Satyakam Bhagavati, MD, JAMA Neurol. Published online October 31, 2016. doi:10.1001/jamaneurol.2016.4332
The review by Corey1 and the accompanying editorial paint a very positive picture about the potential of antisense oligonucleotides (ASOs) to treat neurological diseases such as Friedrich ataxia,2 spinal muscular atrophy,3 and Duchenne muscular dystrophy. Although the principle on which ASO-based treatment is based is promising, a review of the literature, however, reveals critical lacunae in the data that have been used to claim efficacy.
Related Articles:
Clinical Implications of Basic Neuroscience Research, Synthetic Nucleic Acids and Treatment of Neurological Diseases David R. Corey, PhD
Antisense Oligonucleotides for Treating Neurological Diseases, David R. Corey, PhD
Monday, November 28, 2016
Sunday, November 27, 2016
Challenges ahead for trials in Friedreich’s ataxia
David R Lynch, Elizabeth Kichula, The Lancet Neurology, Volume 15, Issue 13, December 2016, Pages 1300-1301, ISSN 1474-4422, doi:10.1016/S1474-4422(16)30281-2.
Nevertheless, although natural history studies such as EFACTS identify the problems in progressing with therapeutic trials in Friedreich’s ataxia, they also identify one mechanism for keeping trials small: stratification.
In all of the natural history studies of Friedreich’s ataxia including the EFACTS, individuals with longer GAA repeat lengths had faster progression.
Nevertheless, although natural history studies such as EFACTS identify the problems in progressing with therapeutic trials in Friedreich’s ataxia, they also identify one mechanism for keeping trials small: stratification.
In all of the natural history studies of Friedreich’s ataxia including the EFACTS, individuals with longer GAA repeat lengths had faster progression.
Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study
Kathrin Reetz, Imis Dogan, Ralf-Dieter Hilgers, Paola Giunti, Caterina Mariotti, Alexandra Durr, Sylvia Boesch, Thomas Klopstock, Francisco Javier Rodriguez de Rivera, Ludger Schöls, Thomas Klockgether, Katrin Bürk, Myriam Rai, Massimo Pandolfo, Jörg B Schulz, The Lancet Neurology, Volume 15, Issue 13, December 2016, Pages 1346-1354, ISSN 1474-4422, http://dx.doi.org/10.1016/S1474-4422(16)30287-3.
"To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial."
In conclusion, our results of the 2 year analysis of the EFACTS cohort allowed substantiation of the suitability of the SARA and ADL as robust outcome measures for future therapeutic trials, which should be designed with an observational period of at least 2 years.
"To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial."
In conclusion, our results of the 2 year analysis of the EFACTS cohort allowed substantiation of the suitability of the SARA and ADL as robust outcome measures for future therapeutic trials, which should be designed with an observational period of at least 2 years.
Saturday, October 29, 2016
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.
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.
Monday, October 24, 2016
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.
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.
Sunday, October 23, 2016
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.
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.
Friday, October 21, 2016
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.
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.
Wednesday, October 19, 2016
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.
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.
Tuesday, October 18, 2016
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)
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)
Monday, October 17, 2016
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.
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.
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