Marissa Z. McMackin, Blythe Durbin-Johnson, Marek Napierala, Jill S. Napierala, Luis Ruiz, Eleonora Napoli, Susan Perlman, Cecilia Giulivi, Gino A. Cortopassi (2019) . PLoS ONE 14(10): e0223209. doi:10.1371/journal.pone.0223209
Friedreich’s ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.
Thursday, October 31, 2019
Wednesday, October 30, 2019
PTC Therapeutics Reports Third Quarter 2019 Financial Results and Provides a Corporate Update
SOUTH PLAINFIELD, N.J., Oct. 29, 2019 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) today announced a corporate update and reported financial results for the third quarter ending September 30, 2019.
The Friedreich ataxia program continues to advance with an IND submission now expected in mid-2020.
The Friedreich ataxia program continues to advance with an IND submission now expected in mid-2020.
Symposium updates Friedreich’s ataxia community on advances against FA
Written by Anne DeLotto Baier · October 29, 2019 @ 12:55 pm · Filed under Hot News, Morsani College of Medicine, Neurosciences & Brain Repair, Patient Care, Research, School of Biomedical Sciences.
Less than three weeks after the 10th annual Friedreich’s Ataxia (FA) Scientific Symposium at USF, Reata Pharmaceuticals Inc. announced that its MOXIe trial of daily therapy with omaveloxolone capsules (RTA 408) improved the neurological function of patients with FA – a rare, debilitating and life-shortening neuromuscular disorder.
Less than three weeks after the 10th annual Friedreich’s Ataxia (FA) Scientific Symposium at USF, Reata Pharmaceuticals Inc. announced that its MOXIe trial of daily therapy with omaveloxolone capsules (RTA 408) improved the neurological function of patients with FA – a rare, debilitating and life-shortening neuromuscular disorder.
Sunday, October 27, 2019
Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study
Lise Legrand, Abdourahmane Diallo, Marie-Lorraine Monin, Claire Ewenczyk, Perrine Charles, Richard Isnard, Eric Vicaut, Gilles Montalescot, Alexandra Durr, Francoise Pousset; Am J Cardiovasc Drugs (2019). doi:10.1007/s40256-019-00375-z
Echocardiographic follow-up combined with size assessment of GAA repeat expansions is a powerful tool to identify patients at high risk of developing LV systolic dysfunction up to 5 years before clinical symptoms. Further studies are mandatory to investigate if these patients would benefit from cardiac interventions.
Echocardiographic follow-up combined with size assessment of GAA repeat expansions is a powerful tool to identify patients at high risk of developing LV systolic dysfunction up to 5 years before clinical symptoms. Further studies are mandatory to investigate if these patients would benefit from cardiac interventions.
Saturday, October 26, 2019
Ironing the mitochondria: Relevance to its dynamics
Mamta Upadhyay, Saloni Agarwal, Mitochondrion, 2019, doi:10.1016/j.mito.2019.09.007.
The mitochondrion is “jack of many trades and master of one”. Despite being a master in energy generation, it plays a significant role in other cellular processes, including calcium homeostasis, cell death, and iron metabolism. Since mitochondria employ the majority of cellular iron, it plays a central role in the iron homeostasis. Iron could be a major regulator of mitochondrial dynamics as the excess of iron leads to oxidative stress, which causes a disturbance in mitochondrial dynamics. Remarkably, abnormal iron accumulation has been observed in the brain regions of the neurodegenerative disorders patients. These neurodegenerative disorders are also often associated with the abnormal mitochondrial dynamics. Here in this article, we will mainly discuss the studies focused on unravelling the role of iron in mitochondrial dynamics.
The mitochondrion is “jack of many trades and master of one”. Despite being a master in energy generation, it plays a significant role in other cellular processes, including calcium homeostasis, cell death, and iron metabolism. Since mitochondria employ the majority of cellular iron, it plays a central role in the iron homeostasis. Iron could be a major regulator of mitochondrial dynamics as the excess of iron leads to oxidative stress, which causes a disturbance in mitochondrial dynamics. Remarkably, abnormal iron accumulation has been observed in the brain regions of the neurodegenerative disorders patients. These neurodegenerative disorders are also often associated with the abnormal mitochondrial dynamics. Here in this article, we will mainly discuss the studies focused on unravelling the role of iron in mitochondrial dynamics.
Friday, October 25, 2019
Cerebellum and cognition in Friedreich ataxia: a voxel-based morphometry and volumetric MRI study
Sirio Cocozza, Te*resa Costabile, Giuseppe Pontillo, Maria Lieto, Camilla Russo, I Leonardo Radice,Chiara Pane, Alessandro Filla, Arturo Brunetti, Francesco Saccà; J Neurol (2019). doi:10.1007/s00415-019-09582-9
With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.
With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.
Thursday, October 24, 2019
Ethical, legal, and social issues (ELSI) in rare diseases: a landscape analysis from funders
Adam L. Hartman, Anneliene Hechtelt Jonker, Melissa A. Parisi, Daria Julkowska, Nicole Lockhart & Rosario Isasi ; Eur J Hum Genet. 2019 Sep 19. doi: 10.1038/s41431-019-0513-3.
Recent interest in personalized medicine has highlighted the importance of research in ethical, legal, and social issues (ELSI). Issues in ELSI research may be magnified in the rare diseases population (i.e., small numbers of affected individuals, challenges in maintaining confidentiality, and paucity of treatments for diseases where natural history information may be limited). More than other areas of research, potential barriers include the lack of funding opportunities and appropriate review processes for applications to funding agencies. The ELSI Working Group of the International Rare Diseases Research Consortium (IRDiRC) performed an informal survey on ELSI funding initiatives to learn more about different funding mechanisms and to identify potential gaps in funding opportunities. The Working Group discusses these challenges and highlights the role of funding agencies and partners such as patient advocacy groups, specialists in social sciences and humanities, and clinicians to advance ELSI research in rare diseases.
Recent interest in personalized medicine has highlighted the importance of research in ethical, legal, and social issues (ELSI). Issues in ELSI research may be magnified in the rare diseases population (i.e., small numbers of affected individuals, challenges in maintaining confidentiality, and paucity of treatments for diseases where natural history information may be limited). More than other areas of research, potential barriers include the lack of funding opportunities and appropriate review processes for applications to funding agencies. The ELSI Working Group of the International Rare Diseases Research Consortium (IRDiRC) performed an informal survey on ELSI funding initiatives to learn more about different funding mechanisms and to identify potential gaps in funding opportunities. The Working Group discusses these challenges and highlights the role of funding agencies and partners such as patient advocacy groups, specialists in social sciences and humanities, and clinicians to advance ELSI research in rare diseases.
Wednesday, October 23, 2019
PTC Therapeutics enters collaboration with Aldevron to support GMP plasmid manufacturing
South Plainfield, New Jersey. Thursday, October 10, 2019.
PTC Therapeutics, global biopharmaceutical company, announced a collaboration with Aldevron, LLC to secure GMP manufacturing capacity for PTC's gene therapy portfolio, including the Friedreich ataxia and Angelman syndrome programmes in PTC's growing gene therapy pipeline.
The central nervous system (CNS) gene therapy platform at PTC uses targeted micro-dosing applied directly to areas involved in the disorder. This allows for greater efficacy, durability, lower risk of immunogenicity or other off-target effect, and efficient and scalable manufacturing. PTC has an advancing gene therapy pipeline for CNS disorders, including programs for AADC deficiency, Friedreich Ataxia, and Angelman Syndrome. PTC is preparing a BLA for the treatment of AADC deficiency for submission to the FDA in the fourth quarter of 2019.
PTC Therapeutics, global biopharmaceutical company, announced a collaboration with Aldevron, LLC to secure GMP manufacturing capacity for PTC's gene therapy portfolio, including the Friedreich ataxia and Angelman syndrome programmes in PTC's growing gene therapy pipeline.
The central nervous system (CNS) gene therapy platform at PTC uses targeted micro-dosing applied directly to areas involved in the disorder. This allows for greater efficacy, durability, lower risk of immunogenicity or other off-target effect, and efficient and scalable manufacturing. PTC has an advancing gene therapy pipeline for CNS disorders, including programs for AADC deficiency, Friedreich Ataxia, and Angelman Syndrome. PTC is preparing a BLA for the treatment of AADC deficiency for submission to the FDA in the fourth quarter of 2019.
Tuesday, October 22, 2019
Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs
Petrillo, S.; D’Amico, J.; La Rosa, P.; Bertini, E.S.; Piemonte, F. Int. J. Mol. Sci. 2019, 20, 5211. Doi:10.3390/ijms20205211 (registering DOI)
Different redox drugs, joined by their ability to modulate the NRF2 pathway, elicit differential response profiles in FRDA fibroblasts. Using drugs aimed at preventing inflammation (SFN, NAC), lipid peroxidation (DMF, OMAV, and EPI-743), or redox imbalance (SFN), “multi-target” synergic therapies can be developed in FRDA, based on the patient’s clinical conditions and therapeutic needs.
Different redox drugs, joined by their ability to modulate the NRF2 pathway, elicit differential response profiles in FRDA fibroblasts. Using drugs aimed at preventing inflammation (SFN, NAC), lipid peroxidation (DMF, OMAV, and EPI-743), or redox imbalance (SFN), “multi-target” synergic therapies can be developed in FRDA, based on the patient’s clinical conditions and therapeutic needs.
Sunday, October 20, 2019
Safety and Biodistribution of Human Bone Marrow-Derived Mesenchymal Stromal Cells Injected Intrathecally in Non-Obese Diabetic Severe Combined Immunodeficiency Mice: Preclinical Study
Mari Paz Quesada, David García-Bernal, Diego PastorAlicia Estirado, Miguel Blanquer, Ana Mª García-HernándezJosé, M. Moraleda, Salvador Martínez. Eng Regen Med (2019) 16: 525. doi:10.1007/s13770-019-00202-1
Mesenchymal stromal cells (MSCs) have potent immunomodulatory and neuroprotective properties, and have been tested in neurodegenerative diseases resulting in meaningful clinical improvements. Regulatory guidelines specify the need to perform preclinical studies prior any clinical trial, including biodistribution assays and tumourigenesis exclusion. We conducted a preclinical study of human bone marrow MSCs (hBM-MSCs) injected by intrathecal route in Non-Obese Diabetic Severe Combined Immunodeficiency mice, to explore cellular biodistribution and toxicity as a privileged administration method for cell therapy in Friedreich’s Ataxia.
Mesenchymal stromal cells (MSCs) have potent immunomodulatory and neuroprotective properties, and have been tested in neurodegenerative diseases resulting in meaningful clinical improvements. Regulatory guidelines specify the need to perform preclinical studies prior any clinical trial, including biodistribution assays and tumourigenesis exclusion. We conducted a preclinical study of human bone marrow MSCs (hBM-MSCs) injected by intrathecal route in Non-Obese Diabetic Severe Combined Immunodeficiency mice, to explore cellular biodistribution and toxicity as a privileged administration method for cell therapy in Friedreich’s Ataxia.
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