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.
Friday, December 23, 2016
Thursday, December 22, 2016
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.
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.
Wednesday, December 21, 2016
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.
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.
Tuesday, December 20, 2016
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.
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.
Monday, December 19, 2016
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.
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.
Sunday, December 18, 2016
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.
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.
Saturday, December 17, 2016
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.
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.
Friday, December 16, 2016
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%.
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%.
Thursday, December 15, 2016
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.
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.
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.
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