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.