Siyuan Zhang, Marek Napierala, Jill S. Napierala; Trends in Pharmacological Sciences, Volume 40, Issue 4, 2019, Pages 229-233, doi:10.1016/j.tips.2019.02.001.
Friedreich’s ataxia (FRDA) is a progressive disease affecting multiple organs that is caused by systemic insufficiency of the mitochondrial protein frataxin. Current therapeutic strategies aim to elevate frataxin levels and/or alleviate the consequences of frataxin deficiency. Recent significant advances in the FRDA therapeutic pipeline are bringing patients closer to a cure.
Monday, March 25, 2019
Thursday, March 21, 2019
Ion Mobility-Mass Spectrometry Reveals Details of Formation and Structure for GAA·TCC DNA and RNA Triplexes
Jiawei Li, Alexander Begbie, Belinda J. Boehm, Alexander Button, Charles Whidborne, Yannii Pouferis, David M. Huang, Tara L. Pukala; J. Am. Soc. Mass Spectrom. (2019) 30: 103. doi:10.1007/s13361-018-2077-9
DNA and RNA triplexes are thought to play key roles in a range of cellular processes such as gene regulation and epigenetic remodeling and have been implicated in human disease such as Friedreich’s ataxia. In this work, ion mobility-mass spectrometry (IM-MS) is used with supporting UV-visible spectroscopy to investigate DNA triplex assembly, considering stability and specificity, for GAA·TTC oligonucleotide sequences of relevance to Friedreich’s ataxia.
DNA and RNA triplexes are thought to play key roles in a range of cellular processes such as gene regulation and epigenetic remodeling and have been implicated in human disease such as Friedreich’s ataxia. In this work, ion mobility-mass spectrometry (IM-MS) is used with supporting UV-visible spectroscopy to investigate DNA triplex assembly, considering stability and specificity, for GAA·TTC oligonucleotide sequences of relevance to Friedreich’s ataxia.
Wednesday, March 20, 2019
Patient reported outcomes in Friedreich's Ataxia after withdrawal from Idebenone
Cook, A. , Boesch, S. , Heck, S. , Brunt, E. , Klockgether, T. , Schöls, L. , Schulz, A. and Giunti, P. (2019). Acta Neurol Scand. Accepted Author Manuscript. doi:10.1111/ane.13088
This study provides no data to suggest that FRDA patients could correctly determine their treatment assignment over a 2‐month period. We hope that this study design will help inform future trials so that patients’ experiences of symptoms are more reliably measured.
This study provides no data to suggest that FRDA patients could correctly determine their treatment assignment over a 2‐month period. We hope that this study design will help inform future trials so that patients’ experiences of symptoms are more reliably measured.
Tuesday, March 19, 2019
CRISPR-cas gene-editing as plausible treatment of neuromuscular and nucleotide-repeat-expansion diseases: A systematic review.
Babačić H, Mehta A, Merkel O, Schoser B (2019); PLOS ONE 14(2): e0212198. doi:10.1371/journal.pone.0212198
Here we give a systematic summary on the preclinical development of CRISPR-cas for therapeutic purposes in NMGDs. Furthermore, we address the clinical interpretability of the findings, giving a comprehensive overview of the current state of the art. Duchenne’s muscular dystrophy (DMD) paves the way forward, with 26 out of 42 studies reporting different strategies on DMD gene editing in different models of the disease. Most of the strategies aimed for permanent exon skipping by deletion with CRISPR-cas. Successful silencing of the mHTT gene with CRISPR-cas led to successful reversal of the neurotoxic effects in the striatum of mouse models of Huntington’s disease. Many other strategies have been explored, including epigenetic regulation of gene expression, in cellular and animal models of: myotonic dystrophy, Fraxile X syndrome, ataxias, and other less frequent dystrophies.
Still, before even considering the clinical application of CRISPR-cas, three major bottlenecks need to be addressed: efficacy, safety, and delivery of the systems. This requires a collaborative approach in the research community, while having ethical considerations in mind.
Here we give a systematic summary on the preclinical development of CRISPR-cas for therapeutic purposes in NMGDs. Furthermore, we address the clinical interpretability of the findings, giving a comprehensive overview of the current state of the art. Duchenne’s muscular dystrophy (DMD) paves the way forward, with 26 out of 42 studies reporting different strategies on DMD gene editing in different models of the disease. Most of the strategies aimed for permanent exon skipping by deletion with CRISPR-cas. Successful silencing of the mHTT gene with CRISPR-cas led to successful reversal of the neurotoxic effects in the striatum of mouse models of Huntington’s disease. Many other strategies have been explored, including epigenetic regulation of gene expression, in cellular and animal models of: myotonic dystrophy, Fraxile X syndrome, ataxias, and other less frequent dystrophies.
Still, before even considering the clinical application of CRISPR-cas, three major bottlenecks need to be addressed: efficacy, safety, and delivery of the systems. This requires a collaborative approach in the research community, while having ethical considerations in mind.
Saturday, March 16, 2019
Inherited Ataxia and Intrathecal Baclofen for the Treatment of Spasticity and Painful Spasms
Berntsson S, G, Gauffin H, Melberg A, Holtz A, Landtblom A, M; Stereotact Funct Neurosurg 2019. doi: 10.1159/000497165
Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury. The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity. A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich’s ataxia were included in this observational multicenter study We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia.
Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury. The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity. A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich’s ataxia were included in this observational multicenter study We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia.
Friday, March 15, 2019
Assessment of cell-free levels of iron and copper in patients with Friedreich’s ataxia
Deepti PathakAchal Kumar SrivastavaSheffali GulatiMoganty R. Rajeswari; Biometals (2019). https://doi.org/10.1007/s10534-019-00186-4
The iron levels mean ± SD (6.2 ± 3.8) in plasma of FRDA patients were found to be significantly decreased as compared to healthy controls mean ± SD (15.2 ± 4.2). A similar trend was observed in case of plasma copper levels in FRDA patient (8.15 ± 4.6) as compared to controls (17.5 ± 3.40). Present results clearly prove abnormal distribution of extra-cellular iron in FRDA patients, which is in accordance with the well established fact of intracellular iron overload, which is the key feature of the pathogenesis of this disease. This can be of importance in understanding the pathophysiology of the disease in association with frataxin/iron. It appears that intracellular sequestration of trace metals in FRDA patients (due to low frataxin) results in their sub-optimal levels in blood plasma (extra-cellular) an observation that can find prognostic application in clinical trials.
The iron levels mean ± SD (6.2 ± 3.8) in plasma of FRDA patients were found to be significantly decreased as compared to healthy controls mean ± SD (15.2 ± 4.2). A similar trend was observed in case of plasma copper levels in FRDA patient (8.15 ± 4.6) as compared to controls (17.5 ± 3.40). Present results clearly prove abnormal distribution of extra-cellular iron in FRDA patients, which is in accordance with the well established fact of intracellular iron overload, which is the key feature of the pathogenesis of this disease. This can be of importance in understanding the pathophysiology of the disease in association with frataxin/iron. It appears that intracellular sequestration of trace metals in FRDA patients (due to low frataxin) results in their sub-optimal levels in blood plasma (extra-cellular) an observation that can find prognostic application in clinical trials.
Wednesday, March 13, 2019
The role of robotic gait training and tDCS in Friedrich ataxia rehabilitation: A case report
Simona Portaro;Margherita Russo;Alessia Bramanti;Antonio Leo;Luana Billeri;Alfredo Manuli;Gianluca La Rosa;Antonino Naro;Rocco Calabrò; Medicine. 98(8):e14447, FEB 2019 DOI: 10.1097/MD.0000000000014447, Publication Date: 2019/02/01
Friedrich ataxia (FA) is the most common inherited neurodegenerative cerebellar ataxic syndrome. In patients with FA, physiotherapy is highly recommended to improve motor function outcome. Cerebellar transcranial direct current stimulation (tDCS) has been demonstrated to be effective in improving symptoms by modulating cerebellar excitability. Recently, robotic rehabilitation with Lokomat-Pro has been used to treat motor impairment in ataxic syndromes by “modulating” cortical plasticity and cerebello-motor connectivity.
Only a single case is described, we found that the combined neuromodulation-neurorobotic approach could become a promising tool in the rehabilitation of cerebellar ataxias, possibly by shaping cerebello-cerebral plasticity and connectivity.
Friedrich ataxia (FA) is the most common inherited neurodegenerative cerebellar ataxic syndrome. In patients with FA, physiotherapy is highly recommended to improve motor function outcome. Cerebellar transcranial direct current stimulation (tDCS) has been demonstrated to be effective in improving symptoms by modulating cerebellar excitability. Recently, robotic rehabilitation with Lokomat-Pro has been used to treat motor impairment in ataxic syndromes by “modulating” cortical plasticity and cerebello-motor connectivity.
Only a single case is described, we found that the combined neuromodulation-neurorobotic approach could become a promising tool in the rehabilitation of cerebellar ataxias, possibly by shaping cerebello-cerebral plasticity and connectivity.
Tuesday, March 12, 2019
Combining nanoparticle and stem cell technologies to develop therapies for Friedreich’s ataxia
IHMRI - Illawarra Health and Medical Research Institute.08/03/2019. Professor Mirella Dottori has been awarded a USA National Ataxia Foundation Grant to continue her research into the neurodegenerative disease, Friedreich’s ataxia (FRDA).
In collaboration with Dr Christina Cortez-Jugo, University of Melbourne, they are using nanoparticles as a vechicle to deliver Frataxin to the diseased cells to see if they can reverse symptoms caused by the faulty gene and could potentially lead to a cure or treatment.
In collaboration with Dr Christina Cortez-Jugo, University of Melbourne, they are using nanoparticles as a vechicle to deliver Frataxin to the diseased cells to see if they can reverse symptoms caused by the faulty gene and could potentially lead to a cure or treatment.
Monday, March 11, 2019
Abnormal Eye Movements in Parkinsonism and Movement Disorders
Ileok Jung, Ji-Soo Kim; J Mov Disord. 2019;12(1):1-13. Published online January 30, 2019 DOI: 10.14802/jmd.18034
Friedreich ataxia (FA) is the most common cause of autosomal recessive ataxias with an onset usually before age 20 years. FA is characterized by ataxia, hyporeflexia, extensor plantar reflexes, neuropathy, cardiomyopathy, and diabetes. FA is mostly due to an unstable GAA repeat expansion within intron 1 of frataxin. Abnormal ocular motor findings of FA include fixation instability manifesting as SWJs and ocular flutter . While saccadic velocity is essentially normal, saccadic latency is prolonged. The latency correlates with clinical measures of disease severity. Saccades may be both hypo- and hypermetric. SP and the VOR may be impaired Caloric tests are abnormal in the majority of FA patients. Thus, severe vestibulopathy with essentially normal saccadic velocity are hallmarks of FA and differentiate it from a number of dominant SCA.
Friedreich ataxia (FA) is the most common cause of autosomal recessive ataxias with an onset usually before age 20 years. FA is characterized by ataxia, hyporeflexia, extensor plantar reflexes, neuropathy, cardiomyopathy, and diabetes. FA is mostly due to an unstable GAA repeat expansion within intron 1 of frataxin. Abnormal ocular motor findings of FA include fixation instability manifesting as SWJs and ocular flutter . While saccadic velocity is essentially normal, saccadic latency is prolonged. The latency correlates with clinical measures of disease severity. Saccades may be both hypo- and hypermetric. SP and the VOR may be impaired Caloric tests are abnormal in the majority of FA patients. Thus, severe vestibulopathy with essentially normal saccadic velocity are hallmarks of FA and differentiate it from a number of dominant SCA.
Sunday, March 10, 2019
Progress in understanding Friedreich’s ataxia using human induced pluripotent stem cells
Anna M. Schreiber, Julia O. Misiorek, Jill S. Napierala & Marek Napierala (2019), Expert Opinion on Orphan Drugs, 7:2, 81-90, DOI: 10.1080/21678707.2019.1562334
The versatility of iPSC-derived cellular models of FRDA is advantageous for developing new therapeutic strategies, and rigorous testing in such models will be critical for approval of the first treatment for FRDA. Creating a well-characterized and diverse set of iPSC lines, including appropriate isogenic controls, will facilitate achieving this goal. Also, improvement of differentiation protocols, especially towards proprioceptive sensory neurons and organoid generation, is necessary to utilize the full potential of iPSC technology in the drug discovery process.
The versatility of iPSC-derived cellular models of FRDA is advantageous for developing new therapeutic strategies, and rigorous testing in such models will be critical for approval of the first treatment for FRDA. Creating a well-characterized and diverse set of iPSC lines, including appropriate isogenic controls, will facilitate achieving this goal. Also, improvement of differentiation protocols, especially towards proprioceptive sensory neurons and organoid generation, is necessary to utilize the full potential of iPSC technology in the drug discovery process.
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