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.
Tuesday, March 19, 2019
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.
Saturday, March 9, 2019
Quantitative assessment of cerebellar ataxia, through automated limb functional tests
Ragil Krishna, Pubudu N. Pathirana, Malcolm Horne, Laura Power and David J. Szmulewicz; Journal of NeuroEngineering and Rehabilitation 2019 16:31 doi:10.1186/s12984-019-0490-3
This paper investigates automated versions of three commonly used tests: Finger to Nose test (FNT), test for upper limb Dysdiadochokinesia Test (DDK) and Heel to Shin Test (HST), in evaluating disability due to CA.
Conclusion: For the predominantly translational movement in the upper limb FNT, the rotation captures disability and for the DDK test with predominantly rotational movements, the linear acceleration captures the disability but cannot be extended to the lower limb HST. The orthogonal direction manifestation of ataxia attributed to sensory measurements was determined for each test.
This paper investigates automated versions of three commonly used tests: Finger to Nose test (FNT), test for upper limb Dysdiadochokinesia Test (DDK) and Heel to Shin Test (HST), in evaluating disability due to CA.
Conclusion: For the predominantly translational movement in the upper limb FNT, the rotation captures disability and for the DDK test with predominantly rotational movements, the linear acceleration captures the disability but cannot be extended to the lower limb HST. The orthogonal direction manifestation of ataxia attributed to sensory measurements was determined for each test.
Friday, March 8, 2019
Identification of a novel missense mutation in Friedreich's ataxia –FXNW168R
Clark, E. , Strawser, C. , Schadt, K. and Lynch, D. R. (2019), Ann Clin Transl Neurol. doi:10.1002/acn3.728
Friedreich's ataxia, characterized by decreased expression of frataxin protein, is caused by GAA trinucleotide repeats within intron 1 in 98% of patients. Two percent of patients carry GAA repeats in conjunction with a point mutation. In this work, we find that frataxinW168R, a novel disease‐causing missense mutation, is expressed predominantly as the intermediate frataxin42‐210 form, with very little expression of mature frataxin81‐210 form. Its localization to mitochondria is not impaired. Additionally, increasing frataxinW168R precursor levels do not lead to an increase in mature frataxin levels, suggesting these patients will require alternative approaches to repair frataxin processing in order to treat the disorder in a disease‐modifying manner.
Friedreich's ataxia, characterized by decreased expression of frataxin protein, is caused by GAA trinucleotide repeats within intron 1 in 98% of patients. Two percent of patients carry GAA repeats in conjunction with a point mutation. In this work, we find that frataxinW168R, a novel disease‐causing missense mutation, is expressed predominantly as the intermediate frataxin42‐210 form, with very little expression of mature frataxin81‐210 form. Its localization to mitochondria is not impaired. Additionally, increasing frataxinW168R precursor levels do not lead to an increase in mature frataxin levels, suggesting these patients will require alternative approaches to repair frataxin processing in order to treat the disorder in a disease‐modifying manner.
Thursday, March 7, 2019
Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism
Nicholas G Fox, Xiaodi Yu, Xidong Feng, Henry J Bailey, Alain Martelli, Joseph F. Nabhan, Claire Strain-Damerell, Christine Bulawa, Wyatt W. Yue, Seungil Han; bioRxiv 561795; doi: 10.1101/561795
Our structure sheds light on how FXN facilitates ISC production through unlocking the zinc inhibition and stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and offers an explanation of how FRDA clinical mutations affect complex formation and FXN activation.
Our structure sheds light on how FXN facilitates ISC production through unlocking the zinc inhibition and stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and offers an explanation of how FRDA clinical mutations affect complex formation and FXN activation.
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