The future of epigenetic drugs

BioMed Central, Sarah Dowie 8 Sep 2016. Insights and opinion from BioMed Central on the latest biology research and developments in the field.

In the light of increasing knowledge on the role epigenetic factors play in disease, it is now becoming apparent that epigenetics could be ideal therapeutic targets - particularly taking into consideration that many of these epigenetic factors are reversible. Epigenetic drugs are incredibly potent and can help reverse abnormal gene expression that can result in various diseases.

Heterologous mitochondrial targeting sequences can deliver functional proteins into mitochondria

Dana Marcus, Michal Lichtenstein, Natali Cohen, Rita Hadad, Tal Erlich-Hadad, Hagar Greif, Haya Lorberboum-Galski, The International Journal of Biochemistry & Cell Biology, Available online 19 October 2016, ISSN 1357-2725, doi:10.1016/j.biocel.2016.10.013.

We chose the FXN protein to examine whether nuclear-encoded mitochondrial proteins can efficiently be targeted via a heterologous MTS (hMTS) and deliver a functional protein into mitochondria.
hMTSs delivered a functional FXN protein into the mitochondria even more efficiently than the native MTSfxn, as evidenced by the rescue of FA patients’ cells from oxidative stress; demonstrating a 18%-54% increase in cell survival; and a 13%-33% increase in ATP levels, as compared to the fusion protein carrying the native MTS.

Cellular thiamine status is coupled to function of mitochondrial 2-oxoglutarate dehydrogenase

G. Mkrtchyan, A. Graf, L. Bettendorff, V. Bunik, Neurochemistry International, Available online 20 October 2016, ISSN 0197-0186, doi:10.1016/j.neuint.2016.10.009.

Our study points to cell-specific regulation of the thiamine-dependent metabolic network, which includes significant coupling between the OGDH reaction, often the TCA cycle “bottle neck”, and thiamine influx in normal rat brain and astrocytes. In the brain with decreased thiamine levels and/or impaired OGDH, which have been observed in aging and/or neurodegenerative diseases, such coupling may require thiamine levels exceeding those known to saturate the ThDPdependent enzymes under normal conditions. The findings may justify therapeutic application of high doses of thiamine in patients with neurodegenerative diseases.

Iron related hemochromatosis (HFE) gene mutations in Friedreich Ataxia patients

Inder Singh, Sunil Shakya, Rakesh Kumar Singh, Istaq Ahmad, Vinay Goyal, Garima Shukla, Madakasira Vasantha Padma Srivastava, Mohammed Faruq, Achal Kumar Srivastava, Parkinsonism & Related Disorders, Available online 19 October 2016, ISSN 1353-8020, doi:10.1016/j.parkreldis.2016.10.015.

This is the first case-control study analyzing HFE mutations as a modifier of FRDA phenotypes and its severity. Our study suggests that the presence of p.H63D may be the risk factor for the occurrence of peripheral neuropathy in FRDA patients.

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Polak Urszula, Li Yanjie, Butler Jill Sergesketter, and Napierala Marek. Stem Cells and Development. October 2016, ahead of print. doi:10.1089/scd.2016.0147.

Taken together, these results demonstrate that transcriptional repression caused by long GAA repeat tracts can be partially or transiently reversed by altering particular epigenetic modifications, thus revealing possibilities for detailed analyses of silencing mechanism and development of new therapeutic approaches for FRDA.

AN AYURVEDIC PERSPECTIVE OF FRIEDREICH’S ATAXIA

Dr. Archana Mogili, Dr. Mrudula Sankaramanchi, Dr. C H.Sadanandam. International Ayurvedic medical Journal, Volume 4; Issue 10; October- 2016

The Ayurveda approach to Friedreich’s ataxia is aimed at controlling the symptoms, treating the degeneration of nervous system and preventing long term complications by considering it as PRANA AVRUTA VYANA UDANA VATA VYADHI.

In FRDA which as no direct reference from the classics, the treatment protocol can be planned by understanding the underlying pathology of the disease in Ayurveda perspective. Here it can be interpreted FRDA has prana avruta vyana, udana vata vyadhi and avarana chikitsa in general and specific to particular avarana can be adopted.

NOTE: Ayurvedic medicine (also called Ayurveda) is one of the world’s oldest medical systems. It originated in India more than 3,000 years ago and remains one of the country’s traditional health care systems. Its concepts about health and disease promote the use of herbal compounds, special diets, and other unique health practices. India’s government and other institutes throughout the world support clinical and laboratory research on Ayurvedic medicine, within the context of the Eastern belief system. But Ayurvedic medicine isn’t widely studied as part of conventional (Western) medicine. This fact sheet provides a general overview of Ayurvedic medicine and suggests sources for additional information. (Recommended reading: Ayurvedic Medicine: In Dept, see the links clicking on the title)

Human neuron-astrocyte 3D co-culture-based assay for evaluation of neuroprotective compounds

Ana Paula Terrasso, Ana Carina Silva, Augusto Filipe, Pedro Pedroso, Ana Lúcia Ferreira, Paula Marques Alves, Catarina Brito, Journal of Pharmacological and Toxicological Methods, Available online 11 October 2016, ISSN 1056-8719, doi: 10.1016/j.vascn.2016.10.001.

Central nervous system drug development has registered high attrition rates, mainly due to the lack of efficacy of drug candidates, highlighting the low reliability of the models used in early-stage drug development and the need for new in vitro human cell-based models and assays to accurately identify and validate drug candidates.

For the assay validation, we have used Idebenone, an antioxidant benzoquinone, shortchain analogue of coenzyme Q10 ; and positive control for neuroprotection over the tBHP insult. It has been widely investigated for the treatment of Friedreich’s ataxia. The Idebenone treatment led to a reduction in oxidative stress markers (Jaber & Polster, 2015). Consistently with its antioxidant activity, Idebenone prevents lipid peroxidation in isolated brain mitochondria, synaptosomes and human hepatic cells (Erb et al., 2012). It was also shown to protect against ROS-induced damage in several in vitro cultures, as primary cortical neurons and immortalized neural cells. We observed a dose-dependent neuroprotective effect over tBHP insult when Idebenone is administrated in pre-incubation.

The specificity of the neuroprotective effect observed for Idebenone over tBHP insult was evaluated using a non-oxidative lesion induced by chloramphenicol. Idebenone did not confer a neuroprotective effect over the chloramphenicol insult indicating that the neuroprotection observed for tBHP is specific and not an assay artefact.

Applications of CRISPR/Cas9 for Gene Editing in Hereditary Movement Disorders

Wooseok Im, Jangsup Moon, Manho Kim; Review Article, J Mov Disord 2016; 9(3): 136-143. Published online: September 21, 2016 DOI:10.14802/jmd.16029

Genome editing using CRISPR/Cas9 is possible in various cell lines, including human induced pluripotent stem cells, which can be utilized as a valuable in vitro tool for the investigation of specific mutations in the pathogenesis of various disorders. For example, Vannocci et al. developed a novel cellular model of Friedreich’s ataxia, which is an autosomal recessive ataxia caused by reduced levels of frataxin, using CRISPR/Cas9 to stably introduce the disease frataxin gene into cells.

hiPSC Disease Modeling of Rare Hereditary Cerebellar Ataxias Opportunities and Future Challenges

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.

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.

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.

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.

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.

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/)

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.

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.

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.

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.

Late-Onset Friedreich’s Ataxia (LOFA) Mimicking Charcot–Marie–Tooth Disease Type 2: What Is Similar and What Is Different?

Rubens Paulo A. Salomão, Maria Thereza Drumond Gama, Flávio Moura Rezende Filho, Fernanda Maggi, José Luiz Pedroso , Orlando G. P. Barsottini; Short Report, The Cerebellum pp 1-3 First online: 29 September 2016 doi:10.​1007/​s12311-016-0822-9

Herein, we report a patient that presented with late-onset progressive steppage gait, neuropathy and pes cavus, suggesting Charcot–Marie–Tooth (CMT) disease. Subsequent genetic investigation confirmed Friedreich’s ataxia (FRDA). We suggest that late-onset forms of hereditary neuropathies should be carefully evaluated, since LOFA may be a CMT mimicker.