Vladislav O. SviderskiyErdem M. TerziRichard Possemato, Ferroptosis in Health and Disease. Springer, Cham. doi:10.1007/978-3-030-26780-3_12
We ask whether dysregulation of ISC synthesis, observed in multiple pathological settings including neurodegenerative diseases such as Friedreich’s Ataxia, sideroblastic anemia, and cancer, leads to pathology as a result of ferroptosis.
Sunday, October 13, 2019
Saturday, October 12, 2019
Reata Pharmaceuticals Reacquires Rights From AbbVie to Develop and Commercialize Bardoxolone Methyl, Omaveloxolone, and All Next-Generation Nrf2 Activators
IRVING, Texas, Oct. 10, 2019 (GLOBE NEWSWIRE) — Reata Pharmaceuticals, Inc. (Nasdaq: RETA), a clinical-stage biopharmaceutical company, today announced the reacquisition of development, manufacturing and commercialization rights concerning its proprietary Nrf2 activator product platform originally licensed to AbbVie, Inc. (AbbVie) for territories outside of the United States with respect to bardoxolone methyl (bardoxolone) and worldwide with respect to omaveloxolone and other next-generation Nrf2 activators. As a result, Reata now possesses exclusive, worldwide rights to develop, manufacture and commercialize bardoxolone methyl (bardoxolone), omaveloxolone, and all other next-generation Nrf2 activators, excluding certain Asian markets for bardoxolone which are licensed to Kyowa Kirin Co., Ltd.
Friday, October 11, 2019
Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
Pauline Georges, Maria-Gabriela Boza-Moran, Jacqueline Gide, Georges Arielle Pêche, Benjamin Forêt, Aurélien Bayot, Pierre Rustin, Marc Peschanski, Cécile Martinat & Laetitia Aubry ; Scientific Reports volume 9, Article number: 14568 (2019) doi:10.1038/s41598-019-49870-y
By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.
By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.
Tuesday, October 8, 2019
Minoryx Therapeutics termine le recrutement de FRAMES, son essai clinique de phase 2 du leriglitazone dans l’ataxie de Friedreich
Mataró, Barcelone, Espagne et Charleroi, Belgique, le 8 octobre 2019 - MinoryxTherapeutics, une société spécialisée dans le développement de traitements innovants contredes maladies orphelines du système nerveux central (SNC), annonce aujourd’hui avoirterminé le recrutement des patients dans son essai clinique de phase 2 FRAMES sur l’ataxiede Friedreich avec son candidat médicament leriglitazone (MIN-102), un nouvel agoniste du PPARγ.
L’essai FRAMES est une étude multicentrique et randomisée, en double-aveugle contreplacebo, qui vise à évaluer l’efficacité et l’innocuité du leriglitazone chez les patients souffrantd’ataxie de Friedreich. Le recrutement de 39 patients dans quatre pays européens a été réalisé au cours des derniers quatre mois et demi en avance sur les prévisions. Les patients, âgés de 12 à 60 ans, vont recevoir durant un an une dose quotidienne de leriglitazone en suspension orale. L’objectif principal de l’essai consiste à évaluer l’effet du candidat médicament sur la progression de la maladie. Cet effet sera mesuré par imagerie de pointe de la moëlle épinière. Les objectifs secondaires incluent l’innocuité et la tolérance, l’effet sur d’autres observations cliniques, telles que les retours des patients, l’échelle d’incapacité fonctionnelle et les biomarqueurs exploratoires.
L’essai FRAMES est une étude multicentrique et randomisée, en double-aveugle contreplacebo, qui vise à évaluer l’efficacité et l’innocuité du leriglitazone chez les patients souffrantd’ataxie de Friedreich. Le recrutement de 39 patients dans quatre pays européens a été réalisé au cours des derniers quatre mois et demi en avance sur les prévisions. Les patients, âgés de 12 à 60 ans, vont recevoir durant un an une dose quotidienne de leriglitazone en suspension orale. L’objectif principal de l’essai consiste à évaluer l’effet du candidat médicament sur la progression de la maladie. Cet effet sera mesuré par imagerie de pointe de la moëlle épinière. Les objectifs secondaires incluent l’innocuité et la tolérance, l’effet sur d’autres observations cliniques, telles que les retours des patients, l’échelle d’incapacité fonctionnelle et les biomarqueurs exploratoires.
Minoryx completa el reclutamiento del ensayo clínico de Fase II de leriglitazona para la ataxia de Friedreich
Mataró (Barcelona)-Charleroi (Bélgica), 8 de octubre de 2019. Minoryx Therapeutics, compañía especializada en el desarrollo de tratamientos innovadores para las enfermedades huérfanas del sistema nervioso central (SNC), anuncia hoy que ha completado el reclutamiento de pacientes en el ensayo clínico FRAMES de Fase II de su fármaco leriglitazona (MIN-102) para la ataxia de Friedreich (FRDA).
FRAMES es un ensayo multicéntrico, aleatorio, doble ciego y controlado con placebo que evaluará la eficacia y la seguridad de leriglitazona en pacientes con FRDA. En total se han reclutado a 39 pacientes en cuatro países europeos en solo cuatro meses y medio, mucho antes de lo previsto. Los pacientes, que tienen entre 12 y 60 años, recibirán leriglitazona administrada una vez al día por vía oral durante un año. El objetivo principal del ensayo es controlar el efecto sobre la progresión de la enfermedad, que se medirá mediante imágenes de resonancia magnética de última generación de la médula espinal. Los objetivos secundarios incluyen la seguridad y tolerabilidad.
FRAMES es un ensayo multicéntrico, aleatorio, doble ciego y controlado con placebo que evaluará la eficacia y la seguridad de leriglitazona en pacientes con FRDA. En total se han reclutado a 39 pacientes en cuatro países europeos en solo cuatro meses y medio, mucho antes de lo previsto. Los pacientes, que tienen entre 12 y 60 años, recibirán leriglitazona administrada una vez al día por vía oral durante un año. El objetivo principal del ensayo es controlar el efecto sobre la progresión de la enfermedad, que se medirá mediante imágenes de resonancia magnética de última generación de la médula espinal. Los objetivos secundarios incluyen la seguridad y tolerabilidad.
MINORYX THERAPEUTICS COMPLETES ENROLLMENT IN FRAMES PHASE 2 TRIAL WITH LERIGLITAZONE IN FRIEDREICH’S ATAXIA
Mataró, Barcelona, Spain and Charleroi, Belgium, October 8, 2019.
Minoryx Therapeutics, a company specializing in the development of innovative treatments for orphan central nervous system (CNS) diseases, today announces that it has completed recruitment in the FRAMES phase 2 clinical trial of its novel PPARγ agonist, leriglitazone (MIN-102), in patients with Friedreich’s Ataxia.
FRAMES is a multicenter, randomized, double-blind, placebo-controlled trial that will assess the efficacy and safety of leriglitazone in patients with Friedreich’s Ataxia. Recruitment of 39 patients in four European countries was completed in just four and a half months, well ahead of schedule. The patients, aged 12-60 years, will receive leriglitazone, administered once a day as an oral suspension, for a total of one year. The primary objective of the trial is to monitor the effect on disease progression. This will be measured through state-of-the art imaging of the spinal cord. Secondary objectives include safety and tolerability, effect on additional clinical measures, such as patient reported outcomes, functional disability scores and exploratory biomarkers.
Minoryx Therapeutics, a company specializing in the development of innovative treatments for orphan central nervous system (CNS) diseases, today announces that it has completed recruitment in the FRAMES phase 2 clinical trial of its novel PPARγ agonist, leriglitazone (MIN-102), in patients with Friedreich’s Ataxia.
FRAMES is a multicenter, randomized, double-blind, placebo-controlled trial that will assess the efficacy and safety of leriglitazone in patients with Friedreich’s Ataxia. Recruitment of 39 patients in four European countries was completed in just four and a half months, well ahead of schedule. The patients, aged 12-60 years, will receive leriglitazone, administered once a day as an oral suspension, for a total of one year. The primary objective of the trial is to monitor the effect on disease progression. This will be measured through state-of-the art imaging of the spinal cord. Secondary objectives include safety and tolerability, effect on additional clinical measures, such as patient reported outcomes, functional disability scores and exploratory biomarkers.
Sunday, October 6, 2019
Primary Cultures of Pure Embryonic Dorsal Root Ganglia Sensory Neurons as a New Cellular Model for Friedreich’s Ataxia
Griso O., Puccio H. (2020). In: Richard GF. (eds) Trinucleotide Repeats. Methods in Molecular Biology, vol 2056. Humana, New York, NY. doi:10.1007/978-1-4939-9784-8_15
We have established a model of primary cultures of DRG sensory neurons in which we induce the loss of the frataxin protein. With such a model we can alleviate the issues related to the complexity of DRG tissues and low amount of sensory neuron material in adult mouse. Hereby, we provide a protocol of detailed and optimized methods to obtain high yield of healthy mouse DRG sensory neuron in culture.
We have established a model of primary cultures of DRG sensory neurons in which we induce the loss of the frataxin protein. With such a model we can alleviate the issues related to the complexity of DRG tissues and low amount of sensory neuron material in adult mouse. Hereby, we provide a protocol of detailed and optimized methods to obtain high yield of healthy mouse DRG sensory neuron in culture.
Saturday, October 5, 2019
SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia
Carlotta Bon, Riccardo Luffarelli, Roberta Russo, Silvia Fortuni, Bianca Pierattini, Chiara Santulli, Cristina Fimiani, Francesca Persichetti, Diego Cotella, Antonello Mallamaci, Claudio Santoro, Piero Carninci, Stefano Espinoza, Roberto Testi, Silvia Zucchelli, Ivano Condò, Stefano Gustincich; Nucleic Acids Research, , gkz798, doi:10.1093/nar/gkz798
We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.
We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.
Friday, October 4, 2019
A case of Friedreich ataxia in an adolescent with 16p11.2 microdeletion syndrome
Valentina Pelliccia, Silvia Ferranti, Rosa Mostardini, Salvatore Grosso; Neurol Sci (2019). doi:10.1007/s10072-019-04075-z
A completely different genetic mechanism is the one responsible for Friedreich ataxia; the disorder is provoked by an unstable expansion of the GAA triplet located in the frataxin gene [4]. Friedreich ataxia is the most common type of inherited ataxia; onset of symptoms usually occurs during adolescence, and clinical course is slowly progressive. The main clinical signs include gait imbalance, abnormal eye movements, scoliosis, feet deformities, urinary dysfunction, and cardiac involvement.
A completely different genetic mechanism is the one responsible for Friedreich ataxia; the disorder is provoked by an unstable expansion of the GAA triplet located in the frataxin gene [4]. Friedreich ataxia is the most common type of inherited ataxia; onset of symptoms usually occurs during adolescence, and clinical course is slowly progressive. The main clinical signs include gait imbalance, abnormal eye movements, scoliosis, feet deformities, urinary dysfunction, and cardiac involvement.
Monday, September 30, 2019
Health-related quality of life and depressive symptoms in Friedreich ataxia
Javier Pérez-Flores, Atteneri Hernández-Torres, Fernando Montón, Antonieta Nieto; Qual Life Res. 2019 Sep 28. doi: 10.1007/s11136-019-02311-9.
Friedreich ataxia (FRDA) is a chronic, progressive and highly disabling cerebellar degenerative disease. Despite this, little attention has been paid to the health-related quality of life (HRQOL) in this disease. The aim of the present study was to assess FRDA patients’ perception of HRQOL and to determine the influence of depression, and demographic and clinical variables.
Our study demonstrates the high impact of Friedreich ataxia on quality of life. This impact does not only occur in those aspects most related to motor disability but it is also present in non-motor dimensions. Depressive symptomatology is the most relevant variable for predicting quality of life.
Friedreich ataxia (FRDA) is a chronic, progressive and highly disabling cerebellar degenerative disease. Despite this, little attention has been paid to the health-related quality of life (HRQOL) in this disease. The aim of the present study was to assess FRDA patients’ perception of HRQOL and to determine the influence of depression, and demographic and clinical variables.
Our study demonstrates the high impact of Friedreich ataxia on quality of life. This impact does not only occur in those aspects most related to motor disability but it is also present in non-motor dimensions. Depressive symptomatology is the most relevant variable for predicting quality of life.
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