D. Jackson, R. Hassam, L. Donelan, R. Peverill, Heart, Lung and Circulation, Volume 25, Supplement 2, August 2016, Page S80, ISSN 1443-9506, http://dx.doi.org/10.1016/j.hlc.2016.06.185.
In FRDA there are complex interrelationships between global longitudinal strain and tissue Doppler imaging mitral annular velocities, but the strongest correlate of the severity of the genetic abnormality (GAA1) is atrial contraction.
Monday, August 8, 2016
Sunday, August 7, 2016
Translating HDAC inhibitors in Friedreich’s ataxia
Elisabetta Soragni & Joel M. Gottesfeld. Expert Opinion on Orphan Drugs, Published online: 31 Jul 2016 DOI:10.1080/21678707.2016.1215910
Expert opinion: 2-aminobenzamide class I HDAC inhibitors are attractive therapeutic small molecules for FRDA. These molecules increase FXN gene expression in human neuronal cells derived from patient induced pluripotent stem cells, and in two mouse models for the disease, as well as in circulating lymphocytes in patients treated in a phase Ib clinical trial. Medicinal chemistry efforts have identified compounds with improved brain penetration, metabolic stability and efficacy in the human neuronal cell model. A clinical candidate will soon be identified for further human testing
Expert opinion: 2-aminobenzamide class I HDAC inhibitors are attractive therapeutic small molecules for FRDA. These molecules increase FXN gene expression in human neuronal cells derived from patient induced pluripotent stem cells, and in two mouse models for the disease, as well as in circulating lymphocytes in patients treated in a phase Ib clinical trial. Medicinal chemistry efforts have identified compounds with improved brain penetration, metabolic stability and efficacy in the human neuronal cell model. A clinical candidate will soon be identified for further human testing
Saturday, August 6, 2016
Voice in Friedreich Ataxia
Adam P. Vogel, Mayumi I. Wardrop, Joanne E. Folker, Matthis Synofzik, Louise A. Corben, Martin B. Delatycki, Shaheen N. Awan, Journal of Voice, Available online 5 August 2016, ISSN 0892-199 doi:10.1016/j.jvoice.2016.04.015.
Objective: To describe the voice profile of individuals with FRDA to inform outcome marker development and goals of speech therapy.
Although dysphonia severity in FRDA did not correlate significantly with overall disease severity, speaking rate and syllabic duration significantly correlated with age at disease onset and disease duration, and also have an effect on listener perception of dysphonia. The relationship between dysphonia and dysarthria in FRDA suggests that reducing overall dysphonia severity via therapeutic techniques that improve phonatory stability and increase speaking rate is a viable target for speech therapy.
Treatments designed to improve communicative function should consider therapeutic approaches that aim to improve phonatory stability (eg, use of increased respiratory support prior to the initiation of voicing), and thereby improve vocal pitch and quality control. In addition, therapeutic methods that aid the patient in increasing rate of speech may also be of benefit.
Objective: To describe the voice profile of individuals with FRDA to inform outcome marker development and goals of speech therapy.
Although dysphonia severity in FRDA did not correlate significantly with overall disease severity, speaking rate and syllabic duration significantly correlated with age at disease onset and disease duration, and also have an effect on listener perception of dysphonia. The relationship between dysphonia and dysarthria in FRDA suggests that reducing overall dysphonia severity via therapeutic techniques that improve phonatory stability and increase speaking rate is a viable target for speech therapy.
Treatments designed to improve communicative function should consider therapeutic approaches that aim to improve phonatory stability (eg, use of increased respiratory support prior to the initiation of voicing), and thereby improve vocal pitch and quality control. In addition, therapeutic methods that aid the patient in increasing rate of speech may also be of benefit.
Friday, August 5, 2016
The Pediatric Cerebellum in Inherited Neurodegenerative Disorders: A Pattern-recognition Approach
Susan I. Blaser, Maja Steinlin, Almundher Al-Maawali, Grace Yoon, Neuroimaging Clinics of North America, Volume 26, Issue 3, August 2016, Pages 373-416, ISSN 1052-5149, doi:10.1016/j.nic.2016.03.007.
FRIEDREICH ATAXIA IS THE PROTOTYPE FOR NEURODEGENERATIVE DISORDERS WITH PREDOMINANT SPINAL CORD ATROPHY:
Assessment of the upper cervical cord is predominantly useful in the evaluation of patients with Friedreich ataxia (FRDA/FXN), in whom cord thinning caused by neuronal loss in the spinal ganglia and Clarke column may be the first imaging clue to the disorder.
Involvement of the cerebellum was initially considered a rare feature in FRDA, however, volumetric analysis of the cerebellum in FRDA confirms volume loss in the rostral vermis, dorsal medulla, the dentate nuclei, the peridentate white matter, and the associated superior cerebellar peduncle.
FRIEDREICH ATAXIA IS THE PROTOTYPE FOR NEURODEGENERATIVE DISORDERS WITH PREDOMINANT SPINAL CORD ATROPHY:
Assessment of the upper cervical cord is predominantly useful in the evaluation of patients with Friedreich ataxia (FRDA/FXN), in whom cord thinning caused by neuronal loss in the spinal ganglia and Clarke column may be the first imaging clue to the disorder.
Involvement of the cerebellum was initially considered a rare feature in FRDA, however, volumetric analysis of the cerebellum in FRDA confirms volume loss in the rostral vermis, dorsal medulla, the dentate nuclei, the peridentate white matter, and the associated superior cerebellar peduncle.
Thursday, August 4, 2016
Long-term treatment with thiamine as possible medical therapy for Friedreich ataxia
Antonio Costantini, Tiziana Laureti, Maria Immacolata Pala, Marco Colangeli, Simona Cavalieri, Elisa Pozzi, Alfredo Brusco, Sandro Salvarani, Carlo Serrati, Roberto Fancellu. Original Communication, Journal of Neurology pp 1-9, First online: 03 August 2016. DOI: 10.1007/s00415-016-8244-7
Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment. Thiamine administration ranged from 80 to 930 days and was effective in improving total SARA scores from 26.6 ± 7.7 to 21.5 ± 6.2 (p < 0.02). Moreover, deep tendon reflexes reappeared in 57 % of patients with areflexia at baseline, and swallowing improved in 63 % of dysphagic patients. Clinical improvement was stable in all patients, who did not show worsening even after 2 years of treatment. In a subgroup of 13 patients who performed echocardiogram before and during treatment, interventricular septum thickness reduced significantly (p < 0.02). Frataxin mRNA blood levels were modestly increased in one-half of treated patients. We suppose that a focal thiamine deficiency may contribute to a selective neuronal damage in the areas involved in FRDA. Further studies are mandatory to evaluate thiamine role on FXN regulation, to exclude placebo effect, to verify our clinical results, and to confirm restorative and neuroprotective action of thiamine.
Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment. Thiamine administration ranged from 80 to 930 days and was effective in improving total SARA scores from 26.6 ± 7.7 to 21.5 ± 6.2 (p < 0.02). Moreover, deep tendon reflexes reappeared in 57 % of patients with areflexia at baseline, and swallowing improved in 63 % of dysphagic patients. Clinical improvement was stable in all patients, who did not show worsening even after 2 years of treatment. In a subgroup of 13 patients who performed echocardiogram before and during treatment, interventricular septum thickness reduced significantly (p < 0.02). Frataxin mRNA blood levels were modestly increased in one-half of treated patients. We suppose that a focal thiamine deficiency may contribute to a selective neuronal damage in the areas involved in FRDA. Further studies are mandatory to evaluate thiamine role on FXN regulation, to exclude placebo effect, to verify our clinical results, and to confirm restorative and neuroprotective action of thiamine.
Wednesday, August 3, 2016
Agilis Biotherapeutics Announces FDA Orphan Drug Designation for the Treatment of Friedreich’s Ataxia (FA)
August 02, 2016 08:30 AM Eastern Daylight Time. August 02, 2016.
First Gene Therapy Candidate to Receive Designation for FA.
CAMBRIDGE, Mass.--(BUSINESS WIRE)--Agilis Biotherapeutics, LLC (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation to Agilis’ gene therapy product candidate, AGIL-FA, being developed for the treatment of Friedreich’s ataxia (FA).
First Gene Therapy Candidate to Receive Designation for FA.
CAMBRIDGE, Mass.--(BUSINESS WIRE)--Agilis Biotherapeutics, LLC (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation to Agilis’ gene therapy product candidate, AGIL-FA, being developed for the treatment of Friedreich’s ataxia (FA).
Tuesday, August 2, 2016
Pfizer buys gene therapy company - Is it a good investment?
Rare Disease Report. James Radke, PhD, Published Online: Monday, Aug 01, 2016
Pfizer has acquired gene therapy company Bamboo Therapeutics for a deal that could be worth up to $645 million.
Bamboo therapeutics is developing gene therapy for Giant Axonal Neuropathy (GAN) that is currently in phase 1/2 trial. The company also has gene therapies in development for 3 other neuromuscular diseases – Duchenne muscular dystrophy, Canavan, and Friedreich’s ataxia.
Pfizer has acquired gene therapy company Bamboo Therapeutics for a deal that could be worth up to $645 million.
Bamboo therapeutics is developing gene therapy for Giant Axonal Neuropathy (GAN) that is currently in phase 1/2 trial. The company also has gene therapies in development for 3 other neuromuscular diseases – Duchenne muscular dystrophy, Canavan, and Friedreich’s ataxia.
Monday, August 1, 2016
Recent advances in understanding transcription termination by RNA polymerase II.
Travis J. Loya and Daniel Reinesa, F1000Research 2016, 5(F1000 Faculty Rev):1478 doi: 10.12688/f1000research.8455.1
R-loop-mediated termination is also proposed to play a role in Friedrich’s ataxia. It was suggested that R-loops aberrantly form in the frataxin gene as a result of expansion of GAA repeats in its first intron 58, 59. Mutated frataxin exhibits features of heterochromatin, H3K9 methylation, and decreased acetylation of H3 and H4, thus a reduced level of expression is to be expected. However, the altered gene also shares many characteristics of canonical R-loop-terminated genes, including a polyA-signal-like sequence upstream of the expansion, followed by a GU-rich sequence similar to the downstream element of polyA signals. This has led to a proposal that the mutated frataxin allele is the victim of premature termination, which contributes to its low level of expression in patients. While experimental verification is still needed, this is an interesting model for a role of termination in disease.
R-loop-mediated termination is also proposed to play a role in Friedrich’s ataxia. It was suggested that R-loops aberrantly form in the frataxin gene as a result of expansion of GAA repeats in its first intron 58, 59. Mutated frataxin exhibits features of heterochromatin, H3K9 methylation, and decreased acetylation of H3 and H4, thus a reduced level of expression is to be expected. However, the altered gene also shares many characteristics of canonical R-loop-terminated genes, including a polyA-signal-like sequence upstream of the expansion, followed by a GU-rich sequence similar to the downstream element of polyA signals. This has led to a proposal that the mutated frataxin allele is the victim of premature termination, which contributes to its low level of expression in patients. While experimental verification is still needed, this is an interesting model for a role of termination in disease.
Sunday, July 31, 2016
Keys to overcoming the challenge of diagnosing autosomal recessive spinocerebellar ataxia / Claves para afrontar el reto diagnóstico de las heredoataxias recesivas
M. Arias, Neurología, Available online 25 July 2016, ISSN 0213-4853, doi:10.1016/j.nrl.2016.06.006
Una cuidadosa evaluación clínica, acompañada de la determinación de ciertos marcadores de laboratorio, la valoración de los datos del estudio electroneuromiográfico y los hallazgos del estudio de resonancia magnética, ayudarán al clínico a establecer unas determinadas sospechas diagnósticas, que siempre procurará confirmar con la detección de la mutación genética causal. El hallazgo de la mutación es decisivo para establecer el pronóstico y consejo genético, además permitirá indicar un tratamiento eficaz en determinadas entidades. Sin diagnóstico genético no será posible realizar investigación básica ni tampoco poner en marcha ensayos terapéuticos.
A thorough assessment of clinical phenotype, laboratory tests, nerve conduction studies, and an magnetic resonance imaging study may help establish a suspected diagnosis, which should be confirmed by detecting the underlying genetic mutation. A positive genetic test result is necessary to determine prognosis and provide adequate genetic counselling, and will also permit appropriate treatment of some entities. Without a genetic diagnosis, conducting basic research and therapeutic trials will not be possible.
Una cuidadosa evaluación clínica, acompañada de la determinación de ciertos marcadores de laboratorio, la valoración de los datos del estudio electroneuromiográfico y los hallazgos del estudio de resonancia magnética, ayudarán al clínico a establecer unas determinadas sospechas diagnósticas, que siempre procurará confirmar con la detección de la mutación genética causal. El hallazgo de la mutación es decisivo para establecer el pronóstico y consejo genético, además permitirá indicar un tratamiento eficaz en determinadas entidades. Sin diagnóstico genético no será posible realizar investigación básica ni tampoco poner en marcha ensayos terapéuticos.
A thorough assessment of clinical phenotype, laboratory tests, nerve conduction studies, and an magnetic resonance imaging study may help establish a suspected diagnosis, which should be confirmed by detecting the underlying genetic mutation. A positive genetic test result is necessary to determine prognosis and provide adequate genetic counselling, and will also permit appropriate treatment of some entities. Without a genetic diagnosis, conducting basic research and therapeutic trials will not be possible.
Friday, July 29, 2016
OCT in Central Nervous System Diseases
Editors: Grzybowski, Andrzej, Barboni, Piero (Eds.) SPRINGER, ISBN 978-3-319-24085-5
The disorders considered include multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, intracranial hypertension, Friedreich’s ataxia, schizophrenia, hereditary optic neuropathies, glaucoma, and amblyopia. Individual chapters are also devoted to OCT technique, new OCT technology in neuro-ophthalmology, OCT and pharmacological treatment, and the use of OCT in animal models. By documenting the ability of OCT to provide key information on CNS diseases, this book illustrates convincingly that the eye is indeed the “window to the brain”.
The disorders considered include multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, intracranial hypertension, Friedreich’s ataxia, schizophrenia, hereditary optic neuropathies, glaucoma, and amblyopia. Individual chapters are also devoted to OCT technique, new OCT technology in neuro-ophthalmology, OCT and pharmacological treatment, and the use of OCT in animal models. By documenting the ability of OCT to provide key information on CNS diseases, this book illustrates convincingly that the eye is indeed the “window to the brain”.
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