Pınar Bengi Boz, Filiz Koç, Sabriye Kocatürk Sel, Ali İrfan Güzel, Halil Kasap, Arch Neuropsychiatry 2016; 53: 115-119, DOI:10.5152/npa.2015.9925
This study aimed to analyze the genotypic characteristics of Friedreich’s ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings.
In our study, 47.2% of patients with FA had developed hereditary cerebellar ataxia. Ground and autosomal dominant-linked SCA1 and SCA6 were each detected in one family. These data suggest that patients with cerebellar ataxia of hereditary origin should be primarily examined for FA.
Sunday, April 2, 2017
Friday, March 31, 2017
Longitudinal Gait and Balance Decline in Friedreich’s Ataxia: A Pilot Study
Theresa A. Zesiewicz, Jeannie B. Stephenson, Seok Hun Kim, Kelly L. Sullivan, Israt Jahan, Yangxin Huang, Jason L. Salemi, Lynn Wecker, Jessica D. Shaw, Clifton L. Gooch, Gait & Posture, Available online 30 March 2017, ISSN 0966-6362, doi:10.1016/j.gaitpost.2017.03.019.
In the FA group, comfortable and fast gait velocity declined 8.0% and 13.9% after 12 months and 24.1% and 30.3% after 24 months, respectively. Postural stability indices increased in FA subjects an average of 41% from baseline to 24 months, representing a decline in balance. Subjects with FA also demonstrated a 17.7% increase in FARS neurological exam scores over 24 months. There were no changes in gait or balance variables in controls. In the FA group, multiple gait and balance measures correlated significantly with FARS neurological exam scores.
The GAITRite and Biodex systems provided objective and clinically relevant measures of functional decline in subjects with FA that correlated significantly with performance measures in the FARS. Gait velocity may be an important objective measure to identify disease progression in adults with FA.
In the FA group, comfortable and fast gait velocity declined 8.0% and 13.9% after 12 months and 24.1% and 30.3% after 24 months, respectively. Postural stability indices increased in FA subjects an average of 41% from baseline to 24 months, representing a decline in balance. Subjects with FA also demonstrated a 17.7% increase in FARS neurological exam scores over 24 months. There were no changes in gait or balance variables in controls. In the FA group, multiple gait and balance measures correlated significantly with FARS neurological exam scores.
The GAITRite and Biodex systems provided objective and clinically relevant measures of functional decline in subjects with FA that correlated significantly with performance measures in the FARS. Gait velocity may be an important objective measure to identify disease progression in adults with FA.
Thursday, March 30, 2017
Ferroptosis Inhibition: Mechanisms and Opportunities
Jose Pedro Friedmann Angeli, Ron Shah, Derek A. Pratt, Marcus Conrad, Trends in Pharmacological Sciences, Available online 28 March 2017, ISSN 0165-6147, doi:10.1016/j.tips.2017.02.005.
The past decade has yielded tremendous insights into how cells die. This has come with our understanding that several distinct forms of cell death are encompassed under the umbrella term necrosis. Among these distinct forms of regulated necrotic cell death, ferroptosis has attracted considerable attention owing to its putative involvement in diverse pathophysiological processes. A key feature of the ferroptosis process is the requirement of phospholipid peroxidation, a process that has been linked with several human pathologies. Now with the establishment of a connection between lipid peroxidation and a distinctive cell death pathway, the search for new small molecules able to suppress lipid peroxidation has gained momentum and may yield novel cytoprotective strategies. We review here advances in our understanding of the ferroptotic process and summarize the development of lipid peroxidation inhibitors with the ultimate goal of suppressing ferroptosis-relevant cell death and related pathologies.
Supplementation of cell media with deuterated linoleic acid (LA) was investigated, and has proven beneficial in several cell models of lipid peroxidation-related neurological disease including PD and Friedreich’s ataxia. In addition,it was also recently shown that cells exposed to deuterated LA presented a marked resistance to ferroptosis.
Ever since therecognition of the privileged position of a-tocopherol as Nature’s premier lipid-soluble Radical-Trapping Antioxidants, researchers have developed with success synthetic compounds with increased reactivity towards peroxyl radicals.
The past decade has yielded tremendous insights into how cells die. This has come with our understanding that several distinct forms of cell death are encompassed under the umbrella term necrosis. Among these distinct forms of regulated necrotic cell death, ferroptosis has attracted considerable attention owing to its putative involvement in diverse pathophysiological processes. A key feature of the ferroptosis process is the requirement of phospholipid peroxidation, a process that has been linked with several human pathologies. Now with the establishment of a connection between lipid peroxidation and a distinctive cell death pathway, the search for new small molecules able to suppress lipid peroxidation has gained momentum and may yield novel cytoprotective strategies. We review here advances in our understanding of the ferroptotic process and summarize the development of lipid peroxidation inhibitors with the ultimate goal of suppressing ferroptosis-relevant cell death and related pathologies.
Supplementation of cell media with deuterated linoleic acid (LA) was investigated, and has proven beneficial in several cell models of lipid peroxidation-related neurological disease including PD and Friedreich’s ataxia. In addition,it was also recently shown that cells exposed to deuterated LA presented a marked resistance to ferroptosis.
Ever since therecognition of the privileged position of a-tocopherol as Nature’s premier lipid-soluble Radical-Trapping Antioxidants, researchers have developed with success synthetic compounds with increased reactivity towards peroxyl radicals.
Wednesday, March 29, 2017
Individualized exergame training improves postural control in advanced degenerative spinocerebellar ataxia: A rater-blinded, intra-individually controlled trial
Conny Schatton, Matthis Synofzik, Zofia Fleszar, Martin A. Giese, Ludger Schöls, Winfried Ilg, Parkinsonism & Related Disorders, Available online 28 March 2017, ISSN 1353-8020, doi:10.1016/j.parkreldis.2017.03.016.
Treatment options are rare in degenerative ataxias, especially in advanced, multisystemic disease. Exergame training might offer a novel treatment strategy, but its effectiveness has not been investigated in advanced stages.
The training improvement of 2.5 SARA points indicates a meaningful improvement, given that a reduction of one SARA point is generally considered as clinically relevant. It represents a treatment effect equivalent to gaining back functional performance of 1.5 years of natural disease progression (e.g. progression in Friedreich’s Ataxia: 1.4 point SARA increase/year). Interestingly, the 2.5 SARA point training improvement is in the same range as training via exergames or via physiotherapy in mild-to-moderate degenerative ataxia. Thus, even largely nonambulatory subjects with advanced degenerative ataxia are still capable of training induced improvements, despite far more progressed and multisystemic neurodegeneration.
This study provides first evidence that, even in advanced stages, subjects with degenerative ataxia may benefit from individualized training, with effects translating into daily living and improving underlying control mechanisms. The proposed training strategy can be performed at home, is motivating and facilitates patient self-empowerment.
Treatment options are rare in degenerative ataxias, especially in advanced, multisystemic disease. Exergame training might offer a novel treatment strategy, but its effectiveness has not been investigated in advanced stages.
The training improvement of 2.5 SARA points indicates a meaningful improvement, given that a reduction of one SARA point is generally considered as clinically relevant. It represents a treatment effect equivalent to gaining back functional performance of 1.5 years of natural disease progression (e.g. progression in Friedreich’s Ataxia: 1.4 point SARA increase/year). Interestingly, the 2.5 SARA point training improvement is in the same range as training via exergames or via physiotherapy in mild-to-moderate degenerative ataxia. Thus, even largely nonambulatory subjects with advanced degenerative ataxia are still capable of training induced improvements, despite far more progressed and multisystemic neurodegeneration.
This study provides first evidence that, even in advanced stages, subjects with degenerative ataxia may benefit from individualized training, with effects translating into daily living and improving underlying control mechanisms. The proposed training strategy can be performed at home, is motivating and facilitates patient self-empowerment.
Tuesday, March 28, 2017
Nonreplicative genomic HSV-1 derived vectors for dorsal root ganglion gene therapy of Friedreich´s ataxia
María Ventosa Rosales, Directores de la Tesis: Filip Lim (dir. tes.) Lectura: En la Universidad Autónoma de Madrid ( España ) en 2016. Idioma: inglés
Our approach has consisted on the construction and preliminary characterization of a high capacity nonreplicative genomic HSV-1 vector carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1. We show that the nonreplicative HSV-1 genomic vector deleted for 23 kb maintains its growth capacity and the FXN transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression.
Transduction of cultured fetal rat DRG neurons with the 27_4_Or2_β22 FXNinlZ vector results in sustained expression of human FXN transcripts and FXN protein. Rat footpad inoculation with the 27_4_Or2_β22 FXNinlZ vector results in human FXN transgene delivery to the DRG, with expression persisting for at least 1 month.
Our results support the feasibility of using this vector for sustained neuronal expression of human FXN for future FRDA gene therapy.
Our approach has consisted on the construction and preliminary characterization of a high capacity nonreplicative genomic HSV-1 vector carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1. We show that the nonreplicative HSV-1 genomic vector deleted for 23 kb maintains its growth capacity and the FXN transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression.
Transduction of cultured fetal rat DRG neurons with the 27_4_Or2_β22 FXNinlZ vector results in sustained expression of human FXN transcripts and FXN protein. Rat footpad inoculation with the 27_4_Or2_β22 FXNinlZ vector results in human FXN transgene delivery to the DRG, with expression persisting for at least 1 month.
Our results support the feasibility of using this vector for sustained neuronal expression of human FXN for future FRDA gene therapy.
Sunday, March 19, 2017
Mitochondrial biogenesis in neurodegeneration
Li, P. A., Hou, X. and Hao, S. (2017), J. Neurosci. Res.. doi: 10.1002/jnr.24042
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral stroke, and others are common neurological disorders that affect millions of people very year. Although there have been advancements in development in the areas of molecular biology, genetics, and pharmaceutical sciences, there are still no effective treatments for these diseases. Activation of mitochondrial biogenesis is a novel therapeutic target that may provide help to inhibit the disease progression or improve the recovery.
Under pathological stresses, mitochondria generate extra amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and/or receive mass influx of calcium. These events trigger the formation of mitochondrial permeability transition pore (MPTP).The MPTP permits proapoptotic molecules to be released from the mitochondria to either the cytosol or nucleus, whereby triggering caspase-dependent and caspase-independent cell death pathways and eventually leading to neurodegeneration. Because of its critical role in mediating neurodegeneration, mitochondrion has been identified as a major target for neuroprotection. Stimulation of mitochondrial biogenesis is a novel approach to preserve mitochondrial function and to improve neuronal cell survival after various injuries.
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral stroke, and others are common neurological disorders that affect millions of people very year. Although there have been advancements in development in the areas of molecular biology, genetics, and pharmaceutical sciences, there are still no effective treatments for these diseases. Activation of mitochondrial biogenesis is a novel therapeutic target that may provide help to inhibit the disease progression or improve the recovery.
Under pathological stresses, mitochondria generate extra amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and/or receive mass influx of calcium. These events trigger the formation of mitochondrial permeability transition pore (MPTP).The MPTP permits proapoptotic molecules to be released from the mitochondria to either the cytosol or nucleus, whereby triggering caspase-dependent and caspase-independent cell death pathways and eventually leading to neurodegeneration. Because of its critical role in mediating neurodegeneration, mitochondrion has been identified as a major target for neuroprotection. Stimulation of mitochondrial biogenesis is a novel approach to preserve mitochondrial function and to improve neuronal cell survival after various injuries.
Saturday, March 18, 2017
Resveratrol regulates microglia M1/M2 polarization via PGC-1α in conditions of neuroinflammatory injury
Xiaodong Yang, Shaoqing Xu, Yiwei Qian, Qin Xiao, Brain, Behavior, and Immunity, Available online 6 March 2017, ISSN 0889-1591, doi:10.1016/j.bbi.2017.03.003.
Microglia are the primary cells that exert immune function in the central nervous system (CNS), and accumulating evidence suggests that microglia act as key players in the initiation of neurodegenerative diseases.
We propose that overexpression PGC-1α by resveratrol could be a potential therapeutic approach to suppress neuroinflammation by regulating microglia polarization.
Microglia are the primary cells that exert immune function in the central nervous system (CNS), and accumulating evidence suggests that microglia act as key players in the initiation of neurodegenerative diseases.
We propose that overexpression PGC-1α by resveratrol could be a potential therapeutic approach to suppress neuroinflammation by regulating microglia polarization.
Friday, March 17, 2017
A wearable proprioceptive stabilizer for rehabilitation of limb and gait ataxia in hereditary cerebellar ataxias: a pilot open-labeled study
Luca Leonardi, Maria Gabriella Aceto, Christian Marcotulli, Giuseppe Arcuria, Mariano Serrao, Francesco Pierelli, Paolo Paone, Alessandro Filla, Alessandro Roca, Carlo Casali; Neurol Sci (2017) 38: 459. doi:10.1007/s10072-016-2800-x
The aim of this pilot study is to test the feasibility and effectiveness of a wearable proprioceptive stabilizer that emits focal mechanical vibrations in patients affected by hereditary cerebellar ataxias. Eleven adult patients with a confirmed genetic diagnosis of autosomal dominant spinocerebellar ataxia or Friedreich’s ataxia were asked to wear an active device for 3 weeks.
This small open-labeled study shows preliminary evidence that focal mechanical vibration exerted by a wearable proprioceptive stabilizer might improve limb and gait ataxia in patients affected by hereditary cerebellar ataxias.
The aim of this pilot study is to test the feasibility and effectiveness of a wearable proprioceptive stabilizer that emits focal mechanical vibrations in patients affected by hereditary cerebellar ataxias. Eleven adult patients with a confirmed genetic diagnosis of autosomal dominant spinocerebellar ataxia or Friedreich’s ataxia were asked to wear an active device for 3 weeks.
This small open-labeled study shows preliminary evidence that focal mechanical vibration exerted by a wearable proprioceptive stabilizer might improve limb and gait ataxia in patients affected by hereditary cerebellar ataxias.
Thursday, March 16, 2017
Voyager Therapeutics: Advance multiple preclinical programs towards clinical trials, with the goal of filing three IND applications within the next 24-months VY-FXN01 program
Voyager Therapeutics Reports Fourth Quarter and Full Year 2016 Financial Results and Corporate Highlights. CAMBRIDGE, Mass., March 15, 2017 (GLOBE NEWSWIRE) . Corporate Goals and 2017 Financial Guidance
Voyager remains committed to becoming the leading gene therapy company focused on severe diseases of the CNS with expertise in discovery, development, manufacturing and commercialization of gene therapy products for people living with these devastating diseases. The significant accomplishments achieved during 2016 provide a solid foundation for continued progress during 2017 and beyond, as measured by the planned achievements of the following corporate goals and 2017 financial guidance:
-Advance multiple preclinical programs towards clinical trials, with the goal of filing three IND applications within the next 24-months for the VY-SOD101, VY-HTT01, and VY-FXN01 (for Friedreich’s ataxia) programs.
Voyager remains committed to becoming the leading gene therapy company focused on severe diseases of the CNS with expertise in discovery, development, manufacturing and commercialization of gene therapy products for people living with these devastating diseases. The significant accomplishments achieved during 2016 provide a solid foundation for continued progress during 2017 and beyond, as measured by the planned achievements of the following corporate goals and 2017 financial guidance:
-Advance multiple preclinical programs towards clinical trials, with the goal of filing three IND applications within the next 24-months for the VY-SOD101, VY-HTT01, and VY-FXN01 (for Friedreich’s ataxia) programs.
Tuesday, March 14, 2017
Affordable orphan drugs: a role for not-for-profit organizations
Davies, E. H., Fulton, E., Brook, D., and Hughes, D. A. (2017). Br J Clin Pharmacol, doi: 10.1111/bcp.13240.
Although the regulatory steps required to obtain an MA for an orphan drug are numerous and challenging, they are not insurmountable and can be achieved by not-for-profit organizations that are socially motivated to reduce the costs of orphan drugs to the payers of healthcare. Opportunities for orphan drug development resulting in affordable products lie mainly with repurposed drugs.
Although the regulatory steps required to obtain an MA for an orphan drug are numerous and challenging, they are not insurmountable and can be achieved by not-for-profit organizations that are socially motivated to reduce the costs of orphan drugs to the payers of healthcare. Opportunities for orphan drug development resulting in affordable products lie mainly with repurposed drugs.
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