Source: MDA.org, 09/21/2017.
Our objective is to develop a treatment strategy for FA, one of the most common forms of ataxia. Specifically, our research plan focuses on the correction of both the cardiac and neurological degeneration found in the disease. These changes are due to harmful changes in the frataxin gene.
This work will specifically answer important mechanistic questions in a new FA mouse model, which has many of the symptoms of the human patients. First, we will identify the best route of delivery for the frataxin gene in the nervous system by comparing three different strategies for injecting the vector (delivery vehicle). Second, we will test the safety of repeated delivery of the frataxin gene vector in combination with medications that will prevent reactions against the frataxin protein and the vector components. Completion of this project will be an important milestone in the development of a treatment strategy that will dramatically improve quality of life for FA patients.
Friday, September 22, 2017
Bioavailability of resveratrol: Possibilities for enhancement
Konrad de Vries, Morné Strydom, Vanessa Steenkamp, Journal of Herbal Medicine, Available online 12 September 2017, ISSN 2210-8033, doi:10.1016/j.hermed.2017.09.002.
Resveratrol is a naturally occurring polyphenol that has been shown to elicit a variety of beneficial effects in vitro. Translating these gains to in vivo and clinical settings has proven to be a major challenge, because of its poor oral bioavailability. This caveat was confirmed after reviewing clinical trials conducted on this investigational product over the past two years. This review provides alternative methods of administration of resveratrol which may enhance its bioavailability. However, these methods: remain to be validated.
From current literature, it is clear that orally administered resveratrol has low bioavailability in vivo. A variety of methods that could overcome the inherent issues with resveratrol bioavailability have been proposed, however these need to be further validated in order to determine which are safe, effective and superior to traditional oral administration of resveratrol before clinical evaluation can take place.
Resveratrol is a naturally occurring polyphenol that has been shown to elicit a variety of beneficial effects in vitro. Translating these gains to in vivo and clinical settings has proven to be a major challenge, because of its poor oral bioavailability. This caveat was confirmed after reviewing clinical trials conducted on this investigational product over the past two years. This review provides alternative methods of administration of resveratrol which may enhance its bioavailability. However, these methods: remain to be validated.
From current literature, it is clear that orally administered resveratrol has low bioavailability in vivo. A variety of methods that could overcome the inherent issues with resveratrol bioavailability have been proposed, however these need to be further validated in order to determine which are safe, effective and superior to traditional oral administration of resveratrol before clinical evaluation can take place.
Thursday, September 21, 2017
Friedreich Ataxia: Treatment with Genetic Approach
Martin L. Nelwan, Journal of Advances in Biology & Biotechnology, 2394-1081,Vol.: 14, Issue.: 4
Adequate treatments are unavailable for this disorder at present. However, to treat FA, genetic approach can be used. The approach may comprise genetic counseling and use of advanced therapy, gene therapy for instance.
Adequate treatments are unavailable for this disorder at present. However, to treat FA, genetic approach can be used. The approach may comprise genetic counseling and use of advanced therapy, gene therapy for instance.
Wednesday, September 20, 2017
Molecular Alterations in a Mouse Cardiac Model of Friedreich’s Ataxia: An Impaired Nrf2 Response Mediated via Up-Regulation of Keap1 and Activation of the Gsk3β Axis
Amy Anzovino, Shannon Chiang, Bronwyn E. Brown, Clare L. Hawkins, Des R. Richardson, Michael L.-H. Huang, The American Journal of Pathology, Available online 19 September 2017, ISSN 0002-9440, doi:10.1016/j.ajpath.2017.08.021.
Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the anti-oxidant response. However, studies in models of Friedreich’s ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due to unknown mechanisms.
Collectively, cardiac frataxin-deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Keap1, and activation of Gsk3β-signaling that decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.
Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the anti-oxidant response. However, studies in models of Friedreich’s ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due to unknown mechanisms.
Collectively, cardiac frataxin-deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Keap1, and activation of Gsk3β-signaling that decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.
Tuesday, September 19, 2017
Movement disorders hidden in the neuromuscular clinic
J. Reimann, S. Paus, Neuromuscular Disorders, Volume 27, Supplement 2, October 2017, Page S243, ISSN 0960-8966, doi:10.1016/j.nmd.2017.06.531.
We present these exemplary cases to increase awareness of these disorders and the differential diagnosis for those working in neuromuscular clinics, as well as an incentive for more interaction with the movement disorder field, in particular when struggling to define a diagnosis. We also observe a number of referrals that turn out to be movement disorders. In some, this is caused by known neuromuscular manifestations while missing the CNS signs. Examples are our cases of Huntington’s disease presenting with weakness, pain and atrophy of the calves and of Friedreich ataxia send for work-up of sensory axonal neuropathy and scoliosis, where “restlessness” and “nasal speech”, respectively, were ignored as symptoms. In others, the attribution of the pathophysiology to muscle is simply wrong.
We present these exemplary cases to increase awareness of these disorders and the differential diagnosis for those working in neuromuscular clinics, as well as an incentive for more interaction with the movement disorder field, in particular when struggling to define a diagnosis. We also observe a number of referrals that turn out to be movement disorders. In some, this is caused by known neuromuscular manifestations while missing the CNS signs. Examples are our cases of Huntington’s disease presenting with weakness, pain and atrophy of the calves and of Friedreich ataxia send for work-up of sensory axonal neuropathy and scoliosis, where “restlessness” and “nasal speech”, respectively, were ignored as symptoms. In others, the attribution of the pathophysiology to muscle is simply wrong.
Monday, September 18, 2017
Relationship Between Neurological Disability and Visual Impairment in Patients With ALS or Friedreich's Ataxia
ClinicalTrials.gov Identifier: NCT03285204, First received: March 8, 2017
Principal Investigator: Jose L Urcelay, PhD HGU Gregorio Marañón.
Location: Madrid, Spain,
The aim of this study is to obtain an early biomarker of amyotrophic lateral sclerosis and Friedreich's Ataxia which allows to diagnose the disease in an initial stage and to follow up the patient with optic coherence tomography, a fast, non-invasive and comfortable method.
Principal Investigator: Jose L Urcelay, PhD HGU Gregorio Marañón.
Location: Madrid, Spain,
The aim of this study is to obtain an early biomarker of amyotrophic lateral sclerosis and Friedreich's Ataxia which allows to diagnose the disease in an initial stage and to follow up the patient with optic coherence tomography, a fast, non-invasive and comfortable method.
Saturday, September 16, 2017
Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots
Shao-Hua Yang, Wenjun Li, Nathalie Sumien, Michael Forster, James W. Simpkins, Ran Liu, In Progress in Neurobiology, Volume 157, 2017, Pages 273-291, ISSN 0301-0082, doi:10.1016/j.pneurobio.2015.10.005.
Highlights:
Reprogramming energetic metabolism is a common feature for neurodegenerative diseases and cancers.
Methylene blue functions as an alternative mitochondrial electron transfer carrier, enhancing bioenergetics and inhibiting biosynthetics.
Methylene blue provides protective effect in rodent models of Parkinson disease, Alzheimer's disease, Huntington's disease, and Friedreich's ataxia.
Methylene blue reverses Warburg's effect and inhibits cancers proliferation.
Alternative mitochondrial electron transfer may provide a common novel therapeutic mechanism for cancers and neurodegenerative diseases.
Highlights:
Reprogramming energetic metabolism is a common feature for neurodegenerative diseases and cancers.
Methylene blue functions as an alternative mitochondrial electron transfer carrier, enhancing bioenergetics and inhibiting biosynthetics.
Methylene blue provides protective effect in rodent models of Parkinson disease, Alzheimer's disease, Huntington's disease, and Friedreich's ataxia.
Methylene blue reverses Warburg's effect and inhibits cancers proliferation.
Alternative mitochondrial electron transfer may provide a common novel therapeutic mechanism for cancers and neurodegenerative diseases.
Sunday, September 10, 2017
Market access of Spinraza (Nusinersen) for spinal muscular atrophy: intellectual property rights, pricing, value and coverage considerations
S Simoens and I Huys; Gene Therapy , (7 September 2017) | doi:10.1038/gt.2017.79
In December 2016, Spinraza (Nusinersen), Biogen (Durham, NC, USA) was the first treatment to be registered as an orphan drug by the US Food and Drug Administration for SMA. In Europe, a gene therapy in principle classifies as an Advanced Therapy Medicinal Product (ATMP), covered by a regulatory framework with particular incentives for drug developers. For Nusinersen, the European Medicines Agency recently granted the Accelerated Assessment status in 2016. With respect to its price, it has been reported that the annual wholesale costs of treating a patient with Nusinersen will amount to $750 000 for the first year and $375 000 for subsequent years. Biogen argues that this price is in line with that of other orphan drugs for rare diseases.
Despite marketing authorization of Nusinersen in the United States and in Europe, patient access to this new promising therapy remains uncertain. The price of this new drug clearly triggers several questions in terms of justification, transparency and responsibility.
The aim of this Comment is to identify and to discuss issues related to the market access of Nusinersen for SMA by focusing specifically on intellectual property rights, pricing, value and coverage considerations from the perspective of the company, patients and society.
The pricing of Nusinersen is a black box, although Biogen claims that the price of Nusinersen is in line with its clinical benefit and with prices of other orphan drugs. Any data about the value assessment of Nusinersen is not (publicly)available. This asymmetry (or even absence) of information between Biogen and insurers needs to be tackled in an era when insurers (and society at large) need to make and justify difficult choices. A quantifiable and evidence-driven approach to pricing and value assessment is required and such data need to be available to the stakeholders involved.
In December 2016, Spinraza (Nusinersen), Biogen (Durham, NC, USA) was the first treatment to be registered as an orphan drug by the US Food and Drug Administration for SMA. In Europe, a gene therapy in principle classifies as an Advanced Therapy Medicinal Product (ATMP), covered by a regulatory framework with particular incentives for drug developers. For Nusinersen, the European Medicines Agency recently granted the Accelerated Assessment status in 2016. With respect to its price, it has been reported that the annual wholesale costs of treating a patient with Nusinersen will amount to $750 000 for the first year and $375 000 for subsequent years. Biogen argues that this price is in line with that of other orphan drugs for rare diseases.
Despite marketing authorization of Nusinersen in the United States and in Europe, patient access to this new promising therapy remains uncertain. The price of this new drug clearly triggers several questions in terms of justification, transparency and responsibility.
The aim of this Comment is to identify and to discuss issues related to the market access of Nusinersen for SMA by focusing specifically on intellectual property rights, pricing, value and coverage considerations from the perspective of the company, patients and society.
The pricing of Nusinersen is a black box, although Biogen claims that the price of Nusinersen is in line with its clinical benefit and with prices of other orphan drugs. Any data about the value assessment of Nusinersen is not (publicly)available. This asymmetry (or even absence) of information between Biogen and insurers needs to be tackled in an era when insurers (and society at large) need to make and justify difficult choices. A quantifiable and evidence-driven approach to pricing and value assessment is required and such data need to be available to the stakeholders involved.
Detection of long repeat expansions from PCR-free whole-genome sequence data
Egor Dolzhenko, Joke J.F.A. van Vugt, Richard J. Shaw, Mitchell A. Bekritsky, Marka van Blitterswijk, Giuseppe Narzisi, Subramanian S. Ajay, Vani Rajan, Bryan Lajoie, Nathan H. Johnson, Zoya Kingsbury, Sean J. Humphray, Raymond D. Schellevis, William J. Brands, Matt Baker, Rosa Rademakers, Maarten Kooyman, Gijs H.P. Tazelaar, Michael A. van Es, Russell McLaughlin, William Sproviero, Aleksey Shatunov, Ashley Jones, Ahmad Al Khleifat, Alan Pittman, Sarah Morgan, Orla Hardiman, Ammar Al-Chalabi, Chris Shaw, Bradley Smith, Edmund J. Neo, Karren Morrison, Pam Shaw, Catherine Reeves, Lara Winterkorn, Nancy S. Wexler, The US-Venezuela Collaborative Research Group, David E. Housman, Christopher W. Ng, Alina L. Li, Ryan J. Taft, Leonard H. van den Berg, David R. Bentley, Jan H. Veldink, and Michael A. Eberle. Genome Res. gr. 225672.117 Published in Advance September 8, 2017, doi:10.1101/gr.225672.117
We further applied our algorithm to a set of 152 samples where every sample had one of eight different pathogenic repeat expansions including those associated with fragile X syndrome, Friedreich's ataxia and Huntington's disease and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions. The software is licensed under GPL v3.0 and the source code is freely available on GitHub.
We further applied our algorithm to a set of 152 samples where every sample had one of eight different pathogenic repeat expansions including those associated with fragile X syndrome, Friedreich's ataxia and Huntington's disease and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions. The software is licensed under GPL v3.0 and the source code is freely available on GitHub.
Saturday, September 9, 2017
Nitric oxide prevents Aft1 activation and metabolic remodeling in Frataxin-deficient yeast
David Alsina, Joaquim Ros, Jordi Tamarit, Redox Biology, Available online 6 September 2017, ISSN 2213-2317, doi:10.1016/j.redox.2017.09.001.
A major conclusion of this work is that Yfh1 deficiency activates the iron regulon by a different pathway than iron-sulfur loss. Therefore, alternative pathways for Aft1 activation may exist in yeast which, as discussed above, could be related to the presence of anomalous iron species. We have also observed that metabolic status can be efficiently monitored using a targeted proteomics strategy focusing on key metabolic enzymes. Finally, the observation that NO can mitigate the defects caused by Yfh1 deficiency supports the hypothesis that Yfh1 loss leads to the increased presence of anomalous iron forms, and that this anomalous iron plays a central role in the events caused by Yfh1 deficiency. It also suggests that NO donors could have a therapeutic effect in FRDA patients. NO donors such as SNP or nitroglycerin have been used for more than a century for controlling congestive heart failure associated with heart attack or lowering blood pressure during surgery. Beyond its vasodilating action, neuroprotective properties have been demonstrated for NO in an iron-induced model of Parkinson's disease. This observation, together with the results presented in this work, opens the possibility to explore the potential therapeutic effect of NO donors in mammalian models of FRDA.
A major conclusion of this work is that Yfh1 deficiency activates the iron regulon by a different pathway than iron-sulfur loss. Therefore, alternative pathways for Aft1 activation may exist in yeast which, as discussed above, could be related to the presence of anomalous iron species. We have also observed that metabolic status can be efficiently monitored using a targeted proteomics strategy focusing on key metabolic enzymes. Finally, the observation that NO can mitigate the defects caused by Yfh1 deficiency supports the hypothesis that Yfh1 loss leads to the increased presence of anomalous iron forms, and that this anomalous iron plays a central role in the events caused by Yfh1 deficiency. It also suggests that NO donors could have a therapeutic effect in FRDA patients. NO donors such as SNP or nitroglycerin have been used for more than a century for controlling congestive heart failure associated with heart attack or lowering blood pressure during surgery. Beyond its vasodilating action, neuroprotective properties have been demonstrated for NO in an iron-induced model of Parkinson's disease. This observation, together with the results presented in this work, opens the possibility to explore the potential therapeutic effect of NO donors in mammalian models of FRDA.
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