Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder / Itay TOKATLY LATZER in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder Type de document : texte imprimé Auteurs : Itay TOKATLY LATZER, Auteur ; Jean-Baptiste ROULLET, Auteur ; Wardiya AFSHAR-SABER, Auteur ; Henry H.C. LEE, Auteur ; Mariarita BERTOLDI, Auteur ; Gabrielle E. MCGINTY, Auteur ; Melissa L. DIBACCO, Auteur ; Erland ARNING, Auteur ; Melissa TSUBOYAMA, Auteur ; Alexander ROTENBERG, Auteur ; Thomas OPLADEN, Auteur ; Kathrin JELTSCH, Auteur ; Àngels GARCÍA-CAZORLA, Auteur ; Natalia JULIÁ-PALACIOS, Auteur ; K Michael GIBSON, Auteur ; Mustafa SAHIN, Auteur ; Phillip L.. PEARL, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Female  Humans  Male  Mice  Amino Acid Metabolism, Inborn  Errors/therapy/physiopathology/genetics/complications/metabolism  Brain/metabolism/physiopathology  Developmental Disabilities  Disease Models, Animal  GABAergic Neurons/metabolism  gamma-Aminobutyric Acid/metabolism  Induced Pluripotent Stem Cells/metabolism  Neurodevelopmental Disorders/metabolism/etiology/genetics  Succinate-Semialdehyde Dehydrogenase/deficiency/metabolism/genetics  Development  Gaba  Neurotransmitters  Succinic semialdehyde dehydrogenase  Inc., which develops treatments for SSADHD including gene replacement therapy  discussed in this study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy. En ligne : https://dx.doi.org/10.1186/s11689-024-09538-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder [texte imprimé] / Itay TOKATLY LATZER, Auteur ; Jean-Baptiste ROULLET, Auteur ; Wardiya AFSHAR-SABER, Auteur ; Henry H.C. LEE, Auteur ; Mariarita BERTOLDI, Auteur ; Gabrielle E. MCGINTY, Auteur ; Melissa L. DIBACCO, Auteur ; Erland ARNING, Auteur ; Melissa TSUBOYAMA, Auteur ; Alexander ROTENBERG, Auteur ; Thomas OPLADEN, Auteur ; Kathrin JELTSCH, Auteur ; Àngels GARCÍA-CAZORLA, Auteur ; Natalia JULIÁ-PALACIOS, Auteur ; K Michael GIBSON, Auteur ; Mustafa SAHIN, Auteur ; Phillip L.. PEARL, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Female  Humans  Male  Mice  Amino Acid Metabolism, Inborn  Errors/therapy/physiopathology/genetics/complications/metabolism  Brain/metabolism/physiopathology  Developmental Disabilities  Disease Models, Animal  GABAergic Neurons/metabolism  gamma-Aminobutyric Acid/metabolism  Induced Pluripotent Stem Cells/metabolism  Neurodevelopmental Disorders/metabolism/etiology/genetics  Succinate-Semialdehyde Dehydrogenase/deficiency/metabolism/genetics  Development  Gaba  Neurotransmitters  Succinic semialdehyde dehydrogenase  Inc., which develops treatments for SSADHD including gene replacement therapy  discussed in this study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy. En ligne : https://dx.doi.org/10.1186/s11689-024-09538-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS) / Jorrit TJEERTES in Journal of Neurodevelopmental Disorders, 15 (2023)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 15 (2023) Titre : Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS) Type de document : texte imprimé Auteurs : Jorrit TJEERTES, Auteur ; Carlos A. BACINO, Auteur ; Terry Jo BICHELL, Auteur ; Lynne M. BIRD, Auteur ; Mariana BUSTAMANTE, Auteur ; Rebecca CREAN, Auteur ; Shafali JESTE, Auteur ; Robert W. KOMOROWSKI, Auteur ; Michelle L. KRISHNAN, Auteur ; Meghan T. MILLER, Auteur ; David NOBBS, Auteur ; Cesar OCHOA-LUBINOFF, Auteur ; Kimberly A. PARKERSON, Auteur ; Alexander ROTENBERG, Auteur ; Anjali SADHWANI, Auteur ; Mark D. SHEN, Auteur ; Lisa SQUASSANTE, Auteur ; Wen-Hann TAN, Auteur ; Brenda VINCENZI, Auteur ; Anne C. WHEELER, Auteur ; Joerg F. HIPP, Auteur ; Elizabeth BERRY-KRAVIS, Auteur Langues : Anglais (eng) Mots-clés : Humans  Angelman Syndrome/complications  Prospective Studies  Pandemics  covid-19  Electroencephalography  Angelman syndrome  Clinical outcome assessments  Clinical trials  Digital health technology  Eeg  Endpoint development  Natural history  Sleep  UBE3A  for clinical trials in Angelman syndrome sponsored by F. Hoffmann-La Roche Ltd.  and Ionis Pharmaceuticals Inc. He is also the Principal Investigator for research  trials in achondroplasia sponsored by BioMarin, Pfizer Pharmaceuticals, and  Ascendis Pharmaceuticals. He is a co-investigator in the Undiagnosed Research  Network grant sponsored by the NIH. He is a consultant for Best Doctors Inc. TJB  has been a paid consultant for F. Hoffmann-La Roche Ltd. LMB has been a paid  consultant for F. Hoffmann-La Roche Ltd. and Ionis Pharmaceuticals Inc. regarding  clinical trial design and is/has been a principal investigator on trials  sponsored by F. Hoffmann-La Roche Ltd., Ionis Pharmaceuticals Inc., Biogen, and  Ovid Therapeutics. MB is an employee of F. Hoffmann-La Roche Ltd. RC is an  employee of Ionis Pharmaceuticals Inc. SJ serves as a consultant for Roche  Pharmaceuticals. RWK was an employee of Biogen and is an employee of Ionis  Pharmaceuticals Inc. MLK was an employee of F. Hoffmann-La Roche Ltd. COL was a  principal investigator or co-investigator for clinical trials in Angelman  syndrome sponsored by Ovid, F. Hoffmann-La Roche Ltd., GeneTx, Biogen, and Ionis  Pharmaceuticals Inc. All funds from clinical trials were paid to Rush University  Medical Center and COL did not keep any personal funds. MTM was an employee of F.  Hoffmann-La Roche Ltd. DN is an employee of F. Hoffmann-La Roche Ltd. KP was an  employee of Biogen. AR has been a paid consultant and has received research  support from F. Hoffmann-La Roche Ltd. He has also received recent research  support from BioMarin, CRE Medical, Encoded, LouLou Foundation, Neuroelectrics,  SSADH Foundation, and Takeda. He is co-founder and has equity in PrevEp Inc. and  Galibra Inc. ACW has been a paid consultant for F. Hoffmann-La Roche Ltd. AS has  been a paid consultant for F. Hoffmann-La Roche Ltd. MDS was Principal  Investigator or co-investigator for clinical trials in Angelman syndrome  sponsored by F. Hoffmann-La Roche Ltd., Biogen, and Ionis Pharmaceuticals Inc.  and served as a consultant for Ionis Pharmaceuticals Inc. during the design of  the trial before study startup. All funds were paid to the University of North  Carolina, and MDS did not receive any personal funds. LS is an employee of F.  Hoffmann-La Roche Ltd. WHT was a paid consultant for F. Hoffmann-La Roche Ltd. BV  is an employee of F. Hoffmann-La Roche Ltd. AW was a paid consultant for F.  Hoffmann-La Roche Ltd. And Ovid. JFH is an employee of F. Hoffmann-La Roche Ltd.  EBK has received funding from Acadia, Alcobra, AMO, Asuragen, Avexis, Biogen,  BioMarin, Cydan, Erydel Fulcrum, GeneTx, GW, Ionis Pharmaceuticals Inc., Jaguar,  Lumos, Marinus, Neuren, Neurogene, Neurotrope, Novartis, Orphazyme, Ovid,  Retrophin, Roche, Seaside Therapeutics, Taysha, Tetra, Ultragenyx, Yamo, Zynerba,  and Vtesse/Sucampo/Mallinckrodt Pharmaceuticals, to consult on trial design or  run clinical or lab validation trials in genetic neurodevelopmental or  neurodegenerative disorders, all of which is directed to RUMC in support of rare  disease programs  EBK receives no personal funds and RUMC has no relevant  financial interest in any of the commercial entities listed. Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits. RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports. CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations. En ligne : https://dx.doi.org/10.1186/s11689-023-09494-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS) [texte imprimé] / Jorrit TJEERTES, Auteur ; Carlos A. BACINO, Auteur ; Terry Jo BICHELL, Auteur ; Lynne M. BIRD, Auteur ; Mariana BUSTAMANTE, Auteur ; Rebecca CREAN, Auteur ; Shafali JESTE, Auteur ; Robert W. KOMOROWSKI, Auteur ; Michelle L. KRISHNAN, Auteur ; Meghan T. MILLER, Auteur ; David NOBBS, Auteur ; Cesar OCHOA-LUBINOFF, Auteur ; Kimberly A. PARKERSON, Auteur ; Alexander ROTENBERG, Auteur ; Anjali SADHWANI, Auteur ; Mark D. SHEN, Auteur ; Lisa SQUASSANTE, Auteur ; Wen-Hann TAN, Auteur ; Brenda VINCENZI, Auteur ; Anne C. WHEELER, Auteur ; Joerg F. HIPP, Auteur ; Elizabeth BERRY-KRAVIS, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 15 (2023) Mots-clés : Humans  Angelman Syndrome/complications  Prospective Studies  Pandemics  covid-19  Electroencephalography  Angelman syndrome  Clinical outcome assessments  Clinical trials  Digital health technology  Eeg  Endpoint development  Natural history  Sleep  UBE3A  for clinical trials in Angelman syndrome sponsored by F. Hoffmann-La Roche Ltd.  and Ionis Pharmaceuticals Inc. He is also the Principal Investigator for research  trials in achondroplasia sponsored by BioMarin, Pfizer Pharmaceuticals, and  Ascendis Pharmaceuticals. He is a co-investigator in the Undiagnosed Research  Network grant sponsored by the NIH. He is a consultant for Best Doctors Inc. TJB  has been a paid consultant for F. Hoffmann-La Roche Ltd. LMB has been a paid  consultant for F. Hoffmann-La Roche Ltd. and Ionis Pharmaceuticals Inc. regarding  clinical trial design and is/has been a principal investigator on trials  sponsored by F. Hoffmann-La Roche Ltd., Ionis Pharmaceuticals Inc., Biogen, and  Ovid Therapeutics. MB is an employee of F. Hoffmann-La Roche Ltd. RC is an  employee of Ionis Pharmaceuticals Inc. SJ serves as a consultant for Roche  Pharmaceuticals. RWK was an employee of Biogen and is an employee of Ionis  Pharmaceuticals Inc. MLK was an employee of F. Hoffmann-La Roche Ltd. COL was a  principal investigator or co-investigator for clinical trials in Angelman  syndrome sponsored by Ovid, F. Hoffmann-La Roche Ltd., GeneTx, Biogen, and Ionis  Pharmaceuticals Inc. All funds from clinical trials were paid to Rush University  Medical Center and COL did not keep any personal funds. MTM was an employee of F.  Hoffmann-La Roche Ltd. DN is an employee of F. Hoffmann-La Roche Ltd. KP was an  employee of Biogen. AR has been a paid consultant and has received research  support from F. Hoffmann-La Roche Ltd. He has also received recent research  support from BioMarin, CRE Medical, Encoded, LouLou Foundation, Neuroelectrics,  SSADH Foundation, and Takeda. He is co-founder and has equity in PrevEp Inc. and  Galibra Inc. ACW has been a paid consultant for F. Hoffmann-La Roche Ltd. AS has  been a paid consultant for F. Hoffmann-La Roche Ltd. MDS was Principal  Investigator or co-investigator for clinical trials in Angelman syndrome  sponsored by F. Hoffmann-La Roche Ltd., Biogen, and Ionis Pharmaceuticals Inc.  and served as a consultant for Ionis Pharmaceuticals Inc. during the design of  the trial before study startup. All funds were paid to the University of North  Carolina, and MDS did not receive any personal funds. LS is an employee of F.  Hoffmann-La Roche Ltd. WHT was a paid consultant for F. Hoffmann-La Roche Ltd. BV  is an employee of F. Hoffmann-La Roche Ltd. AW was a paid consultant for F.  Hoffmann-La Roche Ltd. And Ovid. JFH is an employee of F. Hoffmann-La Roche Ltd.  EBK has received funding from Acadia, Alcobra, AMO, Asuragen, Avexis, Biogen,  BioMarin, Cydan, Erydel Fulcrum, GeneTx, GW, Ionis Pharmaceuticals Inc., Jaguar,  Lumos, Marinus, Neuren, Neurogene, Neurotrope, Novartis, Orphazyme, Ovid,  Retrophin, Roche, Seaside Therapeutics, Taysha, Tetra, Ultragenyx, Yamo, Zynerba,  and Vtesse/Sucampo/Mallinckrodt Pharmaceuticals, to consult on trial design or  run clinical or lab validation trials in genetic neurodevelopmental or  neurodegenerative disorders, all of which is directed to RUMC in support of rare  disease programs  EBK receives no personal funds and RUMC has no relevant  financial interest in any of the commercial entities listed. Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits. RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports. CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations. En ligne : https://dx.doi.org/10.1186/s11689-023-09494-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism / Sameer C. DHAMNE in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 26p. Titre : Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism Type de document : texte imprimé Auteurs : Sameer C. DHAMNE, Auteur ; Jill L. SILVERMAN, Auteur ; Chloe E. SUPER, Auteur ; Stephen H.T. LAMMERS, Auteur ; Mustafa Q. HAMEED, Auteur ; Meera E. MODI, Auteur ; Nycole A. COPPING, Auteur ; Michael C. PRIDE, Auteur ; Daniel G. SMITH, Auteur ; Alexander ROTENBERG, Auteur ; Jacqueline N. CRAWLEY, Auteur ; Mustafa SAHIN, Auteur Article en page(s) : 26p. Langues : Anglais (eng) Mots-clés : Anxiety  Autism  Gamma oscillations  Pentylenetetrazol  Repetitive behavior  Shank3B  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. METHODS: In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. RESULTS: Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. CONCLUSIONS: Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery. En ligne : http://dx.doi.org/10.1186/s13229-017-0142-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism [texte imprimé] / Sameer C. DHAMNE, Auteur ; Jill L. SILVERMAN, Auteur ; Chloe E. SUPER, Auteur ; Stephen H.T. LAMMERS, Auteur ; Mustafa Q. HAMEED, Auteur ; Meera E. MODI, Auteur ; Nycole A. COPPING, Auteur ; Michael C. PRIDE, Auteur ; Daniel G. SMITH, Auteur ; Alexander ROTENBERG, Auteur ; Jacqueline N. CRAWLEY, Auteur ; Mustafa SAHIN, Auteur . - 26p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 26p. Mots-clés : Anxiety  Autism  Gamma oscillations  Pentylenetetrazol  Repetitive behavior  Shank3B  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. METHODS: In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. RESULTS: Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. CONCLUSIONS: Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery. En ligne : http://dx.doi.org/10.1186/s13229-017-0142-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Targeting Gamma-Related Pathophysiology in Autism Spectrum Disorder Using Transcranial Electrical Stimulation: Opportunities and Challenges / Fae B. KAYARIAN in Autism Research, 13-7 (July 2020)  

Public ISBD [article]  inAutism Research > 13-7 (July 2020) . - p.1051-1071 Titre : Targeting Gamma-Related Pathophysiology in Autism Spectrum Disorder Using Transcranial Electrical Stimulation: Opportunities and Challenges Type de document : texte imprimé Auteurs : Fae B. KAYARIAN, Auteur ; Ali JANNATI, Auteur ; Alexander ROTENBERG, Auteur ; Emiliano SANTARNECCHI, Auteur Article en page(s) : p.1051-1071 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  gamma  transcranial alternating current stimulation  transcranial direct current stimulation  transcranial electrical stimulation Index. décimale : PER Périodiques Résumé : A range of scalp electroencephalogram (EEG) abnormalities correlates with the core symptoms of autism spectrum disorder (ASD). Among these are alterations of brain oscillations in the gamma-frequency EEG band in adults and children with ASD, whose origin has been linked to dysfunctions of inhibitory interneuron signaling. While therapeutic interventions aimed to modulate gamma oscillations are being tested for neuropsychiatric disorders such as schizophrenia, Alzheimer's disease, and frontotemporal dementia, the prospects for therapeutic gamma modulation in ASD have not been extensively studied. Accordingly, we discuss gamma-related alterations in the setting of ASD pathophysiology, as well as potential interventions that can enhance gamma oscillations in patients with ASD. Ultimately, we argue that transcranial electrical stimulation modalities capable of entraining gamma oscillations, and thereby potentially modulating inhibitory interneuron circuitry, are promising methods to study and mitigate gamma alterations in ASD. Autism Res 2020, 13: 1051-1071. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Brain functions are mediated by various oscillatory waves of neuronal activity, ranging in amplitude and frequency. In certain neuropsychiatric disorders, such as schizophrenia and Alzheimer's disease, reduced high-frequency oscillations in the "gamma" band have been observed, and therapeutic interventions to enhance such activity are being explored. Here, we review and comment on evidence of reduced gamma activity in ASD, arguing that modalities used in other disorders may benefit individuals with ASD as well. En ligne : http://dx.doi.org/10.1002/aur.2312 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=429 [article] Targeting Gamma-Related Pathophysiology in Autism Spectrum Disorder Using Transcranial Electrical Stimulation: Opportunities and Challenges [texte imprimé] / Fae B. KAYARIAN, Auteur ; Ali JANNATI, Auteur ; Alexander ROTENBERG, Auteur ; Emiliano SANTARNECCHI, Auteur . - p.1051-1071. Langues : Anglais (eng) in Autism Research > 13-7 (July 2020) . - p.1051-1071 Mots-clés : autism spectrum disorder  gamma  transcranial alternating current stimulation  transcranial direct current stimulation  transcranial electrical stimulation Index. décimale : PER Périodiques Résumé : A range of scalp electroencephalogram (EEG) abnormalities correlates with the core symptoms of autism spectrum disorder (ASD). Among these are alterations of brain oscillations in the gamma-frequency EEG band in adults and children with ASD, whose origin has been linked to dysfunctions of inhibitory interneuron signaling. While therapeutic interventions aimed to modulate gamma oscillations are being tested for neuropsychiatric disorders such as schizophrenia, Alzheimer's disease, and frontotemporal dementia, the prospects for therapeutic gamma modulation in ASD have not been extensively studied. Accordingly, we discuss gamma-related alterations in the setting of ASD pathophysiology, as well as potential interventions that can enhance gamma oscillations in patients with ASD. Ultimately, we argue that transcranial electrical stimulation modalities capable of entraining gamma oscillations, and thereby potentially modulating inhibitory interneuron circuitry, are promising methods to study and mitigate gamma alterations in ASD. Autism Res 2020, 13: 1051-1071. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Brain functions are mediated by various oscillatory waves of neuronal activity, ranging in amplitude and frequency. In certain neuropsychiatric disorders, such as schizophrenia and Alzheimer's disease, reduced high-frequency oscillations in the "gamma" band have been observed, and therapeutic interventions to enhance such activity are being explored. Here, we review and comment on evidence of reduced gamma activity in ASD, arguing that modalities used in other disorders may benefit individuals with ASD as well. En ligne : http://dx.doi.org/10.1002/aur.2312 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=429

Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research / Lindsay M. OBERMAN in Autism Research, 9-2 (February 2016)  

Public ISBD [article]  inAutism Research > 9-2 (February 2016) . - p.184-203 Titre : Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research Type de document : texte imprimé Auteurs : Lindsay M. OBERMAN, Auteur ; Peter G. ENTICOTT, Auteur ; Manuel F. CASANOVA, Auteur ; Alexander ROTENBERG, Auteur ; Alvaro PASCUAL-LEONE, Auteur ; James T. MCCRACKEN, Auteur ; THE TMS IN ASD CONSENSUS GROUP, Auteur Article en page(s) : p.184-203 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  transcranial magnetic stimulation  consensus  review  treatment Index. décimale : PER Périodiques Résumé : Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental syndrome characterized by impairments in social communication, by the presence of restricted and repetitive behaviors, interests and activities, and by abnormalities in sensory reactivity. Transcranial magnetic stimulation (TMS) is a promising, emerging tool for the study and potential treatment of ASD. Recent studies suggest that TMS measures provide rapid and noninvasive pathophysiological ASD biomarkers. Furthermore, repetitive TMS (rTMS) may represent a novel treatment strategy for reducing some of the core and associated ASD symptoms. However, the available literature on the TMS use in ASD is preliminary, composed of studies with methodological limitations. Thus, off-label clinical rTMS use for therapeutic interventions in ASD without an investigational device exemption and outside of an IRB approved research trial is premature pending further, adequately powered and controlled trials. Leaders in this field have gathered annually for a two-day conference (prior to the 2014 and 2015 International Meeting for Autism Research, IMFAR) to share recent progress, promote collaboration across laboratories, and establish consensus on protocols. Here we review the literature in the use of TMS in ASD in the context of the unique challenges required for the study and exploration of treatment strategies in this population. We also suggest future directions for this field of investigations. While its true potential in ASD has yet to be delineated, TMS represents an innovative research tool and a novel, possibly transformative approach to the treatment of neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1002/aur.1567 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=282 [article] Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research [texte imprimé] / Lindsay M. OBERMAN, Auteur ; Peter G. ENTICOTT, Auteur ; Manuel F. CASANOVA, Auteur ; Alexander ROTENBERG, Auteur ; Alvaro PASCUAL-LEONE, Auteur ; James T. MCCRACKEN, Auteur ; THE TMS IN ASD CONSENSUS GROUP, Auteur . - p.184-203. Langues : Anglais (eng) in Autism Research > 9-2 (February 2016) . - p.184-203 Mots-clés : autism spectrum disorder  transcranial magnetic stimulation  consensus  review  treatment Index. décimale : PER Périodiques Résumé : Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental syndrome characterized by impairments in social communication, by the presence of restricted and repetitive behaviors, interests and activities, and by abnormalities in sensory reactivity. Transcranial magnetic stimulation (TMS) is a promising, emerging tool for the study and potential treatment of ASD. Recent studies suggest that TMS measures provide rapid and noninvasive pathophysiological ASD biomarkers. Furthermore, repetitive TMS (rTMS) may represent a novel treatment strategy for reducing some of the core and associated ASD symptoms. However, the available literature on the TMS use in ASD is preliminary, composed of studies with methodological limitations. Thus, off-label clinical rTMS use for therapeutic interventions in ASD without an investigational device exemption and outside of an IRB approved research trial is premature pending further, adequately powered and controlled trials. Leaders in this field have gathered annually for a two-day conference (prior to the 2014 and 2015 International Meeting for Autism Research, IMFAR) to share recent progress, promote collaboration across laboratories, and establish consensus on protocols. Here we review the literature in the use of TMS in ASD in the context of the unique challenges required for the study and exploration of treatment strategies in this population. We also suggest future directions for this field of investigations. While its true potential in ASD has yet to be delineated, TMS represents an innovative research tool and a novel, possibly transformative approach to the treatment of neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1002/aur.1567 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=282

Use of Transcranial Magnetic Stimulation in Autism Spectrum Disorders / Lindsay M. OBERMAN in Journal of Autism and Developmental Disorders, 45-2 (February 2015)  

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