Etiane Tatsch José A.M. De Carvalho Yãnaí S. Bollick Thiago Duarte Marta M.M.F. Duarte Rodrigo A. Vaucher Melissa O. Premaor Fabio V. Comim Rafael N. Moresco; Diabetes Metab Res Rev. 2019;e3208. doi:10.1002/dmrr.3208.
Type 2 diabetes patients with low frataxin mRNA levels showed a high degree of inflammation and oxidative stress. It is speculated that frataxin deficiency in T2D patients can contribute to the imbalance in mitochondrial iron homeostasis leading to the acceleration of oxidative stress and inflammation.
Friday, August 2, 2019
Thursday, August 1, 2019
REGENXBIO Announces New License Agreement with Pfizer for the Treatment of Friedreich's Ataxia Using NAV® AAV9 Vector
ROCKVILLE, Md., July 31, 2019 /PRNewswire/ -- REGENXBIO Inc. (Nasdaq: RGNX), a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy based on its proprietary NAV Technology Platform, today announced it entered into a license agreement with Pfizer Inc.
"This license agreement further validates the strength of our intellectual property portfolio and the potential of NAV AAV9 for the treatment of systemic and CNS manifestations of movement disorders," said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. "We are pleased to establish our relationship with Pfizer as they advance this program to develop a potential gene therapy treatment for Friedreich's ataxia."
"This license agreement further validates the strength of our intellectual property portfolio and the potential of NAV AAV9 for the treatment of systemic and CNS manifestations of movement disorders," said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. "We are pleased to establish our relationship with Pfizer as they advance this program to develop a potential gene therapy treatment for Friedreich's ataxia."
Nrf2 Induction Re-establishes a Proper Neuronal Differentiation Program in Friedreich’s Ataxia Neural Stem Cells
La Rosa Piergiorgio, Russo Marta, D’Amico Jessica, Petrillo Sara, Aquilano Katia, Lettieri-Barbato Daniele, Turchi Riccardo, Bertini Enrico S., Piemonte Fiorella; Frontiers in Cellular Neuroscience, vol 3, 2019 DOI=10.3389/fncel.2019.00356
Frataxin deficiency is the pathogenic cause of Friedreich’s Ataxia, an autosomal recessive disease characterized by the increase of oxidative stress and production of free radicals in the cell. Although the onset of the pathology occurs in the second decade of life, cognitive differences and defects in brain structure and functional activation are observed in patients, suggesting developmental defects to take place during fetal neurogenesis. Here we describe impairments in proliferation, stemness potential and differentiation in neural stem cells isolated from the embryonic cortex of the Frataxin Knockin/Knockout mouse, a disease animal model whose slow-evolving phenotype makes it suitable to study pre-symptomatic defects that may manifest before the clinical onset. We demonstrate that enhancing the expression and activity of the antioxidant response master regulator Nrf2 ameliorates the phenotypic defects observed in neural stem cells, re-establishing a proper differentiation program.
Frataxin deficiency is the pathogenic cause of Friedreich’s Ataxia, an autosomal recessive disease characterized by the increase of oxidative stress and production of free radicals in the cell. Although the onset of the pathology occurs in the second decade of life, cognitive differences and defects in brain structure and functional activation are observed in patients, suggesting developmental defects to take place during fetal neurogenesis. Here we describe impairments in proliferation, stemness potential and differentiation in neural stem cells isolated from the embryonic cortex of the Frataxin Knockin/Knockout mouse, a disease animal model whose slow-evolving phenotype makes it suitable to study pre-symptomatic defects that may manifest before the clinical onset. We demonstrate that enhancing the expression and activity of the antioxidant response master regulator Nrf2 ameliorates the phenotypic defects observed in neural stem cells, re-establishing a proper differentiation program.
Tuesday, July 30, 2019
The neuroprotective mechanisms and effects of sulforaphane
Klomparens EA, Ding Y.; Brain Circ 2019;5:74-83 DOI: 10.4103/bc.bc_7_19
Sulforaphane (SFN) is a phytochemical found in cruciferous vegetables. It has been shown to have many protective effects against many diseases, including multiple types of cancer. SFN is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE) genetic pathway. Upregulation of Nrf2-ARE increases the availability of multiple antioxidants. A substantial amount of preclinical research regarding the ability of SFN to protect the nervous system from many diseases and toxins has been done, but only a few small human trials have been completed. Preclinical data suggest that SFN protects the nervous system through multiple mechanisms and may help reduce the risk of many diseases and reduce the burden of symptoms in existing conditions. This review focuses on the literature regarding the protective effects of SFN on the nervous system. A discussion of neuroprotective mechanisms is followed by a discussion of the protective effects elicited by SFN administration in a multitude of neurological diseases and toxin exposures. SFN is a promising neuroprotective phytochemical which needs further human trials to evaluate its efficacy in preventing and decreasing the burden of many neurological diseases.
Sulforaphane (SFN) is a phytochemical found in cruciferous vegetables. It has been shown to have many protective effects against many diseases, including multiple types of cancer. SFN is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE) genetic pathway. Upregulation of Nrf2-ARE increases the availability of multiple antioxidants. A substantial amount of preclinical research regarding the ability of SFN to protect the nervous system from many diseases and toxins has been done, but only a few small human trials have been completed. Preclinical data suggest that SFN protects the nervous system through multiple mechanisms and may help reduce the risk of many diseases and reduce the burden of symptoms in existing conditions. This review focuses on the literature regarding the protective effects of SFN on the nervous system. A discussion of neuroprotective mechanisms is followed by a discussion of the protective effects elicited by SFN administration in a multitude of neurological diseases and toxin exposures. SFN is a promising neuroprotective phytochemical which needs further human trials to evaluate its efficacy in preventing and decreasing the burden of many neurological diseases.
Monday, July 29, 2019
Yeast as a Tool for Deeper Understanding of Human Manganese-Related Diseases
Louise Thines, Antoine Deschamps, Jiri Stribny and Pierre Morsomme; Genes 2019, 10(7), 545; (Review) doi:10.3390/genes10070545
Several manganese-related pathologies whose molecular mechanisms have been studied in yeast are then presented in the light of the function of this cation as a non-enzymatic antioxidant or as a key cofactor of metalloenzymes. In this line, we first describe the Transmembrane protein 165-Congenital Disorder of Glycosylation (TMEM165-CDG) and Friedreich ataxia pathologies.
Several manganese-related pathologies whose molecular mechanisms have been studied in yeast are then presented in the light of the function of this cation as a non-enzymatic antioxidant or as a key cofactor of metalloenzymes. In this line, we first describe the Transmembrane protein 165-Congenital Disorder of Glycosylation (TMEM165-CDG) and Friedreich ataxia pathologies.
Saturday, July 27, 2019
The path toward using microbial metabolites as therapies
Hélène C. Descamps, Beatrice Herrmann, Daphne Wiredu, Christoph A. Thaiss; EBioMedicine (Published by The Lancet), Volume 44, 2019, Pages 747-754, doi:10.1016/j.ebiom.2019.05.063.
Metabolites have emerged as the quintessential effectors mediating the impact of the commensal microbiome on human physiology, both locally at the sites of microbial colonization and systemically. The endocrine activity of the microbiome and its involvement in a multitude of complex diseases has made microbiome-modulated metabolites an attractive target for the development of new therapies.
In neurodegenerative disorders, cerebellar syndrome is thought to be related to a neurochemical deficit of 5-hydroxytryptamine (5-HT). Current clinical trials will evaluate indole-3-propionic acid supplementation, a 5-HT precursor, as a therapeutic strategy for Friedreich's ataxia and multiple sclerosis. Indole can be further converted into indoxyl and indoxyl sulfate by host hepatic oxidases (CYP2E1 and SULT1A1).
Metabolites have emerged as the quintessential effectors mediating the impact of the commensal microbiome on human physiology, both locally at the sites of microbial colonization and systemically. The endocrine activity of the microbiome and its involvement in a multitude of complex diseases has made microbiome-modulated metabolites an attractive target for the development of new therapies.
In neurodegenerative disorders, cerebellar syndrome is thought to be related to a neurochemical deficit of 5-hydroxytryptamine (5-HT). Current clinical trials will evaluate indole-3-propionic acid supplementation, a 5-HT precursor, as a therapeutic strategy for Friedreich's ataxia and multiple sclerosis. Indole can be further converted into indoxyl and indoxyl sulfate by host hepatic oxidases (CYP2E1 and SULT1A1).
Monday, July 22, 2019
New developments in pharmacotherapy for Friedreich ataxia
Alexandra Clay, Patrick Hearle, Kim Schadt & David R. Lynch (2019) New developments in pharmacotherapy for Friedreich ataxia, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2019.1639671
Since the discovery of FXN in 1996, multiple clinical trials have occurred or are currently occurring; at a rapid pace for a rare disease. These trials have been directed at the augmentation of mitochondrial function and/or alleviation of symptoms and are not regarded as potential cures in FRDA. Either a combination of therapies or a drug that replaces or increases the pathologically low levels of frataxin better represent potential cures in FRDA.
Since the discovery of FXN in 1996, multiple clinical trials have occurred or are currently occurring; at a rapid pace for a rare disease. These trials have been directed at the augmentation of mitochondrial function and/or alleviation of symptoms and are not regarded as potential cures in FRDA. Either a combination of therapies or a drug that replaces or increases the pathologically low levels of frataxin better represent potential cures in FRDA.
Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases [version 1; peer review: awaiting peer review]
Gloria C. Ferreira, Jenna Oberstaller, Renée Fonseca, Thomas E. Keller, Swamy Rakesh Adapa, Justin Gibbons, Chengqi Wang, Xiaoming Liu, Chang Li, Minh Pham, Guy W. Dayhoff II, Linh M. Duong, Luis Tañón Reyes, Luciano Enrique Laratelli, Douglas Franz, Segun Fatumo, ATM Golam Bari, Audrey Freischel, Lindsey Fiedler, Omkar Dokur, Krishna Sharma, Deborah Cragun, Ben Busby, Rays H.Y. Jiang; F1000Research 2019, 8:1135 Last updated: 19 JUL 2019
Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information’s (NCBI) Hackathon-model to take full advantage of local expertise in building “Iron Hack”, a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich’s ataxia, pitched at general audiences.
Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information’s (NCBI) Hackathon-model to take full advantage of local expertise in building “Iron Hack”, a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich’s ataxia, pitched at general audiences.
Thursday, July 18, 2019
Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia
Gottesfeld, J.M. Neurotherapeutics (2019). doi:10.1007/s13311-019-00764-x
Numerous approaches are being taken to find a treatment for FRDA, including excision or correction of the repeats by genome engineering methods, gene activation with small molecules or artificial transcription factors, delivery of frataxin to affected cells by protein replacement therapy, gene therapy, or small molecules to increase frataxin protein levels, and therapies aimed at countering the cellular consequences of reduced frataxin. This review will summarize the mechanisms involved in repeat-mediated gene silencing and recent efforts aimed at development of therapeutics.
Numerous approaches are being taken to find a treatment for FRDA, including excision or correction of the repeats by genome engineering methods, gene activation with small molecules or artificial transcription factors, delivery of frataxin to affected cells by protein replacement therapy, gene therapy, or small molecules to increase frataxin protein levels, and therapies aimed at countering the cellular consequences of reduced frataxin. This review will summarize the mechanisms involved in repeat-mediated gene silencing and recent efforts aimed at development of therapeutics.
Tuesday, July 16, 2019
Oxidative post‐translational modifications in histones
José Luis García‐Giménez, Carlos Romá‐Mateo, Federico V. Pallardó; Biofactors. 2019 Jun 11. doi: 10.1002/biof.1532.
Epigenetic regulation is attracting much attention because it explains many of the effects that the external environment induces in organisms. Changes in the cellular redox status and even more specifically in its nuclear redox compartment is one of these examples. Redox changes can induce modulation of the epigenetic regulation in cells. Here we present a few cases where reactive oxygen or nitrogen species induces epigenetic marks in histones. Posttranslational modification of these proteins like histone nitrosylation, carbonylation, or glutathionylation together with other mechanisms not reviewed here are the cornerstones of redox‐related epigenetic regulation. We currently face a new field of research with potential important consequences for the treatment of many pathologies.
Epigenetic regulation is attracting much attention because it explains many of the effects that the external environment induces in organisms. Changes in the cellular redox status and even more specifically in its nuclear redox compartment is one of these examples. Redox changes can induce modulation of the epigenetic regulation in cells. Here we present a few cases where reactive oxygen or nitrogen species induces epigenetic marks in histones. Posttranslational modification of these proteins like histone nitrosylation, carbonylation, or glutathionylation together with other mechanisms not reviewed here are the cornerstones of redox‐related epigenetic regulation. We currently face a new field of research with potential important consequences for the treatment of many pathologies.
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