Eva-Christina Ahlgren, Mostafa Fekry, Mathias Wiemann, Christopher A. Söderberg, Katja Bernfur, Olex Gakh, Morten Rasmussen, Peter Højrup, Cecilia Emanuelsson, Grazia Isaya, Salam Al-Karadaghi. PLoS ONE 12(12): e0188937. doi:10.1371/journal.pone.0188937
Patients suffering from the progressive neurodegenerative disease Friedreich’s ataxia have reduced expression levels of the protein frataxin. Three major isoforms of human frataxin have been identified, FXN42-210, FXN56-210 and FXN81-210, of which FXN81-210 is considered to be the mature form.
Tuesday, December 5, 2017
Monday, December 4, 2017
C-Path And FARA Announce Collaborative Data Aggregation Project For Friedreich’s Ataxia
Tucson, AZ, and Downingtown, PA — Dec. 4, 2017 — Critical Path Institute's (C-Path) Data Collaboration Center (DCC) and the Friedreich's Ataxia Research Alliance (FARA) have announced that they will work together to develop an aggregated database of clinical data for Friedreich's ataxia (FA). Use of this database will promote collaborative research to support the understanding of natural history, potential biomarkers, and potential clinical endpoints for patients with FA, which will help researchers develop more efficient clinical trial protocols to test new therapies more quickly and effectively.
The project will establish an integrated database of clinical data for FA that can be shared and utilized by existing FA researchers. It will enlist companies that have carried out clinical trials in FA to obtain contributions of clinical data, as well as sharing natural history data collected by FARA's collaborative clinical research network.
The project will establish an integrated database of clinical data for FA that can be shared and utilized by existing FA researchers. It will enlist companies that have carried out clinical trials in FA to obtain contributions of clinical data, as well as sharing natural history data collected by FARA's collaborative clinical research network.
Sunday, December 3, 2017
The role of oxidative stress in Friedreich's ataxia
Federica Lupoli, Tommaso Vannocci, Giovanni Longo, Neri Niccolai and Annalisa Pastore. FEBS Letters, DOI: 10.1002/1873-3468.12928
Friedreich's ataxia is an excellent paradigmatic example of a disease in which oxidative stress plays an important, albeit not completely understood, role. Friedreich's ataxia is a rare genetic neurodegenerative disease which involves partial silencing of frataxin, a small mitochondrial protein completely ignored before being linked to Friedreich's ataxia.
Friedreich's ataxia is an excellent paradigmatic example of a disease in which oxidative stress plays an important, albeit not completely understood, role. Friedreich's ataxia is a rare genetic neurodegenerative disease which involves partial silencing of frataxin, a small mitochondrial protein completely ignored before being linked to Friedreich's ataxia.
Saturday, December 2, 2017
Peripheral nerve ultrasound in Friedreich ataxia
Mulroy, E., Pelosi, L., Leadbetter, R., Joshi, P., Rodrigues, M., Mossman, S., Kilfoyle, D. and Roxburgh, R. (2017). Muscle Nerve. doi: 10.1002/mus.26012
The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs.
Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role.
The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs.
Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role.
Friday, December 1, 2017
Synthetic transcription elongation factors license transcription across repressive chromatin
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.
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.
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.
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