Graham S. Erwin, Matthew P. Grieshop, Asfa Ali, Jun Qi, Matthew Lawlor, Deepak Kumar, Istaq Ahmad, Anna McNally, Natalia Teider, Katie Worringer, Rajeev Sivasankaran, Deeba N. Syed, Asuka Eguchi, Md. Ashraf, Justin Jeffery, Mousheng Xu, Paul M. C. Park, Hasan Mukhtar, Achal K. Srivastava, Mohammed Faruq, James E. Bradner, Aseem Z. Ansari; Science 30 Nov 2017 eaan6414, Published Online 30 Nov 2017 DOI: 10.1126/science.aan6414
The molecule being tested is designed to assist the enzyme that reads, or “transcribes,” DNA at the confusing repeats. Once it reaches the other side, the enzyme, called RNA polymerase, reads the gene and makes RNA that in turn codes for frataxin, the protein that is lacking in Friedreich’s ataxia.
Friday, December 1, 2017
Designer molecule points to treatment for diseases caused by DNA repeats
University of Wisconsin–Madison news, November 30, 2017 By David Tenenbaum.
Using a molecule designed to overcome a roadblock formed by a common type of genetic flaw, researchers at the University of Wisconsin–Madison have made progress towards novel molecular treatments for Friedreich’s ataxia — a rare but fatal disorder — in the laboratory dish and in animals.
Using a molecule designed to overcome a roadblock formed by a common type of genetic flaw, researchers at the University of Wisconsin–Madison have made progress towards novel molecular treatments for Friedreich’s ataxia — a rare but fatal disorder — in the laboratory dish and in animals.
Thursday, November 30, 2017
Physical activity in the prevention of human diseases: role of epigenetic modifications
Elisa Grazioli, Ivan Dimauro, Neri Mercatelli, Guan Wang, Yannis Pitsiladis, Luigi Di Luigi and Daniela Caporossi; BMC Genomics 201718 (Suppl 8):802, doi:10.1186/s12864-017-4193-5
This review highlights the most significant findings from epigenetic studies involving physical activity/exercise interventions known to benefit chronic diseases such as metabolic syndrome, diabetes, cancer, cardiovascular and neurodegenerative diseases.
In conclusion, PA promises to be an important tool to be used alone or in combination with traditional therapies to improve the efficacy of strategies for disease prevention and treatment based on epigenetic modification. In this context, exercise remains an essential factor promoting important biological adaptations with profound implications for public health. Future collaborative studies may identify epigenetic markers with translational significance in identifying individuals for whom a personalized exercise regime could significantly alter the epigenomic signature and thus the risk of disease development or progression.
This review highlights the most significant findings from epigenetic studies involving physical activity/exercise interventions known to benefit chronic diseases such as metabolic syndrome, diabetes, cancer, cardiovascular and neurodegenerative diseases.
In conclusion, PA promises to be an important tool to be used alone or in combination with traditional therapies to improve the efficacy of strategies for disease prevention and treatment based on epigenetic modification. In this context, exercise remains an essential factor promoting important biological adaptations with profound implications for public health. Future collaborative studies may identify epigenetic markers with translational significance in identifying individuals for whom a personalized exercise regime could significantly alter the epigenomic signature and thus the risk of disease development or progression.
Wednesday, November 29, 2017
Differentially Regulated Cell-Free MicroRNAs in the Plasma of Friedreich's Ataxia Patients and Their Association with Disease Pathology
Subrahamanyam Dantham, Achal K. Srivastava, Sheffali Gulati, Moganty R. Rajeswari; Neuropediatrics 2017 Nov 27. DOI: 10.1055/s-0037-1607279
Friedreich's ataxia (FRDA) is a multisystem disease affecting the predominately nervous system, followed by muscle, heart, and pancreas. Current research focused on therapeutic interventions aimed at molecular amelioration, but there are no reliable noninvasive signatures available to understand disease pathogenesis. The present study investigates the alterations of plasma cell-free microRNAs (miRNAs) in FRDA patients and attempts to find the significance in relevance with the pathogenesis. Total RNA from the plasma of patients and healthy controls were subjected to miRNA microarray analysis using Agilent Technologies microarray platform. Differentially regulated miRNAs were validated by SYBR-green real-time polymerase chain reaction (Thermo Fisher Scientific). The study identified 20 deregulated miRNAs (false discovery rate < 0.01, fold change ≥ 2.0 ≤) in comparison with healthy controls; out of which 17 miRNAs were upregulated, and 3 miRNAs were downregulated. Target and pathway analysis of these miRNAs have shown association with neurodegenerative and other clinical features in FRDA. Further validation (n = 21) identified a set of significant (p < 0.05) deregulated miRNAs; hsa-miR-15a-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-223–3p, hsa-24–3p, and hsa-miR-21–5p in comparison with healthy controls. These miRNAs were reported to influence various pathological features associated with FRDA. The present study is expected to aid in the understanding of disease pathogenesis.
Friedreich's ataxia (FRDA) is a multisystem disease affecting the predominately nervous system, followed by muscle, heart, and pancreas. Current research focused on therapeutic interventions aimed at molecular amelioration, but there are no reliable noninvasive signatures available to understand disease pathogenesis. The present study investigates the alterations of plasma cell-free microRNAs (miRNAs) in FRDA patients and attempts to find the significance in relevance with the pathogenesis. Total RNA from the plasma of patients and healthy controls were subjected to miRNA microarray analysis using Agilent Technologies microarray platform. Differentially regulated miRNAs were validated by SYBR-green real-time polymerase chain reaction (Thermo Fisher Scientific). The study identified 20 deregulated miRNAs (false discovery rate < 0.01, fold change ≥ 2.0 ≤) in comparison with healthy controls; out of which 17 miRNAs were upregulated, and 3 miRNAs were downregulated. Target and pathway analysis of these miRNAs have shown association with neurodegenerative and other clinical features in FRDA. Further validation (n = 21) identified a set of significant (p < 0.05) deregulated miRNAs; hsa-miR-15a-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-223–3p, hsa-24–3p, and hsa-miR-21–5p in comparison with healthy controls. These miRNAs were reported to influence various pathological features associated with FRDA. The present study is expected to aid in the understanding of disease pathogenesis.
Tuesday, November 28, 2017
Do whole body vibration exercises affect lower limbs neuromuscular activity in populations with a medical condition? A systematic review
Dionello, Carla Fontouraa; de Souza, Patrícia Lopesa; Sá-Caputo, Danubiaa; Morel, Danielle Soaresa; Moreira-Marconi, Eloáb; Paineiras-Domingos, Laisa Lianea; Frederico, Eric Heleno Freire Ferreirab; Guedes-Aguiar, Elianeb; Paiva, Patricia de Castrob; Taiar, Redhah | Chiementin, Xavierh; Marín, Pedro J.i; Bernardo-Filho, Mariob; Restorative Neurology and Neuroscience, vol. 35, no. 6, pp. 667-681, 2017 DOI:10.3233/RNN-170765
The use of surface electromyography (sEMG) to evaluate muscle activation when executing whole body vibration exercises (WBVE) in studies provide neuromuscular findings, in healthy and diseased populations. Objectives:Perform a systematic review of the effects of WBVE by sEMG of lower limbs in non-healthy populations.
The group of Herrero evaluated muscle activation during WBVE of FA patients. The protocol consisted of two familiarization sessions and one working session that comprised six bouts of 3 min WBVE treatments on a tilt-table.
The use of surface electromyography (sEMG) to evaluate muscle activation when executing whole body vibration exercises (WBVE) in studies provide neuromuscular findings, in healthy and diseased populations. Objectives:Perform a systematic review of the effects of WBVE by sEMG of lower limbs in non-healthy populations.
The group of Herrero evaluated muscle activation during WBVE of FA patients. The protocol consisted of two familiarization sessions and one working session that comprised six bouts of 3 min WBVE treatments on a tilt-table.
Thursday, November 23, 2017
Patients organizations and new drug approval in the US. Eteplirsen and Duchenne muscular dystrophy case
Dal-Ré R, Lopez de Munain A, Ayuso C; Rev Neurol. 2017 Oct 16;65(8):373-380. [Article in Spanish]
INTRODUCTION:
In 2016 the US Food and Drug Administration (FDA) granted the marketing authorization for eteplirsen for Duchenne muscular dystrophy. This has been a very controversial decision since it happened after a negative assessment from both the Advisory Committee and the technical FDA evaluation team. The FDA's Center for Drug Evaluation and Research (CDER) director was who ultimately approved the product, while the FDA Commissioner did not overrule that decision.
AIM:
To report about the most relevant events regarding the approval of eteplirsen by the US FDA.
DEVELOPMENT:
All relevant facts that occurred during the clinical development and evaluation phase following 'accelerated approval' procedure of eteplirsen are discussed in detail. The technical FDA evaluation team reasons supporting that the drug has not proven clinical benefit, the attitude of patient advocacy groups and the post-approval FDA requirements to the marketing authorization holder are discussed. Finally, we reflect on what is the situation Spanish patients face once eteplirsen is on the US market.
CONCLUSIONS:
This is a unique case in the history of drug authorizations in western countries, that shows the difficulties that current regulations on accelerated approval of new medicines could have when interpreting scarce and low quality clinical development data, when dealing with rare diseases with no available therapies.
INTRODUCTION:
In 2016 the US Food and Drug Administration (FDA) granted the marketing authorization for eteplirsen for Duchenne muscular dystrophy. This has been a very controversial decision since it happened after a negative assessment from both the Advisory Committee and the technical FDA evaluation team. The FDA's Center for Drug Evaluation and Research (CDER) director was who ultimately approved the product, while the FDA Commissioner did not overrule that decision.
AIM:
To report about the most relevant events regarding the approval of eteplirsen by the US FDA.
DEVELOPMENT:
All relevant facts that occurred during the clinical development and evaluation phase following 'accelerated approval' procedure of eteplirsen are discussed in detail. The technical FDA evaluation team reasons supporting that the drug has not proven clinical benefit, the attitude of patient advocacy groups and the post-approval FDA requirements to the marketing authorization holder are discussed. Finally, we reflect on what is the situation Spanish patients face once eteplirsen is on the US market.
CONCLUSIONS:
This is a unique case in the history of drug authorizations in western countries, that shows the difficulties that current regulations on accelerated approval of new medicines could have when interpreting scarce and low quality clinical development data, when dealing with rare diseases with no available therapies.
Sunday, November 19, 2017
Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor.
Amelie Hu, Myriam Rai, Simona Donatello, Massimo Pandolfo; bioRxiv 221242; doi:10.1101/221242 (This article is a preprint and has not been peer-reviewed)
We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.
We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.
Friday, November 17, 2017
Voyager Therapeutics "update"
CAMBRIDGE, Mass., Nov. 16, 2017 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases, today at its R&D Day highlighted recent progress and plans for VY-AADC for advanced Parkinson’s disease, and progress with testing novel adeno-associated virus (AAV) capsids and delivery optimization efforts, along with its ALS, Huntington’s disease, Friedreich’s ataxia, anti-Tau antibody and severe chronic pain preclinical programs.
"Preclinical data from its Friedreich’s ataxia (FA) program in a transgenic mouse model of FA, with a one-time intravenous (IV) dosing of an AAV vector composed of a novel capsid and a frataxin transgene, together with intracerebral dosing of an AAV vector with the same transgene, that led to a rapid halting and reduction of FA disease progression in multiple functional tests of motor behavior. Additional preclinical studies are underway at Voyager including steps to identify a lead clinical candidate for the treatment of FA during 2018."
"Preclinical data from its Friedreich’s ataxia (FA) program in a transgenic mouse model of FA, with a one-time intravenous (IV) dosing of an AAV vector composed of a novel capsid and a frataxin transgene, together with intracerebral dosing of an AAV vector with the same transgene, that led to a rapid halting and reduction of FA disease progression in multiple functional tests of motor behavior. Additional preclinical studies are underway at Voyager including steps to identify a lead clinical candidate for the treatment of FA during 2018."
Wednesday, November 15, 2017
Proactive Ethical Design for Neuroengineering, Assistive and Rehabilitation Technologies: the Cybathlon Lesson
Marcello Ienca, Reto W. Kressig, Fabrice Jotterand and Bernice Elger; ournal of NeuroEngineering and Rehabilitation 201714:115 doi:10.1186/s12984-017-0325-z
As the fields of assistive technology and neuroengineering are entering a new phase of clinical and commercial maturity, there is an increasing need to address the ethical implications associated with the design and development of novel assistive and rehabilitative technological solutions. After reviewing various ethically-sensitive approaches to the design of NART, we proposed a framework for ethical design and development, which we call the Proactive Ethical Design (PED) framework. This framework is characterized by the convergence of user-centered and value-sensitive approaches to product design through a proactive mode of ethical evaluation. Four basic normative requirements are necessary for the realization of this framework: minimization of power imbalances, compliance with biomedical ethics, translationality and social awareness.
As the fields of assistive technology and neuroengineering are entering a new phase of clinical and commercial maturity, there is an increasing need to address the ethical implications associated with the design and development of novel assistive and rehabilitative technological solutions. After reviewing various ethically-sensitive approaches to the design of NART, we proposed a framework for ethical design and development, which we call the Proactive Ethical Design (PED) framework. This framework is characterized by the convergence of user-centered and value-sensitive approaches to product design through a proactive mode of ethical evaluation. Four basic normative requirements are necessary for the realization of this framework: minimization of power imbalances, compliance with biomedical ethics, translationality and social awareness.
Saturday, November 11, 2017
RESONANCIA MAGNÉTICA CARDIACA EN ATAXIA DE FRIEDREICH: SEGUIMIENTO CARDIACO DE LAS TERAPIAS ANTIOXIDANTES
Emilio Cuesta López. Tesis doctoral, UNIVERSIDAD AUTONOMA DE MADRID FACULTAD DE MEDICINA DEPARTAMENTO DE MEDICINA, Madrid 2017
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