Dunja Lukovic, Victoria Moreno-Manzano, Francisco Javier Rodriguez-Jimenez, Angel Vilches, Eva Sykova, Pavla Jendelova, Miodrag Stojkovic, Slaven Erceg; Neuroscientist 1073858416672652, first published on October 6, 2016 DOI:10.1177/1073858416672652
This work, for the first time, bridges the preclinical drug evaluation in FRDA-specific patient neurons derived from hiPSC and clearly shows the advantages of using hiPSC differentiated cells compared with other widely used cellular models, such as immortalized cell lines and those tested on rodent cells. Although these studies have provided insights into the pathogenesis of FRDA in cardiomyocytes and neurons, additional work is required to elucidate the role of frataxin deficits in other affected cell types, such as the cerebellar neurons.
Friday, October 14, 2016
Thursday, October 13, 2016
New Reasons to Pursue the Therapeutic Potential of Synthetic Nucleic Acids for Neurological Diseases
Jill Sergesketter Butler, PhD; Marek Napierala, PhD; Editorial. JAMA Neurol. 2016;73(10):1175-1177. doi:10.1001/jamaneurol.2016.2571
Findings published by Corey’s group demonstrate a novel use for synthetic nucleic acids in restoring frataxin (FXN) levels in cell line models derived from patients with FRDA.The mechanism of increased expression does not rely merely on activating transcription at the FXN locus, nor is the RNA interference pathway required. Instead, data from either approach indicate that the ability of the engineered nucleic acids to specifically bind the mutant FXN pre–messenger RNA and block its interaction with the genomic locus is sufficient to restore FXN messenger RNA and protein levels. Thus, in addition to relieving transcription inhibition, elimination of detrimental R-loops might also result in stabilization of the expanded repeat sequences and prevention of somatic instability. Extensive data related to dosing, toxicity, and biodistribution, to name a few, have already been collected and can be used to pave the way for moving R-loop specific nucleic acids to the clinic much more quickly.
Findings published by Corey’s group demonstrate a novel use for synthetic nucleic acids in restoring frataxin (FXN) levels in cell line models derived from patients with FRDA.The mechanism of increased expression does not rely merely on activating transcription at the FXN locus, nor is the RNA interference pathway required. Instead, data from either approach indicate that the ability of the engineered nucleic acids to specifically bind the mutant FXN pre–messenger RNA and block its interaction with the genomic locus is sufficient to restore FXN messenger RNA and protein levels. Thus, in addition to relieving transcription inhibition, elimination of detrimental R-loops might also result in stabilization of the expanded repeat sequences and prevention of somatic instability. Extensive data related to dosing, toxicity, and biodistribution, to name a few, have already been collected and can be used to pave the way for moving R-loop specific nucleic acids to the clinic much more quickly.
Wednesday, October 12, 2016
Synthetic Nucleic Acids and Treatment of Neurological Diseases
David R. Corey, PhD; JAMA Neurol. 2016;73(10):1238-1242. doi:10.1001/jamaneurol.2016.2089
Emerging Target: Frataxin/Friedreich’s Ataxia: We reasoned that oligonucleotides that blocked the expanded repeat could prevent R-loop formation and release the break on transcription We designed duplex RNAs or ASOs to be complementary to the AAG repeat. Both approaches led to increased expression of RNA and protein. Levels of FXN protein were similar to those observed in wild-type cells. Our data suggest that the mechanism of action of either the ASOs or the duplex RNAs involves binding to the expanded repeat and physically preventing it from associating chromosomal DNA to form the critical R-loop structure. Antisense oligonucleotides efficiently inhibit gene expression in liver and the central nervous system.Using them to treat the broad range of tissues necessary to fully treat Friedreich’s ataxia will require more potent compounds and more effective strategies for delivering oligonucleotides in to all tissues that are affected.
Emerging Target: Frataxin/Friedreich’s Ataxia: We reasoned that oligonucleotides that blocked the expanded repeat could prevent R-loop formation and release the break on transcription We designed duplex RNAs or ASOs to be complementary to the AAG repeat. Both approaches led to increased expression of RNA and protein. Levels of FXN protein were similar to those observed in wild-type cells. Our data suggest that the mechanism of action of either the ASOs or the duplex RNAs involves binding to the expanded repeat and physically preventing it from associating chromosomal DNA to form the critical R-loop structure. Antisense oligonucleotides efficiently inhibit gene expression in liver and the central nervous system.Using them to treat the broad range of tissues necessary to fully treat Friedreich’s ataxia will require more potent compounds and more effective strategies for delivering oligonucleotides in to all tissues that are affected.
Monday, October 10, 2016
Modeling and correction of structural variations in patient-derived iPSCs using CRISPR/Cas9
Chul-Yong Park, Jin Jea Sung, Sang-Hwi Choi, Dongjin R Lee, In-Hyun Park & Dong-Wook Kim; Nature Protocols 11, 2154–2169 (2016) doi:10.1038/nprot.2016.129 Published online 06 October 2016
This protocol enables the correction of large inverted segments and short nucleotide repeat expansions in diseases such as hemophilia A, fragile X syndrome, Hunter syndrome, and Friedreich's ataxia.
This protocol enables the correction of large inverted segments and short nucleotide repeat expansions in diseases such as hemophilia A, fragile X syndrome, Hunter syndrome, and Friedreich's ataxia.
Sunday, October 9, 2016
The rare and undiagnosed diseases diagnostic service – application of massively parallel sequencing in a state-wide clinical service
Gareth Baynam, Nicholas Pachter, Fiona McKenzie, Sharon Townshend, Jennie Slee, Cathy Kiraly-Borri, Anand Vasudevan, Anne Hawkins, Stephanie Broley, Lyn Schofield, Hedwig Verhoef, Caroline E. Walker, Caron Molster, Jenefer M. Blackwell, Sarra Jamieson, Dave Tang, Timo Lassmann, Kym Mina, John Beilby, Mark Davis, Nigel Laing, Lesley Murphy, Tarun Weeramanthri, Hugh Dawkins and Jack Goldblatt. Orphanet Journal of Rare Diseases 201611:77 DOI: 10.1186/s13023-016-0462-7
OPEN ACCESS
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
We describe an iteratively improving diagnostic platform provided within a public health service that is aligned to the unmet needs of people living with rare and undiagnosed diseases, by supporting equitable state-wide diagnostic health care provision for the world’s geographically largest public health jurisdiction. It is largely been performed within existing budgets through a patient-centric approach and clinically informed re-alignment of existing resources.
OPEN ACCESS
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
We describe an iteratively improving diagnostic platform provided within a public health service that is aligned to the unmet needs of people living with rare and undiagnosed diseases, by supporting equitable state-wide diagnostic health care provision for the world’s geographically largest public health jurisdiction. It is largely been performed within existing budgets through a patient-centric approach and clinically informed re-alignment of existing resources.
Friday, October 7, 2016
Systematic review on the evaluation criteria of orphan medicines in Central and Eastern European countries
Tamás Zelei, Mária J. Molnár, Márta Szegedi and Zoltán Kaló. Orphanet Journal of Rare Diseases 201611:72 DOI:10.1186/s13023-016-0455-6 Published: 4 June 2016
Open Access.
Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)
Open Access.
Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)
Thursday, October 6, 2016
NRF2 in neurodegenerative diseases
Antonio Cuadrado, Current Opinion in Toxicology, Available online 3 October 2016, ISSN 2468-2020, doi:10.1016/j.cotox.2016.09.004.
Neurodegenerative diseases, and degenerative disorders as a whole, share in common the deviation from homeostatic responses related to the control of proteostasis and low-grade chronic oxidative, inflammatory, and metabolic stress. These are all crucial events where transcription factor Nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a very important defensive role. In this paper, biochemical and genetic evidence connecting NRF2 with neurodegenerative diseases will be discussed, mainly in the context of preclinical mouse models and in patients with Alzheimer’s and Parkinson’s disease. NRF2 can be targeted pharmacologically and the most successful drugs to endorse a neuroprotective therapy will be commented, including dimethyl fumarate.
Neurodegenerative diseases, and degenerative disorders as a whole, share in common the deviation from homeostatic responses related to the control of proteostasis and low-grade chronic oxidative, inflammatory, and metabolic stress. These are all crucial events where transcription factor Nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a very important defensive role. In this paper, biochemical and genetic evidence connecting NRF2 with neurodegenerative diseases will be discussed, mainly in the context of preclinical mouse models and in patients with Alzheimer’s and Parkinson’s disease. NRF2 can be targeted pharmacologically and the most successful drugs to endorse a neuroprotective therapy will be commented, including dimethyl fumarate.
Wednesday, October 5, 2016
Mitochondrial Lon Protease in Human Disease and Aging: Including an etiologic classification of Lon-related diseases and disorders
Daniela A. Bota, Kelvin J.A. Davies, Free Radical Biology and Medicine, Available online 5 July 2016, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.06.031.
Friedreich ataxia (FRDA)show a clear progressive increase in Lon protein levels. Lon upregulation is also accompanied by an increase in proteolytic activity, and by decreased levels of mitochondrial Fe–S proteins. The effect of Lon upregulation on loss of mitochondrial Fe-S proteins during the progression of the disease suggests that Fe-S proteins may be targets of Lon in FRDA.
Friedreich ataxia (FRDA)show a clear progressive increase in Lon protein levels. Lon upregulation is also accompanied by an increase in proteolytic activity, and by decreased levels of mitochondrial Fe–S proteins. The effect of Lon upregulation on loss of mitochondrial Fe-S proteins during the progression of the disease suggests that Fe-S proteins may be targets of Lon in FRDA.
Monday, October 3, 2016
A neurodegenerative perspective on mitochondrial optic neuropathies
Patrick Yu-Wai-Man , Marcela Votruba, Florence Burté, Chiara La Morgia, Piero Barboni, Valerio Carelli; Review: Acta Neuropathologica pp 1-18 First online: 30 September 2016 doi:10.1007/s00401-016-1625-2
Open Access
Friedreich Ataxia (FRDA) is the most common form of hereditary ataxia and it is due to recessive mutations in the FXN gene, which encodes for a mitochondrial protein involved in the biosynthetic pathways of iron-sulphur clusters. The latter are essential components of aconitase and the mitochondrial respiratory chain complexes I, II and III, and their combined dysfunction probably contributes to the development of optic neuropathy, which is now a well-recognised feature of FRDA.
Open Access
Friedreich Ataxia (FRDA) is the most common form of hereditary ataxia and it is due to recessive mutations in the FXN gene, which encodes for a mitochondrial protein involved in the biosynthetic pathways of iron-sulphur clusters. The latter are essential components of aconitase and the mitochondrial respiratory chain complexes I, II and III, and their combined dysfunction probably contributes to the development of optic neuropathy, which is now a well-recognised feature of FRDA.
Sunday, October 2, 2016
Use of CRISPR/Cas9 system to correct mutations responsible for Duchenne Muscular Dystrophy and Friedreich ataxia.
(1888PressRelease) October 01, 2016 - MarketsandMarkets Conferences. Dr. Jacques P. Tremblay from University of Laval, Quebec joins the speaker panel for the 2nd Annual Genome Editing & Engineering Conference
Dr. Tremblay will be presenting at the conference on use of CRISPR/Cas9 system to correct mutations responsible for Duchenne Muscular Dystrophy and Friedreich ataxia. Joining Dr. Tremblay on the panel will be experts representing organizations such as University of Utah School of Medicine, Massachusetts Institute of Technology, J. Craig Venter Institute, University of Nebraska Medical Center, University of California, University of Washington, University of Southern California, University of Rochester, National Institutes of Health, University of Texas, University of Minnesota, Hiroshima University and Wellcome Trust Sanger Institute.
Dr. Tremblay will be presenting at the conference on use of CRISPR/Cas9 system to correct mutations responsible for Duchenne Muscular Dystrophy and Friedreich ataxia. Joining Dr. Tremblay on the panel will be experts representing organizations such as University of Utah School of Medicine, Massachusetts Institute of Technology, J. Craig Venter Institute, University of Nebraska Medical Center, University of California, University of Washington, University of Southern California, University of Rochester, National Institutes of Health, University of Texas, University of Minnesota, Hiroshima University and Wellcome Trust Sanger Institute.
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