ClinicalTrials.gov Identifier: NCT04255680, February 5, 2020
Intervention: Diagnostic Test: Buccal Swabs and Blood Draws
Sponsors: Chondrial Therapeutics, Inc.; Children's Hospital of Philadelphia. Enrolling by invitation
To test the variability of specific ribonucleic acid (RNA) and proteins as well as frataxin levels in samples of blood and buccal cells taken directly from patients with Friedreich's ataxia (FRDA) in order to confirm potential new biomarkers of disease in patients with FRDA.
Friday, February 7, 2020
Monday, February 3, 2020
DDIEM: Drug Database for Inborn Errors of Metabolism
Marwa Abdelhakim, Eunice McMurray, Ali Raza Syed, Senay Kafkas, Allan Anthony Kamau, Paul N Schofield, Robert Hoehndorf, bioRxiv 2020.01.08.897223; doi: doi:10.1101/2020.01.08.897223
We gathered data on therapeutic strategies for 299 diseases into the Drug Database for Inborn Errors of Metabolism (DDIEM), (FA included). Therapeutic approaches, including both successful and ineffective treatments, were manually classified by their mechanisms of action using a new ontology. Conclusions: We present a manually curated, ontologically formalized knowledgebase of drugs, therapeutic procedures, and mitigated phenotypes.
We gathered data on therapeutic strategies for 299 diseases into the Drug Database for Inborn Errors of Metabolism (DDIEM), (FA included). Therapeutic approaches, including both successful and ineffective treatments, were manually classified by their mechanisms of action using a new ontology. Conclusions: We present a manually curated, ontologically formalized knowledgebase of drugs, therapeutic procedures, and mitigated phenotypes.
NfL and pNfH are increased in Friedreich’s ataxia
Stefanie Nicole Hayer, Inga Liepelt, Christian Barro, Carlo Wilke, Jens Kuhle, Peter Martus, Ludger Schöls, the EFACTS study group; J Neurol (2020). doi:10.1007/s00415-020-09722-6
Serum levels of NfL and pNfH are elevated in Friedreich’s ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up—a period relevant for biomarkers indicating treatment effects—we found NfL levels to be stable.
Serum levels of NfL and pNfH are elevated in Friedreich’s ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up—a period relevant for biomarkers indicating treatment effects—we found NfL levels to be stable.
Sunday, February 2, 2020
Ocular Involvement in Friedreich Ataxia Patients and its Relationship with Neurological Disability, a Follow-up Study
Rojas, P.; Ramírez, A.I.; Hoz, R.; Cadena, M.; Ferreras, A.; Monsalve, B.; Salobrar-García, E.; Muñoz-Blanco, J.L.; Urcelay-Segura, J.L.; Salazar, J.J.; Ramírez, J.M.; Diagnostics 2020, 10, 75. doi:10.3390/diagnostics10020075
The follow-up study showed a progression in OCT parameters. Findings showed a sequential effect in pRNFL, ganglion cell complex (GCC), and macula. The VF and the OCT could be useful biomarkers in FRDA, both for their correlation with neurological disease as well as for their ability to evaluate disease progression.
The follow-up study showed a progression in OCT parameters. Findings showed a sequential effect in pRNFL, ganglion cell complex (GCC), and macula. The VF and the OCT could be useful biomarkers in FRDA, both for their correlation with neurological disease as well as for their ability to evaluate disease progression.
Saturday, February 1, 2020
Developing an objective evaluating system to quantify the degree of upper limb movement impairment in patients with severe Friedreich's ataxia
Giuseppe Arcuria, Christian Marcotulli, Raffaele Amuso, Giuliano Dattilo, Claudio Galasso, Francesco Pierelli, Carlo Casali; Neurol Sci (2020). doi:10.1007/s10072-020-04249-0
The purpose of our study was to develop an easy-to-use application, for touchscreen devices, able to quantify the degree of upper limb movement impairment in patients with severe Friedreich’s ataxia. The APP, which we named “Twelve-Red-Squares App-Coo-Test” (12-RSACT), assesses the upper limb ataxia by measuring the test execution time. 12-RSACT is an inexpensive test and is easy to use, which can be administered quickly. Therefore, 12-RSACT is a promising tool to assess the upper limb ataxia in FRDA patients and even those with severe diseases.
The purpose of our study was to develop an easy-to-use application, for touchscreen devices, able to quantify the degree of upper limb movement impairment in patients with severe Friedreich’s ataxia. The APP, which we named “Twelve-Red-Squares App-Coo-Test” (12-RSACT), assesses the upper limb ataxia by measuring the test execution time. 12-RSACT is an inexpensive test and is easy to use, which can be administered quickly. Therefore, 12-RSACT is a promising tool to assess the upper limb ataxia in FRDA patients and even those with severe diseases.
Friday, January 31, 2020
The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia
Rosa, P.L.; Bertini, E.S.; Piemonte, F.; Int. J. Mol. Sci. 2020, 21, 916. doi:10.3390/ijms21030916
Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.
Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.
Tuesday, January 28, 2020
Europe’s drug regulator wins court backing for data transparency policy
Clare Dyer, BMJ 2020;368:m302
The European Union’s highest court has decisively upheld the European Medicines Agency’s right to publish clinical trial data from drug companies’ applications to market their products in the EU.
In two keenly awaited judgments, the European Court of Justice has comprehensively rejected appeals by two companies against rulings in 2018 by the General Court of the European Union upholding the European Medicines Agency’s open data policy.12
In 2010 the agency adopted a policy of making available all documents underlying a successful drug licence application from January 2014, setting aside its previous presumption of confidentiality. But the move was resisted by pharmaceutical companies, which mounted legal challenges, arguing that their commercial confidentiality was at risk.
The European Union’s highest court has decisively upheld the European Medicines Agency’s right to publish clinical trial data from drug companies’ applications to market their products in the EU.
In two keenly awaited judgments, the European Court of Justice has comprehensively rejected appeals by two companies against rulings in 2018 by the General Court of the European Union upholding the European Medicines Agency’s open data policy.12
In 2010 the agency adopted a policy of making available all documents underlying a successful drug licence application from January 2014, setting aside its previous presumption of confidentiality. But the move was resisted by pharmaceutical companies, which mounted legal challenges, arguing that their commercial confidentiality was at risk.
Monday, January 27, 2020
Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network
Jean-Michel Heard, Charlotte Vrinten, Michael Schlander, Cinzia Maria Bellettato, Corine van Lingen, Maurizio Scarpa & the MetabERN collaboration group. Orphanet J Rare Dis 15, 3 (2020) doi:10.1186/s13023-019-1280-5
It was not the scope of this study to examine the impact of treatment costs, which was debated elsewhere, but rather to bring some indications on benefits for patient populations that are relevant to the assessment of treatment value. More accurate assessment of patient’s population benefit would require measuring markers of disease natural history and patient’s quality of life in treated patient cohorts and analysis of the results by all stakeholders, including HCPs, patients and families. Such methodological approach is needed to ensuring appropriate assessment of marketed treatment value and adapted decision on reimbursement. It is also desirable that end-users and public policy makers are involved at early steps of product development, in order to estimate the potential and/or expected value of the candidate treatments that are selected for development and future marketing. This might reduce the risk of developing and marketing products that do not adequately meet patient’s needs, and might optimize priority investments for OMPs.
It was not the scope of this study to examine the impact of treatment costs, which was debated elsewhere, but rather to bring some indications on benefits for patient populations that are relevant to the assessment of treatment value. More accurate assessment of patient’s population benefit would require measuring markers of disease natural history and patient’s quality of life in treated patient cohorts and analysis of the results by all stakeholders, including HCPs, patients and families. Such methodological approach is needed to ensuring appropriate assessment of marketed treatment value and adapted decision on reimbursement. It is also desirable that end-users and public policy makers are involved at early steps of product development, in order to estimate the potential and/or expected value of the candidate treatments that are selected for development and future marketing. This might reduce the risk of developing and marketing products that do not adequately meet patient’s needs, and might optimize priority investments for OMPs.
Sunday, January 26, 2020
Correlation of Visual Quality of Life With Clinical and Visual Status in Friedreich Ataxia
Afsharian P, Nolan-Kenney R, Lynch AE, Balcer LJ, Lynch DR.; J Neuroophthalmol. 2020 Jan 17. doi: 10.1097/WNO.0000000000000878.
Scores for the NEI-VFQ-25 were lower in patients with FRDA (n = 99) compared with published disease-free controls, particularly reduced in a subgroup of FRDA patients with features of early onset, older age, and abnormal visual function.
Scores for the NEI-VFQ-25 were lower in patients with FRDA (n = 99) compared with published disease-free controls, particularly reduced in a subgroup of FRDA patients with features of early onset, older age, and abnormal visual function.
Saturday, January 25, 2020
Modeling cardiac dysfunction of Friedreich's ataxia using ventricular sheets, tissues and chambers engineered from human pluripotent stem cells
Andy O.-T. Wong, Deborah K. Lieu, Gabriel K. Wong, Bimal Gurung, Wan Wai Tse, Kevin D. Costa, Camie W. Chan, Joseph D. Nabhan, Ronald A. Li; Journal of Pharmacological and Toxicological Methods, Volume 99, 2019, 106595, doi:10.1016/j.vascn.2019.05.175.
We conclude that these humanbased FRDA models provide a biomimetic platform suitable to facilitate the studies of disease pathogenesis and pharmaceutical testing.
We conclude that these humanbased FRDA models provide a biomimetic platform suitable to facilitate the studies of disease pathogenesis and pharmaceutical testing.
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