Daniel R. Crooks, Nunziata Maio§, Andrew N. Lane, Michal Jarnik, Richard M. Higashi, Ronald G. Haller, Ye Yang, Teresa W-M. Fan, W. Marston Linehan and Tracey A. Rouault; The Journal of Biological Chemistry 293, 8297-8311. doi: 10.1074/jbc.RA118.001885
Elucidation of the mechanisms of citrate and lipid droplet accumulation in nonadipose tissues during disease states may reveal important insights into the pathogenesis of a significant number of poorly understood diseases.
Saturday, May 26, 2018
Friday, May 25, 2018
Improving the analysis of composite endpoints in rare disease trials
Martina McMenami, Anna Berglind and James M. S. Wason; Orphanet Journal of Rare Diseases 201813:81 doi:10.1186/s13023-018-0819-1
In rare diseases where there are few or no available treatments and limited opportunity to test emerging new treatments, the power to detect an effective treatment is of critical importance. The augmented binary method with small sample adjustments offers a substantial improvement for trials in these populations over methods currently being used, which throw away valuable information. We recommend the use of the augmented binary method in relevant rare disease trials using composite endpoints and supply R code to assist with the implementation.
In rare diseases where there are few or no available treatments and limited opportunity to test emerging new treatments, the power to detect an effective treatment is of critical importance. The augmented binary method with small sample adjustments offers a substantial improvement for trials in these populations over methods currently being used, which throw away valuable information. We recommend the use of the augmented binary method in relevant rare disease trials using composite endpoints and supply R code to assist with the implementation.
Biomimetic Artificial Epigenetic Code for Targeted Acetylation of Histones
Junichi Taniguchi, Yihong Feng, Ganesh N. Pandian, Fumitaka Hashiya, Takuya Hidaka, Kaori Hashiya, Soyoung Park, Toshikazu Bando, Shinji Ito, and Hiroshi Sugiyama; . Am. Chem. Soc., Article ASAP DOI: 10.1021/jacs.8b01518 Publication Date (Web): May 24, 2018
Recently, Ansari’s group reported a conjugate called Syn-TEF by coupling a PIP with another bromodomain inhibitor(+)-JQ1, selective to the bromodomain and extraterminal(BET) protein family. 45 Syn-TEF1 targeting expanded GAA repeats in the frataxin (FXN) gene successfully recruited BET protein BRD4 (bromodomain 4) to the gene locus in Friedreich’s ataxia (FRDA) patient-derived cells, resulting intranscriptional elongation of FXN. However, Syn-TEF and Bi-PIP target different members of the BD protein family and, therefore, are demonstrated to cause different outcomes; i.e.,while Syn-TEF causes BRD4-dependent transcriptional elongation, Bi-PIP causes P300 dependent histone acetylation. Thus,Bi-PIP and Syn-TEF can be used for different purposes, and this allows us to expand the range of potential applications of the synthetic epigenetic regulators.
Recently, Ansari’s group reported a conjugate called Syn-TEF by coupling a PIP with another bromodomain inhibitor(+)-JQ1, selective to the bromodomain and extraterminal(BET) protein family. 45 Syn-TEF1 targeting expanded GAA repeats in the frataxin (FXN) gene successfully recruited BET protein BRD4 (bromodomain 4) to the gene locus in Friedreich’s ataxia (FRDA) patient-derived cells, resulting intranscriptional elongation of FXN. However, Syn-TEF and Bi-PIP target different members of the BD protein family and, therefore, are demonstrated to cause different outcomes; i.e.,while Syn-TEF causes BRD4-dependent transcriptional elongation, Bi-PIP causes P300 dependent histone acetylation. Thus,Bi-PIP and Syn-TEF can be used for different purposes, and this allows us to expand the range of potential applications of the synthetic epigenetic regulators.
Sunday, May 20, 2018
Voyager Therapeutics Announces Additional Data at the American Society of Gene and Cell Therapy 2018 Annual Meeting
CAMBRIDGE, Mass., May 18, 2018 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases today announced additional data presentations at the American Society of Gene and Cell Therapy (ASGCT) taking place May 16-19, 2018, in Chicago, Ill.
Oral Presentation Title: "Rescue of Central and Peripheral Neurological Phenotype in a Mouse Model of Friedreich's Ataxia by Intravenous Delivery of AAV Frataxin with a Novel Capsid" Abstract O672.
Data presented at this year's ASGCT meeting demonstrated in a transgenic mouse model of FA, that one-time, post-symptomatic IV dosing of Voyager's vector composed of a novel AAV capsid and a frataxin transgene durably improved motor function and rescued the FA phenotype based on multiple functional tests of sensory and motor behavior.
Oral Presentation Title: "Rescue of Central and Peripheral Neurological Phenotype in a Mouse Model of Friedreich's Ataxia by Intravenous Delivery of AAV Frataxin with a Novel Capsid" Abstract O672.
Data presented at this year's ASGCT meeting demonstrated in a transgenic mouse model of FA, that one-time, post-symptomatic IV dosing of Voyager's vector composed of a novel AAV capsid and a frataxin transgene durably improved motor function and rescued the FA phenotype based on multiple functional tests of sensory and motor behavior.
Thursday, May 17, 2018
Pediatric Ataxia: Focus on Chronic Disorders.
Lynch DR, McCormick A, Schadt K, Kichula E.; Semin Pediatr Neurol. 2018 Apr;25:54-64. doi: 10.1016/j.spen.2018.01.001.
FRDA is the most common ataxia, and its phenotype is readily recognized. In children of typical age, it is frequently possible to diagnose FRDA by examination and genetic testing without the need for adjunctive tests (MRI and EMG). Genetic confirmation is required for diagnosis. In addition, one must remember that all patients with FRDA identified have at least one expanded GAA repeat. Thus GAA repeat expansion testing should occur before sequencing for point mutations. (This is a common mistake in genetic testing). Currently, genetic panels and exome sequencing does not include the ability to test for repeats, so this testing must be requested separately.
FRDA is the most common ataxia, and its phenotype is readily recognized. In children of typical age, it is frequently possible to diagnose FRDA by examination and genetic testing without the need for adjunctive tests (MRI and EMG). Genetic confirmation is required for diagnosis. In addition, one must remember that all patients with FRDA identified have at least one expanded GAA repeat. Thus GAA repeat expansion testing should occur before sequencing for point mutations. (This is a common mistake in genetic testing). Currently, genetic panels and exome sequencing does not include the ability to test for repeats, so this testing must be requested separately.
DNA triplex structure, thermodynamics, and destabilisation: insight from molecular simulations
Belinda J. Boehm, Charles Whidborne, Alexander L. Button, Tara L. Pukala and David M. Huang; Phys Chem Chem Phys. 2018 May 10. doi: 10.1039/c8cp02385a
A structural analysis of the DNA triplexes that can form with the FRDA-related duplex sequence indicates that the triplex with a parallel homopyrimidine TFO is likely to be more stable than the antiparallel homopurine-TFO triplex, which may have implications for disease onset and treatment.
A structural analysis of the DNA triplexes that can form with the FRDA-related duplex sequence indicates that the triplex with a parallel homopyrimidine TFO is likely to be more stable than the antiparallel homopurine-TFO triplex, which may have implications for disease onset and treatment.
Cardiovascular and sudomotor autonomic assessment in Friedreich’s Ataxia
Karen A. Girotto Takazaki, Alberto Martinez, Thiago Junqueira Rezende, Carelis González-Salazar, Anamarli Nucci, Iscia Lopes-Cendes, Marcondes C. Franca; Clinical Neurophysiology, Volume 129, Supplement 1, May 2018, Pages e86
doi:10.1016/j.clinph.2018.04.216
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
doi:10.1016/j.clinph.2018.04.216
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
Peripheral nerve ultrasound in Friedreich’s ataxia
Eoin Mulroy, Luciana Pelosi, Ruth Leadbetter, Purwa Joshi, Miriam Rodrigues, Stuart Mossman, Dean Kilfoyle, Richard Roxburgh; Clinical Neurophysiology, Volume 129, Supplement 1, May 2018, Pages e167-e168 doi:10.1016/j.clinph.2018.04.429
Our findings add further weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are likely to also play a role.
Our findings add further weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are likely to also play a role.
The dys-regulation of anti-oxidant defense via an impairment of Nrf2 response in the pathology of Friedreich’s ataxia
Shannon Chiang, Amy Anzovino, Bronwyn E. Brown, Clare L. Hawkins, Des R. Richardson, Michael L.-H. Huang; Free Radical Biology and Medicine, Volume 120, Supplement 1, 20 May 2018, Pages S35 doi:10.1016/j.freeradbiomed.2018.04.120
The transcription factor, nuclear factor-erythroid 2-related factor-2 (Nrf2), is the master regulator of antioxidant response. Decreased Nrf2 expression was previously reported in studies with models of the neuro-and cardio-degenerative disease, Friedreich’s ataxia (FA), where oxidative stress is a key contributor to its pathology. Using a mouse conditional frataxin knockout (KO) model, we examined the Nrf2 pathway in the frataxin-deficient heart and skeletal muscle. In the KO heart, our studies have demonstrated increased protein and GSH oxidation, decreased total and nuclear Nrf2 levels, and increased expression of its inhibitor, Keap1. However, the opposite was found in skeletal muscle. The activation of nuclear Nrf2 export/degradation machinery via Gsk3f3-signaling was demonstrated in the KO heart through the process of: (i) increased Gsk3f3 activation; (ii) f3-TrCP nuclear accumulation; and (iii) Fyn phosphorylation. This corresponded with decreased Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA in KO hearts. Overall, increased levels of cytosolic Keap1, and activation of Gsk3f3-signaling are potential mechanisms for the decreased Nrf2 levels in the frataxin-deficient Heart, in contrast to skeletal muscle, where Nrf2 was not decreased.
The transcription factor, nuclear factor-erythroid 2-related factor-2 (Nrf2), is the master regulator of antioxidant response. Decreased Nrf2 expression was previously reported in studies with models of the neuro-and cardio-degenerative disease, Friedreich’s ataxia (FA), where oxidative stress is a key contributor to its pathology. Using a mouse conditional frataxin knockout (KO) model, we examined the Nrf2 pathway in the frataxin-deficient heart and skeletal muscle. In the KO heart, our studies have demonstrated increased protein and GSH oxidation, decreased total and nuclear Nrf2 levels, and increased expression of its inhibitor, Keap1. However, the opposite was found in skeletal muscle. The activation of nuclear Nrf2 export/degradation machinery via Gsk3f3-signaling was demonstrated in the KO heart through the process of: (i) increased Gsk3f3 activation; (ii) f3-TrCP nuclear accumulation; and (iii) Fyn phosphorylation. This corresponded with decreased Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA in KO hearts. Overall, increased levels of cytosolic Keap1, and activation of Gsk3f3-signaling are potential mechanisms for the decreased Nrf2 levels in the frataxin-deficient Heart, in contrast to skeletal muscle, where Nrf2 was not decreased.
A CRISPR/TALEN-mediated gene editing approach for the Frataxin gene
Silvia Zaccagnino. Edizioni Accademiche Italiane, ISBN: 978-3-330-77664-7
Development and characterization of a new Friedreich Ataxia cellular model
Development and characterization of a new Friedreich Ataxia cellular model
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