Sunday, December 11, 2016

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.

Friday, December 9, 2016

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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Thursday, December 8, 2016

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.

Wednesday, December 7, 2016

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



Tuesday, December 6, 2016

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.

Monday, December 5, 2016

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.

Sunday, December 4, 2016

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.

Friday, December 2, 2016

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.

Thursday, December 1, 2016

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.