20/11/2019. European Medicines Agency.
On 1 April 2019, orphan designation (EU/3/19/2148) was granted by the European Commission to Takeda Pharma A/S, Denmark, for 4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one (also known as TAK-831) for the treatment of Friedreich’s ataxia.
Please note that this product was withdrawn from the Union Register of orphan medicinal products in November 2019 on request of the Sponsor.
Key facts
Active substance: 4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one
Disease / condition: Treatment of Friedreich’s ataxia
Date of first decision: 01/04/2019
Outcome: Withdrawn
EU designation number: EU/3/19/2148
Friday, November 22, 2019
N-terminomics/TAILS profiling of macrophages after chemical inhibition of legumain
Bethany M AndersonLuiz G. N. de AlmeidaHenna SekhonDaniel YoungAntoine DufourLaura Edgington-Mitchell; Biochemistry 2019, XXXX, XXX, XXX-XXX, Publication Date: November 14, 2019 doi:10.1021/acs.biochem.9b00821
We confirmed that frataxin, a mitochondrial protein associated with the formation of iron-sulfur clusters, can be cleaved by legumain. This further asserts a potential contribution of legumain to mitochondrial function and iron metabolism.
We confirmed that frataxin, a mitochondrial protein associated with the formation of iron-sulfur clusters, can be cleaved by legumain. This further asserts a potential contribution of legumain to mitochondrial function and iron metabolism.
Thursday, November 21, 2019
Analysis of Friedreich's ataxia patient clinical data reveals importance of accurate GAA repeat determination in disease prognosis and gender differences in cardiac measures
Mohammadmersad Ghorbani, Françoise Pousset, Allan Tucker, Stephen Swift, Paola Giunti, Michael Parkinson, David Gilbert, XiaoHui Liu, Annette Payne, Informatics in Medicine Unlocked, 2019, doi:10.1016/j.imu.2019.100266.
This work uses computer aided classification techniques to identify which measures of the disease progression, including accurate determination of the shortest allele repeat length, are the most informative when trying to predict likely disease progression and prognosis. Further we investigate the possibility of a gender difference in the progression of the disease. Our results highlight the importance of accurate determination GAA repeat length in any clinical predictions showing that the number of repeats is the best prognostic tool in FRDA and is strongly linked to the age at onset disease. Further that there are possible gender dependent differences in cardiac measurements recorded from patients of similar age of onset and GAA repeat length.
This work uses computer aided classification techniques to identify which measures of the disease progression, including accurate determination of the shortest allele repeat length, are the most informative when trying to predict likely disease progression and prognosis. Further we investigate the possibility of a gender difference in the progression of the disease. Our results highlight the importance of accurate determination GAA repeat length in any clinical predictions showing that the number of repeats is the best prognostic tool in FRDA and is strongly linked to the age at onset disease. Further that there are possible gender dependent differences in cardiac measurements recorded from patients of similar age of onset and GAA repeat length.
Wednesday, November 20, 2019
Metformin-dependent Exacerbation of Pathologies in Friedreich’s Ataxia
Free Radical Biology and Medicine, Volume 145, Supplement 1, 2019, Page S81, doi:10.1016/j.freeradbiomed.2019.10.216.
One case report describes metformin treatment for diabetes in a FRDA patient, he developed severe ventricular arrhythmia and died of cardiac failure during a surgery. Future research of FRDA-relevant tissues will better inform on disease exacerbation.
One case report describes metformin treatment for diabetes in a FRDA patient, he developed severe ventricular arrhythmia and died of cardiac failure during a surgery. Future research of FRDA-relevant tissues will better inform on disease exacerbation.
Tuesday, November 19, 2019
Left ventricular structural and functional changes in Friedreich ataxia – Relationship with body size, sex, age and genetic severity
Peverill RE, Romanelli G, Donelan L, Hassam R, Corben LA, Delatycki MB (2019); PLoS ONE 14(11): e0225147. doi:10.1371/journal.pone.0225147
In FRDA, increases in RWT and age-normalized RWT are the most frequent LV structural abnormalities, sex and body size are important determinants of most other LV structural variables in both children and adults, and increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children.
In FRDA, increases in RWT and age-normalized RWT are the most frequent LV structural abnormalities, sex and body size are important determinants of most other LV structural variables in both children and adults, and increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children.
Tuesday, November 12, 2019
Minoryx Therapeutics receives Orphan Drug Designation from the European Commission for leriglitazone in the treatment of Friedreich’s Ataxia
Mataró, Barcelona, Spain and Charleroi, Belgium, November 12, 2019 – Minoryx Therapeutics, a company that specializes in the development of innovative treatments for orphan Central Nervous System (CNS) diseases, today announces that its lead drug candidate, leriglitazone (MIN-102), has been granted Orphan Drug Designation by the European Commission in the treatment of Friedreich’s Ataxia.
Leriglitazone (MIN-102) is a novel, brain penetrant, orally bioavailable and selective PPARγ agonist that engages the target receptor within the central nervous system. The disease-modifying potential and unique mode-of-action of leriglitazone have been demonstrated in multiple preclinical CNS disease models showing that it has an anti-oxidant, anti-inflammatory and neuroprotective effect. Leriglitazone improves mitochondrial function and biogenesis, promotes remyelination, ameliorates lipid metabolism and delays the progression of neurological disability. Leriglitazone is currently in late-stage clinical development in adrenomyeloneuropathy (AMN) and Friedreich’s Ataxia (FRDA).
“We are very pleased that, following the recent FDA Orphan Drug Designation for leriglitazone in Friedreich’s Ataxia, the European Commission has also granted Orphan Drug Status, further demonstrating the potential of this novel drug candidate and our commitment to changing the lives of patients suffering from severe orphan diseases,” said Marc Martinell, CEO of Minoryx. “Leriglitazone is our lead drug candidate currently in late-stage clinical development in a number of life-threatening orphan CNS diseases. Patient enrollment has been completed in both the AMN and the FRDA studies and we are on track to present our results by the end of 2020.”
Leriglitazone (MIN-102) is a novel, brain penetrant, orally bioavailable and selective PPARγ agonist that engages the target receptor within the central nervous system. The disease-modifying potential and unique mode-of-action of leriglitazone have been demonstrated in multiple preclinical CNS disease models showing that it has an anti-oxidant, anti-inflammatory and neuroprotective effect. Leriglitazone improves mitochondrial function and biogenesis, promotes remyelination, ameliorates lipid metabolism and delays the progression of neurological disability. Leriglitazone is currently in late-stage clinical development in adrenomyeloneuropathy (AMN) and Friedreich’s Ataxia (FRDA).
“We are very pleased that, following the recent FDA Orphan Drug Designation for leriglitazone in Friedreich’s Ataxia, the European Commission has also granted Orphan Drug Status, further demonstrating the potential of this novel drug candidate and our commitment to changing the lives of patients suffering from severe orphan diseases,” said Marc Martinell, CEO of Minoryx. “Leriglitazone is our lead drug candidate currently in late-stage clinical development in a number of life-threatening orphan CNS diseases. Patient enrollment has been completed in both the AMN and the FRDA studies and we are on track to present our results by the end of 2020.”
Monday, November 11, 2019
Reducing complexity: explaining inborn errors of metabolism and their treatment to children and adolescents
Nina A. Zeltner, Mendy M. Welsink-Karssies, Markus A. Landolt, Dominique Bosshard-Bullinger, Fabia Keller, Annet M. Bosch, Marike Groenendijk, Sarah C. Grünert, Daniela Karall, Beatrix Rettenbacher, Sabine Scholl-Bürgi, Matthias R. Baumgartner & Martina Huemer, Orphanet J Rare Dis 14, 248 (2019) doi:10.1186/s13023-019-1236-9
Medical jargon and incomprehensive disease information constitute a barrier to informed and shared decision-making. Over 80% of the study participants indicated that they liked the materials and appreciated them as an indicator of a respectful approach of care. Facilitated communication between patient and metabolic care team may not only enhance patients’ safety, outcome, attitude towards the care team and quality of life but does significantly reduce the workload of metabolic professionals due to increased independence of patients and families. Involvement of parents in teaching sessions and provision of the materials enables parents to explain the contents repeatedly to their child at home and to involve siblings, other family members or external caregivers to gain social support.
Medical jargon and incomprehensive disease information constitute a barrier to informed and shared decision-making. Over 80% of the study participants indicated that they liked the materials and appreciated them as an indicator of a respectful approach of care. Facilitated communication between patient and metabolic care team may not only enhance patients’ safety, outcome, attitude towards the care team and quality of life but does significantly reduce the workload of metabolic professionals due to increased independence of patients and families. Involvement of parents in teaching sessions and provision of the materials enables parents to explain the contents repeatedly to their child at home and to involve siblings, other family members or external caregivers to gain social support.
Sunday, November 10, 2019
Temporal but not spatial dysmetria relates to disease severity in FA
Manuela Corti, Agostina Casamento Moran, Stefan Delmas, Samantha Bracksieck, Jessica Bowman, Blake Meyer, Samantha Norman, Sub Subramony, and Evangelos A Christou, Journal of Neurophysiology 0 0:0 Doi:10.1152/jn.00165.2019
The aim of this study is to characterize dysmetria and its association to functional capacity. Also, we examine the neural mechanisms of dysmetria by quantifying the EMG burst area, duration, and time-to-peak of the agonist muscle. Methods.27 individuals with FA and 13 healthy controls (HC) performed the modified Functional Ataxia Rating Scale (mFARS), and goal-directed movements with the ankle. Dysmetria was quantified as position and time error during dorsiflexion. Results. FA individuals exhibited greater time but not position error than HC. Moreover, time error correlated with disease severity and was related to increased agonist EMG burst. Discussion. Temporal dysmetria is associated to functional capacity, likely due to altered activation of the agonist muscle.
The aim of this study is to characterize dysmetria and its association to functional capacity. Also, we examine the neural mechanisms of dysmetria by quantifying the EMG burst area, duration, and time-to-peak of the agonist muscle. Methods.27 individuals with FA and 13 healthy controls (HC) performed the modified Functional Ataxia Rating Scale (mFARS), and goal-directed movements with the ankle. Dysmetria was quantified as position and time error during dorsiflexion. Results. FA individuals exhibited greater time but not position error than HC. Moreover, time error correlated with disease severity and was related to increased agonist EMG burst. Discussion. Temporal dysmetria is associated to functional capacity, likely due to altered activation of the agonist muscle.
Saturday, November 9, 2019
Speech and Language Disorders in Friedreich Ataxia: Highlights on Phenomenology, Assessment, and Therapy
ommaso Schirinzi, Andrea Sancesario, Enrico Bertini, Enrico Castelli, Gessica Vasco. Cerebellum (2019). Doi:10.1007/s12311-019-01084-8
FRDA patients often present dysarthria, resulting from central and peripheral causes and additional primary language disorders. Speech disturbances have peculiar characteristics, although variable among patients, and progress along the disease course. Assessment relies on multiple but not specific clinical scales, some of which can also reflect the general severity of ataxia; classical instrumental investigations and novel technologies allow more accurate measurements of several speech parameters, which could found application as potential disease’s biomarkers. No successful treatments exist for communication disorders of FRDA patients; however, the tailored speech training or the non-invasive neuromodulation appear as the most reliable therapeutic options to be validate in future trials.
FRDA patients often present dysarthria, resulting from central and peripheral causes and additional primary language disorders. Speech disturbances have peculiar characteristics, although variable among patients, and progress along the disease course. Assessment relies on multiple but not specific clinical scales, some of which can also reflect the general severity of ataxia; classical instrumental investigations and novel technologies allow more accurate measurements of several speech parameters, which could found application as potential disease’s biomarkers. No successful treatments exist for communication disorders of FRDA patients; however, the tailored speech training or the non-invasive neuromodulation appear as the most reliable therapeutic options to be validate in future trials.
Friday, November 8, 2019
Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model
Chiara Dionisi, Myriam Rai, Marine Chazalon, Serge Schiffmann, Massimo Pandolfo, bioRxiv 829358 doi:10.1101/829358
We modified the dual-SMAD inhibition/WNT activation protocol, previously used to generate nociceptor-enriched cultures of primary sensory neurons from iPSCs, to favor instead the generation of proprioceptors. We succeeded in substantially enriching iPSC-derived primary sensory neuron cultures in proprioceptors, largely exceeding the proportion normally represented by these cells in dorsal root ganglia. We also showed that almost pure populations of proprioceptors can be purified from these cultures by fluorescence-activated cell sorting. Finally, we demonstrated that iPSCs from a FRDA patient can generate normal appearing proprioceptors but have subtle differentiation deficits and more limited survival.
We modified the dual-SMAD inhibition/WNT activation protocol, previously used to generate nociceptor-enriched cultures of primary sensory neurons from iPSCs, to favor instead the generation of proprioceptors. We succeeded in substantially enriching iPSC-derived primary sensory neuron cultures in proprioceptors, largely exceeding the proportion normally represented by these cells in dorsal root ganglia. We also showed that almost pure populations of proprioceptors can be purified from these cultures by fluorescence-activated cell sorting. Finally, we demonstrated that iPSCs from a FRDA patient can generate normal appearing proprioceptors but have subtle differentiation deficits and more limited survival.
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