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.
Thursday, December 8, 2016
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
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.
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.
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.
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
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.
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.
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.
Wednesday, November 30, 2016
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."
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.
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.
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