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Auteur Mark F. BEAR |
Documents disponibles écrits par cet auteur (8)
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Arbaclofen in fragile X syndrome: results of phase 3 trials / Elizabeth BERRY-KRAVIS in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)
[article]
Titre : Arbaclofen in fragile X syndrome: results of phase 3 trials Type de document : Texte imprimé et/ou numérique Auteurs : Elizabeth BERRY-KRAVIS, Auteur ; Randi J. HAGERMAN, Auteur ; J. VISOOTSAK, Auteur ; Dejan B. BUDIMIROVIC, Auteur ; W. E. KAUFMANN, Auteur ; M. CHERUBINI, Auteur ; P. ZAREVICS, Auteur ; Karen WALTON-BOWEN, Auteur ; P. WANG, Auteur ; Mark F. BEAR, Auteur ; Randall L. CARPENTER, Auteur Article en page(s) : p.3 Langues : Anglais (eng) Mots-clés : Arbaclofen Fmr1 Fragile X syndrome GABA agonist Neurodevelopmental disorder Targeted treatment Index. décimale : PER Périodiques Résumé : BACKGROUND: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. METHODS: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. RESULTS: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). CONCLUSIONS: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS. En ligne : http://dx.doi.org/10.1186/s11689-016-9181-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349
in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.3[article] Arbaclofen in fragile X syndrome: results of phase 3 trials [Texte imprimé et/ou numérique] / Elizabeth BERRY-KRAVIS, Auteur ; Randi J. HAGERMAN, Auteur ; J. VISOOTSAK, Auteur ; Dejan B. BUDIMIROVIC, Auteur ; W. E. KAUFMANN, Auteur ; M. CHERUBINI, Auteur ; P. ZAREVICS, Auteur ; Karen WALTON-BOWEN, Auteur ; P. WANG, Auteur ; Mark F. BEAR, Auteur ; Randall L. CARPENTER, Auteur . - p.3.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.3
Mots-clés : Arbaclofen Fmr1 Fragile X syndrome GABA agonist Neurodevelopmental disorder Targeted treatment Index. décimale : PER Périodiques Résumé : BACKGROUND: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. METHODS: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. RESULTS: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). CONCLUSIONS: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS. En ligne : http://dx.doi.org/10.1186/s11689-016-9181-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349 Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis / Sek KONG in Molecular Autism, (February 2014)
[article]
Titre : Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis Type de document : Texte imprimé et/ou numérique Auteurs : Sek KONG, Auteur ; Mustafa SAHIN, Auteur ; Christin COLLINS, Auteur ; Mary WERTZ, Auteur ; Malcolm CAMPBELL, Auteur ; Jarrett LEECH, Auteur ; Dilja D. KRUEGER, Auteur ; Mark F. BEAR, Auteur ; Louis KUNKEL, Auteur ; Isaac KOHANE, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/ mice mirror some, but not all, of the perturbed molecular pathways in the brain. En ligne : http://dx.doi.org/10.1186/2040-2392-5-16 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227
in Molecular Autism > (February 2014)[article] Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis [Texte imprimé et/ou numérique] / Sek KONG, Auteur ; Mustafa SAHIN, Auteur ; Christin COLLINS, Auteur ; Mary WERTZ, Auteur ; Malcolm CAMPBELL, Auteur ; Jarrett LEECH, Auteur ; Dilja D. KRUEGER, Auteur ; Mark F. BEAR, Auteur ; Louis KUNKEL, Auteur ; Isaac KOHANE, Auteur.
Langues : Anglais (eng)
in Molecular Autism > (February 2014)
Index. décimale : PER Périodiques Résumé : Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/ mice mirror some, but not all, of the perturbed molecular pathways in the brain. En ligne : http://dx.doi.org/10.1186/2040-2392-5-16 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 Fragile x syndrome and autism: from disease model to therapeutic targets / G. DOLEN in Journal of Neurodevelopmental Disorders, 1-2 (June 2009)
[article]
Titre : Fragile x syndrome and autism: from disease model to therapeutic targets Type de document : Texte imprimé et/ou numérique Auteurs : G. DOLEN, Auteur ; Mark F. BEAR, Auteur Article en page(s) : p.133-40 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism is an umbrella diagnosis with several different etiologies. Fragile X syndrome (FXS), one of the first identified and leading causes of autism, has been modeled in mice using molecular genetic manipulation. These Fmr1 knockout mice have recently been used to identify a new putative therapeutic target, the metabotropic glutamate receptor 5 (mGluR5), for the treatment of FXS. Moreover, mGluR5 signaling cascades interact with a number of synaptic proteins, many of which have been implicated in autism, raising the possibility that therapeutic targets identified for FXS may have efficacy in treating multiple other causes of autism. En ligne : http://dx.doi.org/10.1007/s11689-009-9015-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341
in Journal of Neurodevelopmental Disorders > 1-2 (June 2009) . - p.133-40[article] Fragile x syndrome and autism: from disease model to therapeutic targets [Texte imprimé et/ou numérique] / G. DOLEN, Auteur ; Mark F. BEAR, Auteur . - p.133-40.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 1-2 (June 2009) . - p.133-40
Index. décimale : PER Périodiques Résumé : Autism is an umbrella diagnosis with several different etiologies. Fragile X syndrome (FXS), one of the first identified and leading causes of autism, has been modeled in mice using molecular genetic manipulation. These Fmr1 knockout mice have recently been used to identify a new putative therapeutic target, the metabotropic glutamate receptor 5 (mGluR5), for the treatment of FXS. Moreover, mGluR5 signaling cascades interact with a number of synaptic proteins, many of which have been implicated in autism, raising the possibility that therapeutic targets identified for FXS may have efficacy in treating multiple other causes of autism. En ligne : http://dx.doi.org/10.1007/s11689-009-9015-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341 Future Directions in the Treatment of Autism Spectrum Disorders / Evdokia ANAGNOSTOU
Titre : Future Directions in the Treatment of Autism Spectrum Disorders Type de document : Texte imprimé et/ou numérique Auteurs : Evdokia ANAGNOSTOU, Auteur ; Mark F. BEAR, Auteur ; Geraldine DAWSON, Auteur Année de publication : 2011 Importance : p.1259-1267 Langues : Anglais (eng) Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=140 Future Directions in the Treatment of Autism Spectrum Disorders [Texte imprimé et/ou numérique] / Evdokia ANAGNOSTOU, Auteur ; Mark F. BEAR, Auteur ; Geraldine DAWSON, Auteur . - 2011 . - p.1259-1267.
Langues : Anglais (eng)
Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=140 Exemplaires
Code-barres Cote Support Localisation Section Disponibilité aucun exemplaire Gene expression analysis in Fmr1KO mice identifies an immunological signature in brain tissue and mGluR5-related signaling in primary neuronal cultures / Daria PRILUTSKY in Molecular Autism, (December 2015)
[article]
Titre : Gene expression analysis in Fmr1KO mice identifies an immunological signature in brain tissue and mGluR5-related signaling in primary neuronal cultures Type de document : Texte imprimé et/ou numérique Auteurs : Daria PRILUTSKY, Auteur ; Alvin T. KHO, Auteur ; Nathan P. PALMER, Auteur ; Asha L. BHAKAR, Auteur ; Niklas SMEDEMARK-MARGULIES, Auteur ; Sek Won KONG, Auteur ; David M. MARGULIES, Auteur ; Mark F. BEAR, Auteur ; Isaac S. KOHANE, Auteur Article en page(s) : p.1-14 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Fragile X syndrome (FXS) is a neurodevelopmental disorder whose biochemical manifestations involve dysregulation of mGluR5-dependent pathways, which are widely modeled using cultured neurons. In vitro phenotypes in cultured neurons using standard morphological, functional, and chemical approaches have demonstrated considerable variability. Here, we study transcriptomes obtained in situ in the intact brain tissues of a murine model of FXS to see how they reflect the in vitro state. En ligne : http://dx.doi.org/10.1186/s13229-015-0061-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277
in Molecular Autism > (December 2015) . - p.1-14[article] Gene expression analysis in Fmr1KO mice identifies an immunological signature in brain tissue and mGluR5-related signaling in primary neuronal cultures [Texte imprimé et/ou numérique] / Daria PRILUTSKY, Auteur ; Alvin T. KHO, Auteur ; Nathan P. PALMER, Auteur ; Asha L. BHAKAR, Auteur ; Niklas SMEDEMARK-MARGULIES, Auteur ; Sek Won KONG, Auteur ; David M. MARGULIES, Auteur ; Mark F. BEAR, Auteur ; Isaac S. KOHANE, Auteur . - p.1-14.
Langues : Anglais (eng)
in Molecular Autism > (December 2015) . - p.1-14
Index. décimale : PER Périodiques Résumé : Fragile X syndrome (FXS) is a neurodevelopmental disorder whose biochemical manifestations involve dysregulation of mGluR5-dependent pathways, which are widely modeled using cultured neurons. In vitro phenotypes in cultured neurons using standard morphological, functional, and chemical approaches have demonstrated considerable variability. Here, we study transcriptomes obtained in situ in the intact brain tissues of a murine model of FXS to see how they reflect the in vitro state. En ligne : http://dx.doi.org/10.1186/s13229-015-0061-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome? / Talakad LOHITH in Molecular Autism, (May 2013)
PermalinkSTX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study / Craig ERICKSON in Journal of Autism and Developmental Disorders, 44-4 (April 2014)
PermalinkThe mGluR Theory of Fragile X Syndrome / Dilja D. KRUEGER
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