Friday, January 22, 2010
Two New Pimelic Diphenylamide HDAC Inhibitors Induce Sustained Frataxin Upregulation in Cells from Friedreich's Ataxia Patients and in a Mouse Model
Myriam Rai1, Elisabetta Soragni2, C. James Chou2¤, Glenn Barnes3, Steve Jones3, James R. Rusche3, Joel M. Gottesfeld2, Massimo Pandolfo1*
1 Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Brussels, Belgium, 2 Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America, 3 Repligen Corporation, Waltham, Massachusetts, United States of America
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Abstract
Background
Friedreich's ataxia (FRDA), the most common recessive ataxia in Caucasians, is due to severely reduced levels of frataxin, a highly conserved protein, that result from a large GAA triplet repeat expansion within the first intron of the frataxin gene (FXN). Typical marks of heterochromatin are found near the expanded GAA repeat in FRDA patient cells and mouse models. Histone deacetylase inhibitors (HDACIs) with a pimelic diphenylamide structure and HDAC3 specificity can decondense the chromatin structure at the FXN gene and restore frataxin levels in cells from FRDA patients and in a GAA repeat based FRDA mouse model, KIKI, providing an appealing approach for FRDA therapeutics.
Methodology/Principal Findings
In an effort to further improve the pharmacological profile of pimelic diphenylamide HDACIs as potential therapeutics for FRDA, we synthesized additional compounds with this basic structure and screened them for HDAC3 specificity. We characterized two of these compounds, 136 and 109, in FRDA patients' peripheral blood lymphocytes and in the KIKI mouse model. We tested their ability to upregulate frataxin at a range of concentrations in order to determine a minimal effective dose. We then determined in both systems the duration of effect of these drugs on frataxin mRNA and protein, and on total and local histone acetylation. The effects of these compounds exceeded the time of direct exposure in both systems.
Conclusions/Significance
Our results support the pre-clinical development of a therapeutic approach based on pimelic diphenylamide HDACIs for FRDA and provide information for the design of future human trials of these drugs, suggesting an intermittent administration of the drug.
1 Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Brussels, Belgium, 2 Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America, 3 Repligen Corporation, Waltham, Massachusetts, United States of America
OPEN ACCES
Abstract
Background
Friedreich's ataxia (FRDA), the most common recessive ataxia in Caucasians, is due to severely reduced levels of frataxin, a highly conserved protein, that result from a large GAA triplet repeat expansion within the first intron of the frataxin gene (FXN). Typical marks of heterochromatin are found near the expanded GAA repeat in FRDA patient cells and mouse models. Histone deacetylase inhibitors (HDACIs) with a pimelic diphenylamide structure and HDAC3 specificity can decondense the chromatin structure at the FXN gene and restore frataxin levels in cells from FRDA patients and in a GAA repeat based FRDA mouse model, KIKI, providing an appealing approach for FRDA therapeutics.
Methodology/Principal Findings
In an effort to further improve the pharmacological profile of pimelic diphenylamide HDACIs as potential therapeutics for FRDA, we synthesized additional compounds with this basic structure and screened them for HDAC3 specificity. We characterized two of these compounds, 136 and 109, in FRDA patients' peripheral blood lymphocytes and in the KIKI mouse model. We tested their ability to upregulate frataxin at a range of concentrations in order to determine a minimal effective dose. We then determined in both systems the duration of effect of these drugs on frataxin mRNA and protein, and on total and local histone acetylation. The effects of these compounds exceeded the time of direct exposure in both systems.
Conclusions/Significance
Our results support the pre-clinical development of a therapeutic approach based on pimelic diphenylamide HDACIs for FRDA and provide information for the design of future human trials of these drugs, suggesting an intermittent administration of the drug.
Wednesday, January 20, 2010
Tri-partite complex for axonal transport drug delivery achieves pharmacological effect
Aaron G Filler , Garth T Whiteside , Mark Bacon , Martyn Frederickson , Franklyn A Howe , Miri D Rabinowitz , Alan J Sokoloff , Terrence W Deacon , Chris Abell , Raj Munglani , John R Griffiths , B ANTHONY Bell and Andrew ML Lever
BMC Neuroscience 2010, 11:8doi:10.1186/1471-2202-11-8, Published: 20 January 2010
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Background
Targeted delivery of pharmaceutical agents into selected populations of CNS neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.
FULL TEXT
BMC Neuroscience 2010, 11:8doi:10.1186/1471-2202-11-8, Published: 20 January 2010
OPEN ACCESS
Background
Targeted delivery of pharmaceutical agents into selected populations of CNS neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.
FULL TEXT
Neurons Developed from Stem Cells Successfully Wired With Other Brain Regions in Animals
ScienceDaily (Jan. 19, 2010) — Transplanted neurons grown from embryonic stem cells can fully integrate into the brains of young animals, according to new research in the Jan. 20 issue of The Journal of Neuroscience.
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Sunday, January 17, 2010
Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies
Russell H. Swerdlow
Departments of Neurology and Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, MO, Kansas 66160, USA
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Departments of Neurology and Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, MO, Kansas 66160, USA
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Abstract: Neurodegenerative diseases are a common late-life scourge for which diseasemodifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale underlying past and current efforts to treat neurodegenerative diseases using mitochondrial medicine, and tries to predict how future efforts might proceed.
Keywords: mitochondria; mitochondrial biogenesis; mitochondriopathies; neurodegenerative diseases; oxidative stress
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Friday, January 15, 2010
Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology
Citation: Haugen AC, Di Prospero NA, Parker JS, Fannin RD, Chou J, et al. (2010) Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology. PLoS Genet 6(1): e1000812. doi:10.1371/journal.pgen.1000812
Editor: Christopher E. Pearson, The Hospital for Sick Children and University of Toronto, Canada
Received: May 5, 2009; Accepted: December 10, 2009; Published: January 15, 2010
OPEN ACCESS This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Abstract
The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.
FULL TEXT
Editor: Christopher E. Pearson, The Hospital for Sick Children and University of Toronto, Canada
Received: May 5, 2009; Accepted: December 10, 2009; Published: January 15, 2010
OPEN ACCESS This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Abstract
The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.
FULL TEXT
Excess DNA damage found in cells of patients with Friedreich's ataxia. Biomarkers, new treatments possible for Friedreich's ataxia
Genetic Engineering & Biotechnology News, PITTSBURGH, Jan. 14
Thursday, January 14, 2010
Autosomal recessive ataxias: 20 types, and counting
Embiruçu EK, Martyn ML, Schlesinger D, Kok F.
Outpatient Neurogenetics Clinic, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, SP, Brazil.
Keywords: Friedreich ataxia, autosomal recessive ataxias, neurogenetics, clinical and pathophysiological aspects, diagnosis.
Outpatient Neurogenetics Clinic, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, SP, Brazil.
Keywords: Friedreich ataxia, autosomal recessive ataxias, neurogenetics, clinical and pathophysiological aspects, diagnosis.
Tuesday, January 12, 2010
Treatment of mitochondrial electron transport chain disorders: A review of clinical trials over the past decade.
Mol Genet Metab. 2009 Nov 26. [Epub ahead of print]
Center for Inherited Disorders of Metabolism, University Hospitals Case Medical Center, Rainbow Babies and Childrens Hospital, Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-6004, USA.
Keywords: mitochondrial electron transport chain disorders, controlled clinical trials, dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, neuropathy, Friedreich ataxia, cardiomyopathy, neurological protection.
Keywords: mitochondrial electron transport chain disorders, controlled clinical trials, dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, neuropathy, Friedreich ataxia, cardiomyopathy, neurological protection.
Monday, January 11, 2010
Penwest Announces Initiation of Phase IIa Clinical Trial of A0001 in Patients With Friedreich's Ataxia
PATTERSON, N.Y., Jan. 11, 2010 (GLOBE NEWSWIRE)
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