Liwei Weng, Qingqing Wang, Sixiang Yu, Xiaolu Yang, David R. Lynch, Clementina Mesaros, Ian A. Blair, Journal of Immunological Methods, Volume 474, 2019, 112629, doi:10.1016/j.jim.2019.07.001.
Frataxin is the protein that is down-regulated in Friedreich ataxia (FRDA), an autosomal recessive genetic disease caused by an intronic GAA repeat expansion in intron-1 of the FXN gene. The GAA repeats result in epigenetic silencing of the FXN gene and reduced expression of the cytosolic full-length frataxin (1−210) protein. Full length frataxin translocates to the mitochondria, leading to formation of mature frataxin (81–210) formed by cleavage of the mitochondrial targeting sequence at K-80 of the full-length protein. There are currently no approved treatments for FRDA, although experimental approaches involving up-regulation or replacement of mature frataxin protein through numerous approaches are being tested. Many of the pre-clinical studies of these experimental approaches are conducted in mouse and monkey models as well as in human cell lines. Consequently, well-validated antibodies are required for use in western blot analysis to determine whether levels of various forms of frataxin have been increased. Here we examined the specificity of five commercially available anti-frataxin antibodies and determined whether they detect mature frataxin in mouse heart tissue. Four protein standards of monkey, human, and mouse frataxin as well as mouse heart tissue were examined using polyacrylamide gel electrophoresis (PAGE) in combination with western blot analysis. One antibody failed to detect any of the frataxin standards or endogenous frataxin in mouse heart tissue. Three of the antibodies detected a protein in mouse heart tissue that ran slightly faster on PAGE (at 23.4 kDa) to that predicted for full-length frataxin (23.9 kDa). One antibody detected all four frataxin standards as well as endogenous mouse mature frataxin in mouse tissue. Significantly, this antibody, which will be useful for monitoring mature frataxin levels in monkey, human, and mouse tissues, did not detect a protein in mouse heart tissue at 23.4 kDa. Therefore, antibodies detecting the immunoreactive protein at 23.4 kDa could be misleading when testing for the up-regulation of frataxin in animal models.
Sunday, November 3, 2019
Saturday, November 2, 2019
The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype
YAyşe Candayan, Gulshan Yunisova, Arman Çakar, Hacer Durmuş, A. Nazlı Başak, Yeşim Parman, Esra Battaloğlu. Neurogenetics (2019). doi:10.1007/s10048-019-00594-1
To the best of our knowledge, this family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that we believe may have important implications on understanding the pathogenesis of these neurological disorders.
To the best of our knowledge, this family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that we believe may have important implications on understanding the pathogenesis of these neurological disorders.
Thursday, October 31, 2019
Potential biomarker identification for Friedreich’s ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion
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.
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.
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.
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