitive impairment, but with increased oxidative stress with alterations in lipid metabolism, which are discussed as potential therapeutic approaches in Friedreich ataxia. The mitochondrial Lon protease is involved in several neurological disorders, such as hereditary Parkinson’s disease, Friedreich ataxia, familial amyotrophic lateral sclerosis, brain ischemia and stroke. In these disorders, the physiological functions of the Lon protease are altered: as a protease, as a chaperone,and as a mtDNA binding protein.

Functional and Gait Assessment in Children and Adolescents Affected by Friedreich’s Ataxia: A One-Year Longitudinal Study

Gessica Vasco , Simone Gazzellini, Maurizio Petrarca, Maria Luisa Lispi, Alessandra Pisano, Marco Zazza, Gessica Della Bella, Enrico Castelli, Enrico Bertini, PLoS ONE 11(9): e0162463. doi:10.1371/journal.pone.0162463

Open access

Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models

Luana Naia, Tatiana R. Rosenstock, Ana M. Oliveira, Sofia I. Oliveira-Sousa, Gladys L. Caldeira, Catarina Carmo, Mário N. Laço, Michael R. Hayden, Catarina R. Oliveira, A. Cristina Rego; Mol Neurobiol (2016). doi:10.1007/s12035-016-0048-3

In this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.

Friedreich ataxia induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor

Franca Codazzi, Amelié Hu, Myriam Rai, Floramarida Salerno Scarzella, Elisabeth Mangiameli, Ilaria Pelizzoni, Fabio Grohovaz and Massimo Pandolfo3; Hum. Mol. Genet. (2016) doi: 10.1093/hmg/ddw308 First published online: September 4, 2016

Findings suggest that correction of frataxin deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.

R loops and links to human disease

Patricia Richard, James L. Manley, Journal of Molecular Biology, Available online 4 September 2016, ISSN 0022-2836, doi:10.1016/j.jmb.2016.08.031.

More than 40 genetic disorders are caused by gene-specific repeat expansions. These include Huntington’s disease (HD) (CAG repeats in huntingtin (HTT)), myotonic dystrophy type 1 (MD1) (CTG repeats in dystrophia myotonica protein kinase (DMPK)), spinocerebellar ataxia type 1 (SCA1) (CAG repeats in ataxin1 (ATXN1)), fragile X mental retardation or fragile X syndrome (FXS) (CGG repeats in fragile X mental retardation 1 (FMR1)) and Friedreich ataxia (FDRA) (GAA repeats in frataxin (FXN)).

Biomarkers and progress of antioxidant therapy for rare mitochondrial disorders

Lucia Chico, Daniele Orsucci, Annalisa Lo Gerfo, Letizia Marconi, Michelangelo Mancuso & Gabriele Siciliano. Expert Opinion on Orphan Drugs Volume 4, Issue 6, 2016, DOI:10.1080/21678707.2016.1178570



Promising clinical trials have been recently described including the use of different compounds and molecules that can reduce oxidative stress levels and simultaneously act as electron carriers to modulate mitochondrial electron flow.
Several compounds and therapies have been demonstrated to possess mitochondrial restoring and antioxidant properties such as vitamins and cofactors like Coenzyme Q10 (CoQ10) folic acid, vitamin B12, riboflavin, L-carnitine, and creatine, electron acceptors like vitamin C, free radical scavengers like idebenone, EPI-743, vitamin E, alpha lipoic acid, and curcumin, inhibitors of toxic metabolites (dicholoroacetate). Therapeutic potentials of these compounds have been suggested to restoring mitochondrial functions, transport and synaptic plasticity, and showed some neuroprotective role not only in rare mitochondrial disease, but also in other neurodegenerative disorders.
More evidence supports also the use of a combination of “mitococktails”, this referring to as the combination of several and different vitamins, with antioxidant supplements tailored for individual patients to increase mitochondrial respiration and scavenge free radicals to reduce ROS produced in mitochondria diseases.

Pharmacological treatments for Friedreich ataxia

Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M. Pharmacological treatments for Friedreich ataxia. Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No.: CD007791. DOI: 10.1002/14651858.CD007791.pub4.

Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability

Arnaud Chevalier, Mohammad Parvez Alam, Omar M. Khdour, Margaret Schmierer, Pablo M. Arce, Cameron D. Cripe, Sidney M. Hecht,Bioorganic & Medicinal Chemistry, Available online 23 August 2016, ISSN 0968-0896, doi:10.1016/j.bmc.2016.08.039.

The compounds were evaluated for their ability to suppress ROS and lipid peroxidation, and for their effects on mitochondrial membrane potential, and their ability to protect cultured FRDA lymphocytes from oxidative stress induced by glutathione depletion. The compounds were also evaluated for their ability to increase ATP levels in FRDA lymphocytes.

Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia

Marissa Z. McMackin, Chelsea K. Henderson, Gino A. Cortopassi, Behavioural Brain Research SreeTestContent1 SreeTestContent1, Available online 26 August 2016, ISSN 0166-4328, doi:/10.1016/j.bbr.2016.08.053.

The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA.

Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery

Benjamí Oller-Salvia, Macarena Sánchez-Navarro, Ernest Giralt and Meritxell Teixidó, (Review Article) Chem. Soc. Rev., 2016, 45, 4690-4707 DOI: 10.1039/C6CS00076B

Open Access Article

Although the BBB remains a formidable obstacle, since the Trojan horse concept was coined in the 1980s, the field of drug delivery to the brain has made remarkable progress. In the last few years, a plethora of new BBB shuttle peptides have emerged and hold great promise to overcome the limitations of the first generation of shuttles dominated by large proteins. Peptides are more affordable, easier to characterize and to link to nanocarriers or proteins. Moreover, they have lower immunogenicity and often have a reduced effect on the activity of the cargo than their larger counterparts. Furthermore, many peptide shuttles do not compete with endogenous substrates in contrast to endogenous proteins, nor stay bound to the receptor unlike some antibodies. BBB shuttle peptides have so far provided promising results in terms of brain delivery in preclinical settings. In addition, a relevant increase in the therapeutic effect has been proven in a wide variety of animal disease models, with a focus on brain tumours but also including neurodegenerative and lysosomal diseases as well as epilepsy among others.

Despite the considerable achievements described, new shuttles with higher transport capacity and selectivity are required. Approaches like phage display and natural sources of peptides that reach the CNS offer an excellent opportunity to explore the multitude of poorly characterized or still unknown routes into the brain. These strategies should be complemented with additional efforts in the characterization of the transport mechanisms and in global proteomic approaches to identify new receptors. Also, further comparative studies between shuttles and a more accurate quantification of the free drug in the brain parenchyma would enable a more efficient identification and optimization of BBB shuttles. The next generation of BBB shuttle peptides should aim for an enhanced metabolic stability, a higher transendothelial transport and an improved selectivity for the brain – even for particular regions of this organ – possibly through yet uncharacterized transctytotic pathways.

Acknowledgements: IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We appreciate financial support from MINECO-FEDER (Bio2013-40716-R and CTQ2013-49462-EXP), MINECO (PCIN-2015-051 Cure2DIPG), RecerCaixa-2014-Gate2Brain, Generalitat de Catalunya (XRB and 2014-SGR-521), FARA and GENEFA. B.O.-S. and M.S.-N. are grateful for “La Caixa”/IRB Barcelona and Juan de la Cierva fellowships, respectively.

CONTINUUM: Lifelong Learning in Neurology

Ashizawa, Tetsuo MD, FAAN; Xia, Guangbin MD, PhD; August 2016 - Volume 22 - Issue 4, Movement Disorders - p 1208–1226 doi: 10.1212/CON.0000000000000362

Purpose of Review: This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia.

Movement disorders in mitochondrial diseases

Tranchant, Anheim. Rev Neurol (Paris). 2016 Jul 28. pii: S0035-3787(16)30025-X. doi: 10.1016/j.neurol.2016.07.003.

Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns–Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function.

Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

Nishaki Mehta, Paul Chacko, James Jin, Tam Tran, Thomas W. Prior, Xin He, Gunjan Agarwal, and Subha V. Raman (2016). Texas Heart Institute Journal: August 2016, Vol. 43, No. 4, pp. 305-310.
doi:10.14503/THIJ-14-4198

We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy.

Tech giants moving into health may widen inequalities and harm research, unless people can access and share their data, warn John T. Wilbanks and Eric J. Topol.

John T. Wilbanks & Eric J. Topol, Nature 535, 345–348 (21 July 2016) doi:10.1038/535345a

Nature-Comment OPEN

Citizens worldwide have too long a history of being passive players in health care — blindly following instructions from providers. And studies that have tracked reactions to revelations about global surveillance programmes suggest that most people are resigned to the idea that ownership and control of personal information is incompatible with the Internet age.

Yet just as social networking has rocketed around the world in a decade, a worldwide knowledge resource could soon be used to identify the best course of treatment for an individual on the basis of the experiences of millions. This resource will never be built unless each of us takes responsibility for our own health and disease, and for the information that we can generate about ourselves. When it comes to control over our own data, health data must be where we draw the line.

Drug screening: Drug repositioning needs a rethink

Xianting Ding, Nature 535, 355 (21 July 2016) doi:10.1038/535355d  Published online 20 July 2016

Repurposing drugs to treat illnesses for which they were not originally intended can be faster and cheaper than developing new ones. Disease is often an integration of multiple pathologies, so these are potentially treatable with different drug combinations that act in synergy.

For commercial reasons, pharmaceutical firms tend to dismiss reposition testing of drugs that are off patent. I therefore suggest that governments step in to fund the repurposing of established drugs to broaden the search.

Cerebral and cerebellar grey matter atrophy in Friedreich ataxia: the IMAGE-FRDA study.

Selvadurai LP , Harding IH , Corben LA , Stagnitti MR , Storey E , Egan GF , Delatycki MB , Georgiou-Karistianis N
J Neurol [2016] doi:10.1007/s00415-016-8252-7

This study supports a disease model involving neural aberrations within the cerebral and cerebellar cortices, beyond those traditionally associated with this disorder.

Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo

Rowena Schultz; Otto W. Witte; Christian Schmeer; Investigative Ophthalmology & Visual Science August 2016, Vol.57, 4115-4124. doi:10.1167/iovs.16-19260
OPEEN ACCES This work is licensed under a Creative Commons 

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

Khonsari H , Schneider M , Al-Mahdawi S , Chianea YG , Themis M , Parris C , Pook MA , Themis M; Gene Therapy accepted article preview 12 August 2016; doi: 10.1038/gt.2016.61

Open

Frataxin silencing alters microtubule stability in motor neurons: implications for Friedreich's Ataxia

Emanuela Piermarini, Daniele Cartelli, Anna Pastore, Giulia Tozzi, Claudia Compagnucci, Ezio Giorda, Jessica D’Amico, Stefania Petrini, Enrico Bertini E, Graziella Cappelletti and Fiorella Piemonte, Hum. Mol. Genet. (2016) doi: 10.1093/hmg/ddw260, First published online: August 11, 2016

We hypothesize that oxidative stress, determined by high GSSG levels, induces axonal retraction by interfering with MT dynamics. We propose a mechanism of the axonopathy in FRDA where GSSG overload and MT de-polymerization are strictly interconnected. Indeed, using a frataxin-silenced neuronal model we show a significant reduction of neurites extension, a shift of tubulin toward the unpolymerized fraction and a consistent increase of glutathione bound to the cytoskeleton.

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

Oleksandr Gakh, Wasantha Ranatunga, Douglas Y. Smith IV, Eva-Christina Ahlgren, Salam Al-Karadaghi, James R. Thompson and Grazia Isaya. JBC, First Published on August 12, 2016 doi: 10.1074/jbc.M116.738542

Characterization of Novel Small-Molecule NRF2 Activators: Structural and Biochemical Validation of Stereospecific KEAP1 Binding

Carlos Huerta, Xin Jiang, Isaac Trevino, Christopher F. Bender, Deborah A. Ferguson, Brandon Probst, Kerren K. Swinger, Vincent S. Stoll, Philip J. Thomas, Irina Dulubova, Melean Visnick, W. Christian Wigley, Biochimica et Biophysica Acta (BBA) - General Subjects, Available online 27 July 2016, ISSN 0304-4165, doi:10.1016/j.bbagen.2016.07.026.

Clinical trials of omaveloxolone are currently underway in several indications, including Friedreich’s Ataxia, mitochondrial myopathies, corneal endothelial cell loss following cataract surgery, and melanoma. The increased risk for acute fluid overload adverse events observed in BEACON with late-stage CKD patients has not been observed in subsequent studies with bardoxolone methyl or omaveloxolone.

Synthetic Nucleic Acids and Treatment of Neurological Diseases

David R. Corey, PhD, JAMA Neurol. Published online August 01, 2016. doi:10.1001/jamaneurol.2016.2089

OPEN

EMERGING TARGET: FRATAXIN/FRIEDREICH’S ATAXIA

Friedreich’s ataxia is a multiorgan disease that affects the central nervous system, heart, pancreas, and other diseases.25 Antisense oligonucleotides efficiently inhibit gene expression in liver and the central nervous system. Using them to treat the broad range of tissues necessary to fully treat Friedreich’s ataxia will require more potent compounds and more effective strategies for delivering oligonucleotides in to all tissues that are affected.

 The expanded RNA binds to chromosomal DNA to form an R-loop. This R-loop induces histone modifications and reduces transcription. The antisense oligonucleotide binds the expanded repeat, prevents the RNA from binding to the DNA, and releases the break on transcription. The expression of FXN increases to normal levels.


Further testing of anti-AAG oligonucleotides will focus on generalizing the findings to a wider variety of patient-derived cell lines with various numbers of repeats. In the longer term, preclinical and clinical testing will likely benefit from the lessons learned developing nucleic acid drugs for the treatment of other diseases.

Variable sensory nerve conduction parameters in late onset Friedreich ataxia

Alix, J. J.P., Alam, T., Garrard, K., Martindale, J., Shanmugarajah, P., Rao, D. G. and Hadjivassiliou, M. (2016). Muscle Nerve. Accepted Author Manuscript. doi:10.1002/mus.25363

Overall, in LOFA, S-NCS may be variable, and clinicians should consider genetic testing in patients with late onset ataxia and normal nerve conduction studies.

Long-Axis Left Ventricular and Left Atrial Dysfunction in Friedreich Ataxia with Normal Ejection Fraction – Global Longitudinal Strain Versus Tissue Doppler Imaging Velocities

D. Jackson, R. Hassam, L. Donelan, R. Peverill, Heart, Lung and Circulation, Volume 25, Supplement 2, August 2016, Page S80, ISSN 1443-9506, http://dx.doi.org/10.1016/j.hlc.2016.06.185.

In FRDA there are complex interrelationships between global longitudinal strain and tissue Doppler imaging mitral annular velocities, but the strongest correlate of the severity of the genetic abnormality (GAA1) is atrial contraction.

Translating HDAC inhibitors in Friedreich’s ataxia

Elisabetta Soragni & Joel M. Gottesfeld. Expert Opinion on Orphan Drugs, Published online: 31 Jul 2016 DOI:10.1080/21678707.2016.1215910

Expert opinion: 2-aminobenzamide class I HDAC inhibitors are attractive therapeutic small molecules for FRDA. These molecules increase FXN gene expression in human neuronal cells derived from patient induced pluripotent stem cells, and in two mouse models for the disease, as well as in circulating lymphocytes in patients treated in a phase Ib clinical trial. Medicinal chemistry efforts have identified compounds with improved brain penetration, metabolic stability and efficacy in the human neuronal cell model. A clinical candidate will soon be identified for further human testing

Voice in Friedreich Ataxia

Adam P. Vogel, Mayumi I. Wardrop, Joanne E. Folker, Matthis Synofzik, Louise A. Corben, Martin B. Delatycki, Shaheen N. Awan, Journal of Voice, Available online 5 August 2016, ISSN 0892-199 doi:10.1016/j.jvoice.2016.04.015.

Objective: To describe the voice profile of individuals with FRDA to inform outcome marker development and goals of speech therapy.

Although dysphonia severity in FRDA did not correlate significantly with overall disease severity, speaking rate and syllabic duration significantly correlated with age at disease onset and disease duration, and also have an effect on listener perception of dysphonia. The relationship between dysphonia and dysarthria in FRDA suggests that reducing overall dysphonia severity via therapeutic techniques that improve phonatory stability and increase speaking rate is a viable target for speech therapy.

 Treatments designed to improve communicative function should consider therapeutic approaches that aim to improve phonatory stability (eg, use of increased respiratory support prior to the initiation of voicing), and thereby improve vocal pitch and quality control. In addition, therapeutic methods that aid the patient in increasing rate of speech may also be of benefit.

The Pediatric Cerebellum in Inherited Neurodegenerative Disorders: A Pattern-recognition Approach

Susan I. Blaser, Maja Steinlin, Almundher Al-Maawali, Grace Yoon, Neuroimaging Clinics of North America, Volume 26, Issue 3, August 2016, Pages 373-416, ISSN 1052-5149, doi:10.1016/j.nic.2016.03.007.

FRIEDREICH ATAXIA IS THE PROTOTYPE FOR NEURODEGENERATIVE DISORDERS WITH PREDOMINANT SPINAL CORD ATROPHY:
Assessment of the upper cervical cord is predominantly useful in the evaluation of patients with Friedreich ataxia (FRDA/FXN), in whom cord thinning caused by neuronal loss in the spinal ganglia and Clarke column may be the first imaging clue to the disorder.
Involvement of the cerebellum was initially considered a rare feature in FRDA, however, volumetric analysis of the cerebellum in FRDA confirms volume loss in the rostral vermis, dorsal medulla, the dentate nuclei, the peridentate white matter, and the associated superior cerebellar peduncle.

Long-term treatment with thiamine as possible medical therapy for Friedreich ataxia

Antonio Costantini, Tiziana Laureti, Maria Immacolata Pala, Marco Colangeli, Simona Cavalieri, Elisa Pozzi, Alfredo Brusco, Sandro Salvarani, Carlo Serrati, Roberto Fancellu. Original Communication, Journal of Neurology pp 1-9, First online: 03 August 2016. DOI: 10.1007/s00415-016-8244-7

Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment. Thiamine administration ranged from 80 to 930 days and was effective in improving total SARA scores from 26.6 ± 7.7 to 21.5 ± 6.2 (p < 0.02). Moreover, deep tendon reflexes reappeared in 57 % of patients with areflexia at baseline, and swallowing improved in 63 % of dysphagic patients. Clinical improvement was stable in all patients, who did not show worsening even after 2 years of treatment. In a subgroup of 13 patients who performed echocardiogram before and during treatment, interventricular septum thickness reduced significantly (p < 0.02). Frataxin mRNA blood levels were modestly increased in one-half of treated patients. We suppose that a focal thiamine deficiency may contribute to a selective neuronal damage in the areas involved in FRDA. Further studies are mandatory to evaluate thiamine role on FXN regulation, to exclude placebo effect, to verify our clinical results, and to confirm restorative and neuroprotective action of thiamine.

Agilis Biotherapeutics Announces FDA Orphan Drug Designation for the Treatment of Friedreich’s Ataxia (FA)

August 02, 2016 08:30 AM Eastern Daylight Time. August 02, 2016.

First Gene Therapy Candidate to Receive Designation for FA.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Agilis Biotherapeutics, LLC (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation to Agilis’ gene therapy product candidate, AGIL-FA, being developed for the treatment of Friedreich’s ataxia (FA).

Pfizer buys gene therapy company - Is it a good investment?

Rare Disease Report. James Radke, PhD, Published Online: Monday, Aug 01, 2016

Pfizer has acquired gene therapy company Bamboo Therapeutics for a deal that could be worth up to $645 million.
Bamboo therapeutics is developing gene therapy for Giant Axonal Neuropathy (GAN) that is currently in phase 1/2 trial. The company also has gene therapies in development for 3 other neuromuscular diseases – Duchenne muscular dystrophy, Canavan, and Friedreich’s ataxia.

Recent advances in understanding transcription termination by RNA polymerase II.

Travis J. Loya and Daniel Reinesa,  F1000Research 2016, 5(F1000 Faculty Rev):1478  doi: 10.12688/f1000research.8455.1

R-loop-mediated termination is also proposed to play a role in Friedrich’s ataxia. It was suggested that R-loops aberrantly form in the frataxin gene as a result of expansion of GAA repeats in its first intron 58, 59. Mutated frataxin exhibits features of heterochromatin, H3K9 methylation, and decreased acetylation of H3 and H4, thus a reduced level of expression is to be expected. However, the altered gene also shares many characteristics of canonical R-loop-terminated genes, including a polyA-signal-like sequence upstream of the expansion, followed by a GU-rich sequence similar to the downstream element of polyA signals. This has led to a proposal that the mutated frataxin allele is the victim of premature termination, which contributes to its low level of expression in patients. While experimental verification is still needed, this is an interesting model for a role of termination in disease.

Keys to overcoming the challenge of diagnosing autosomal recessive spinocerebellar ataxia / Claves para afrontar el reto diagnóstico de las heredoataxias recesivas

M. Arias, Neurología, Available online 25 July 2016, ISSN 0213-4853, doi:10.1016/j.nrl.2016.06.006

Una cuidadosa evaluación clínica, acompañada de la determinación de ciertos marcadores de laboratorio, la valoración de los datos del estudio electroneuromiográfico y los hallazgos del estudio de resonancia magnética, ayudarán al clínico a establecer unas determinadas sospechas diagnósticas, que siempre procurará confirmar con la detección de la mutación genética causal. El hallazgo de la mutación es decisivo para establecer el pronóstico y consejo genético, además permitirá indicar un tratamiento eficaz en determinadas entidades. Sin diagnóstico genético no será posible realizar investigación básica ni tampoco poner en marcha ensayos terapéuticos.

A thorough assessment of clinical phenotype, laboratory tests, nerve conduction studies, and an magnetic resonance imaging study may help establish a suspected diagnosis, which should be confirmed by detecting the underlying genetic mutation. A positive genetic test result is necessary to determine prognosis and provide adequate genetic counselling, and will also permit appropriate treatment of some entities. Without a genetic diagnosis, conducting basic research and therapeutic trials will not be possible.

OCT in Central Nervous System Diseases

Editors: Grzybowski, Andrzej, Barboni, Piero (Eds.) SPRINGER, ISBN 978-3-319-24085-5

The disorders considered include multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, intracranial hypertension, Friedreich’s ataxia, schizophrenia, hereditary optic neuropathies, glaucoma, and amblyopia. Individual chapters are also devoted to OCT technique, new OCT technology in neuro-ophthalmology, OCT and pharmacological treatment, and the use of OCT in animal models. By documenting the ability of OCT to provide key information on CNS diseases, this book illustrates convincingly that the eye is indeed the “window to the brain”.

Supporting Treatment Adherence in Rare Disease

PM360, Health Psychology by John Weinman, PhD and Kate Perry on May 25th, 2016

Living with a rare disease presents multiple challenges to patients and their families, including those associated with adherence to long-term treatments. As with other chronic conditions, the discipline of health psychology enables us to identify the barriers and motivators specific to individuals with rare disease—and helps us create successful interventions for improved self-management.

Four Key Considerations for Rare Disease Treatment Adherence:
1. Family involvement
2. Lack of local knowledge
3. Perceived stigma
4. Feelings of isolation

The Replication of Frataxin Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion

Stevanoni M, Palumbo E, Russo A (2016). PLoS Genet 12(7): e1006201. doi:10.1371/journal.pgen.1006201

Open access (Creative Commons Attribution License)



In this study we defined the replication program of the FXN gene in human cells, providing for the first time a wide view of origin firing and fork progression within an endogenous genomic context harboring an expanded GAA-repeat. In comparison to the normal FXN sequence, we found an altered replication timing of the mutated alleles. According to our results, the replication of expanded FXN alleles is slowed or delayed during the first half of the S-phase as compared with the wildtype sequence, while a normalization of this effect can be inferred in the second part of the S-phase.

Progression of Friedreich ataxia: quantitative characterization over 5 years

Patel, M., Isaacs, C. J., Seyer, L., Brigatti, K., Gelbard, S., Strawser, C., Foerster, D., Shinnick, J., Schadt, K., Yiu, E. M., Delatycki, M. B., Perlman, S., Wilmot, G. R., Zesiewicz, T., Mathews, K., Gomez, C. M., Yoon, G., Subramony, S. H., Brocht, A., Farmer, J. and Lynch, D. R. (2016), Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.332

Open access article (Creative Commons Attribution-NonCommercial-NoDerivs License)

Objective: Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials.