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1. Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial

Author

Christine, Chadwick W, Richardson, R Mark, Van Laar, Amber D, Thompson, Marin E, Fine, Elisabeth M, Khwaja, Omar S, Li, Chunming, Liang, Grace S, Meier, Andreas, Roberts, Eiry W, Pfau, Madeline L, Rodman, Josh R, Bankiewicz, Krystof S, and Larson, Paul S

Subjects
Orphan Drug, Parkinson's Disease, Clinical Research, Neurodegenerative, Aging, Patient Safety, Neurosciences, Brain Disorders, Rare Diseases, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Neurological, Amino Acids, Antiparkinson Agents, Carboxy-Lyases, Genetic Therapy, Humans, Parkinson Disease, Quality of Life, Treatment Outcome, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Background and objectivesTo report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations.MethodsPD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg.ResultsNo serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III "off"-medication and "on"-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts.DiscussionsVY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years.Trial registration informationNCT01973543.Classification of evidenceThis study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Published
2022

2. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial

Author

Volpe, Joseph J, Posner, John, Kellner, Ulrich, Quinlivan, Rosaline, Gerber, Marianne, Khwaja, Omar, Scalco, Renata S, Seabrook, Timothy, Koch, Armin, Balikova, Irina, Joniau, Inge, Accou, Geraldine, Tahon, Valentine, Wittevrongel, Sylvia, De Vos, Elke, de Holanda Mendonça, Rodrigo, Matsui Jr, Ciro, Fornazieri Darcie, Ana Letícia, Machado, Cleide, Kiyoko Oyamada, Maria, Martini, Joyce, Polido, Graziela, Rodrigues Iannicelli, Juliana, Caires de Oliveira Achili Ferreira, Juliana, Hu, Chaoping, Zhu, Xiaomei, Qian, Chen, Shen, Li, Li, Hui, Shi, Yiyun, Zhou, Shuizhen, Xiao, Ying, Zhou, Zhenxuan, Wang, Sujuan, Sang, Tian, Wei, Cuijie, Dong, Hui, Cao, Yiwen, Wen, Jing, Li, Wenzhu, Qin, Lun, Barisic, Nina, Celovec, Ivan, Galiot Delic, Martina, Ivkic, Petra Kristina, Vukojevic, Nenad, Kern, Ivana, Najdanovic, Boris, Skugor, Marin, Tomas, Josipa, Boespflug-Tanguy, Odile, De Lucia, Silvana, Seferian, Andrea, Barreau, Emmanuel, Mnafek, Nabila, Peche, Helene, Grange, Allison, Trang Nguyen, Diem, Milascevic, Darko, Tachibana, Shotaro, Pagliano, Emanuela, Bianchi Marzoli, Stefania, Santarsiero, Diletta, Garcia Sierra, Myriam, Tremolada, Gemma, Arnoldi, Maria Teresa, Vigano, Marta, Dosi, Claudia, Zanin, Riccardo, Schembri, Veronica, Brolatti, Noemi, Rao, Giuseppe, Tassara, Elisa, Morando, Simone, Tacchetti, Paola, Pedemonte, Marina, Priolo, Enrico, Sposetti, Lorenza, Comi, Giacomo Pietro, Govoni, Alessandra, Osnaghi, Silvia Gabriella, Minorini, Valeria, Abbati, Francesca, Fassini, Federica, Foa, Michaela, Lopopolo, Amalia, Pane, Marika, Palermo, Concetta, Pera, Maria Carmela, Amorelli, Giulia Maria, Barresi, Costanza, D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Leone, Daniela, Laura, Antonaci, De Sanctis, Roberto, Berti, Beatrice, Kimura, Naoki, Takeshima, Yasuhiro, Shimomura, Hideki, Lee, Tomoko, Gomi, Fumi, Morimatsu, Takanobu, Furukawa, Toru, Stodolska-Koberda, Urszula, Waskowska, Agnieszka, Kolendo, Jagoda, Sobierajska-Rek, Agnieszka, Modrzejewska, Sandra, Lemska, Anna, Melnik, Evgenia, Artemyeva, Svetlana, Leppenen, Natalya, Yupatova, Nataliya, Monakhova, Anastasya, Papina, Yulia, Shidlovsckaia, Olga, Litvinova, Elena, Enzmann, Cornelia, Galiart, Elea, Gugleta, Konstantin, Wondrusch Haschke, Christine, Topaloglu, Haluk, Oncel, Ibrahim, Ertugrul, Nesibe Eroglu, Konuskan, Bahadir, Eldem, Bora, Kadayifçilar, Sibel, Alemdaroglu, Ipek, Sari, Seher, Bilgin, Neslihan, Karaduman, Aynur Ayse, Sarikaya, Fatma Gokcem Yildiz, Graham, Robert J, Ghosh, Partha, Casavant, David, Levine, Alexis, Titus, Rachael, Engelbrekt, Amanda, Ambrosio, Lucia, Fulton, Anne, Baglieri, Anna Maria, Dias, Courtney, Maczek, Elizabeth, Pasternak, Amy, Beres, Shannon, Duong, Tina, Gee, Richard, Young, Sally, Masson, Riccardo, Mazurkiewicz-Bełdzińska, Maria, Rose, Kristy, Servais, Laurent, Xiong, Hui, Zanoteli, Edmar, Baranello, Giovanni, Bruno, Claudio, Day, John W, Deconinck, Nicolas, Klein, Andrea, Mercuri, Eugenio, Vlodavets, Dmitry, Wang, Yi, Dodman, Angela, El-Khairi, Muna, Gorni, Ksenija, Jaber, Birgit, Kletzl, Heidemarie, Gaki, Eleni, Fontoura, Paulo, and Darras, Basil T

Published
2022
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3. A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d’Ardhuy, Xavier Liogier

Published
2022
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5. Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes

Author

Frohlich, Joel, Miller, Meghan T, Bird, Lynne M, Garces, Pilar, Purtell, Hannah, Hoener, Marius C, Philpot, Benjamin D, Sidorov, Michael S, Tan, Wen-Hann, Hernandez, Maria-Clemencia, Rotenberg, Alexander, Jeste, Shafali S, Krishnan, Michelle, Khwaja, Omar, and Hipp, Joerg F

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Neurosciences, Mental Health, Genetics, Human Genome, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Angelman Syndrome, Beta Rhythm, Brain Waves, Cerebral Cortex, Child, Child, Preschool, Delta Rhythm, Electroencephalography, Genotype, Humans, Infant, Phenotype, Theta Rhythm, Angelman syndrome, Biomarkers, EEG, GABA, GABRB3-GABRA5-GABRG3 gene cluster, UBE3A, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BACKGROUND:Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by either disruptions of the gene UBE3A or deletion of chromosome 15 at 15q11-q13, which encompasses UBE3A and several other genes, including GABRB3, GABRA5, GABRG3, encoding gamma-aminobutyric acid type A receptor subunits (β3, α5, γ3). Individuals with deletions are generally more impaired than those with other genotypes, but the underlying pathophysiology remains largely unknown. Here, we used electroencephalography (EEG) to test the hypothesis that genes other than UBE3A located on 15q11-q13 cause differences in pathophysiology between AS genotypes. METHODS:We compared spectral power of clinical EEG recordings from children (1-18 years of age) with a deletion genotype (n = 37) or a nondeletion genotype (n = 21) and typically developing children without Angelman syndrome (n = 48). RESULTS:We found elevated theta power (peak frequency: 5.3 Hz) and diminished beta power (peak frequency: 23 Hz) in the deletion genotype compared with the nondeletion genotype as well as excess broadband EEG power (1-32 Hz) peaking in the delta frequency range (peak frequency: 2.8 Hz), shared by both genotypes but stronger for the deletion genotype at younger ages. CONCLUSIONS:Our results provide strong evidence for the contribution of non-UBE3A neuronal pathophysiology in deletion AS and suggest that hemizygosity of the GABRB3-GABRA5-GABRG3 gene cluster causes abnormal theta and beta EEG oscillations that may underlie the more severe clinical phenotype. Our work improves the understanding of AS pathophysiology and has direct implications for the development of AS treatments and biomarkers.

Published
2019

6. Exploring Social Biomarkers in High-Functioning Adults with Autism and Asperger's versus Healthy Controls: A Cross-Sectional Analysis

Author

Del Valle Rubido, Marta, Hollander, Eric, McCracken, James T., Shic, Frederick, Noeldeke, Jana, Boak, Lauren, Khwaja, Omar, Sadikhov, Shamil, Fontoura, Paulo, and Umbricht, Daniel

Abstract

Biomarkers for autism spectrum disorder (ASD) are lacking but would facilitate drug development for the core deficits of the disorder. We evaluated markers proposed for characterization of differences in social communication and interaction in adults with ASD versus healthy controls (HC) for utility as biomarkers. Data pooled from an observational study and baseline data from a placebo-controlled study were analyzed. Between-group differences were observed in eye-tracking tasks for activity monitoring, biomotion, human activity preference, composite score (p = 0.0001-0.037) and pupillometry (various tasks, p = 0.017-0.05). Impaired olfaction was more common in the ASD sample versus HC (p = 0.018). Our preliminary results suggest the potential use for stratification and response sub-analyses outcome-prediction of specific eye-tracking tasks, pupillometry and olfaction tests in ASD trials.

Published
2020
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7. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author

Volpe, Joseph J., Posner, John, Kellner, Ulrich, Quinlivan, Rosaline, Daron, Aurore, Delstanche, Stéphanie, Bruninx, Romain, Dal Farra, Fabian, Schneider, Olivier, Deconinck, Nicolas, Balikova, Irina, Delbeke, Patricia, Joniau, Inge, Tahon, Valentine, Wittevrongel, Sylvia, De Vos, Elke, Goemans, Nathalie, Casteels, Ingele, De Waele, Liesbeth, Cassiman, Catherine, Prové, Lies, Kinoo, David, Vancampenhout, Lisa, Van Den Hauwe, Marleen, Van Impe, Annelies, Prufer de Queiroz Campos Araujo, Alexandra, Chacon Pereira, Aline, Nardes, Flávia, Haefeli, Lorena, Rossetto, Julia, Ferreira Rebel, Marcos, Almeida Pereira, Jaqueline, Campbell, Craig, Sharan, Sapna, McDonald, Wendy, Scholtes, Cheryl, Mah, Jean, Sframeli, Maria, Chiu, Angela, Hagel, Jane, Oskoui, Maryam, Beneish, Raquel, Cariou-Palmer, Gaela, Pham, Connie, Toffoli, Daniela, Arpin, Stephanie, Turgeon Desilets, Sarah, Wang, Yi, Hu, Chaoping, Huan, Jianfeng, Qian, Chen, Shen, Li, Xiao, Ying, Zhou, Zhenxuan, Li, Hui, Wang, Sujuan, Xiong, Hui, Chang, Xingzhi, Dong, Hui, Liu, Ying, Sang, Tian, Wei, Cuijie, Wen, Jing, Cao, Yiwen, Ly, Xingyao, Zhao, Jingjing, Li, Wenzhu, Qin, Lun, Barisic, Nina, Galiot Delic, Martina, Ivkic, Petra Kristina, Vukojevic, Nenad, Kern, Ivana, Najdanovic, Boris, Skugor, Marin, Servais, Laurent, Boespflug-Tanguy, Odile, Gidaro, Teresa, Seferian, Andreea, De Lucia, Silvana, Barreau, Emmanuel, Mnafek, Nabila, Momtchilova, Marta Milkova, Peche, Helene, Valherie, Carole, Grange, Allison, Lilien, Charlotte, Milascevic, Darko, Tachibana, Shotaro, Ravelli, Claudia, Cardas, Ruxandra, Taytard, Jessica, Aubertin, Guillaume, Vanden Brande, Laure, Davion, Jean-Baptiste, Coopman, Stephanie, Bouacha, Ikram, Debruyne, Philippe, Defoort, Sabine, Derlyn, Gilles, Leroy, Florian, Danjoux, Loïc, Guilbaud, Julie, Desguerre, Isabelle, Barnérias, Christine, Semeraro, Michaela, Bremond-Gignac, Dominique, Bruere, Lenaic, Rateaux, Maxence, Deladrière, Élodie, Germa, Virginie, Pereon, Yann, Mercie, Sandra, Billaud, Fanny, Le Goff, Lucie, Letellier, Guy, Vuillerot, Carole, Portefaix, Aurélie, De-Montferrand, Camille, Le-Goff, Laure, Fontaine, Stephanie, Saidi, Manel, Bouzid, Nabil, Barriere, Aurélie, Tinat, Marie, Kirschner, Janbernd, Dreesbach, Michelle, Lagréze, Wolf, Michaelis, Bettina, Molnar, Fanni, Seger, Dorina, Vogt, Sibylle, Bertini, Enrico, D'Amico, Adele, Petroni, Sergio, Bonetti, Anna Maria, Carlesi, Adelina, Mizzoni, Irene, Bruno, Claudio, Priolo, Enrico, Rao, Giuseppe, Morando, Simone, Tacchetti, Paola, Zuffi, Ambra, Comi, Giacomo Pietro, Brusa, Roberta, Corti, Stefania, Daniele, Velardo, Govoni, Alessandra, Magri, Francesca, Minorini, Valeria, Osnaghi, Silvia Gabriella, Abbati, Francesca, Fassini, Federica, Foa, Michaela, Lopopolo, Amaqlia, Meneri, Megi, Zoppas, Francesca, Parente, Valeria, Baranello, Giovanni, Masson, Riccardo, Bianchi Marzoli, Stefania, Santarsiero, Diletta, Garcia Sierra, Myriam, Tremolada, Gemma, Arnoldi, Maria Teresa, Vigano, Marta, Zanin, Riccardo, Mercuri, Eugenio, Antonaci, Laura, de Sanctis, Roberto, Pane, Marika, Pera, Maria Carmela, Amorelli, Giulia Maria, Barresi, Costanza, D'Amico, Gugliemo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, Kazuhiro, Kato, Atsuko, Morishita, Yuko, Kira, Ryutaro, Akiyama, Kiyomu, Goto, Miwako, Mori, Yujiro, Okamoto, Misato, Tsutsui, Saki, Takatsuji, Yuta, Tanaka, Aya, Komaki, Hirofumi, Omori, Miina, Suzuki, Ippei, Takeuchi, Mizuki, Todoroki, Daisuke, Watanabe, Seji, Matsubayashi, Tomoko, Inakazu, Emi, Nagura, Hiroe, Suzuki, Akira, Usui, Manami, Ishikawa, Nobutsune, Harada, Yousuke, Fudeyasu, Kenishi, Hirata, Kazuhiko, Michiue, Kana, Ueda, Kazuyuki, Saito, Kayoko, Fujitani, Junko, Arakawa, Reiko, Takano, Kozue, Yashiro, Shigeko, Seki, Maiko, Sano, Nozomi, Fukuyama, Koji, Matsumoto, Yuki, Miyazaki, Hirofumi, Shibata, Minoru, Kobayashi, Kyoko, Nakamura, Yukie, Takeshima, Yasuhiro, Kuma, Moe, Kostera-Pruszczyk, Anna, Fraczek, Anna, Jedrzejowska, Maria, Lusakowska, Anna, Czeszyk-Piotrowicz, Agnieszka, Hautz, Wojciech, Rakusiewicz, Klaudia, Burlewicz, Malgorzata, Gierlak-Wojcicka, Zuzanna, Kepa, Malwina, Sikorski, Adam, Sobieraj, Marcin, Mazurkiewicz-Beldzinska, Maria, Lemska, Anna, Modrzejewska, Sandra, Koberda, Mateusz, Stodolska-Koberda, Urszula, Waskowska, Agnieszka, Kolendo, Jagoda, Sobierajska-Rek, Agnieszka, Steinborn, Barbara, Dalz, Magdalena, Grabowska, Julia, Hajduk, Wojciech, Janasiewicz-Karachitos, Justyna, Klimas, Monika, Stopa, Marcin, Gajewska, Ewa, Pusz, Beata, Vlodavets, Dmitry, Melnik, Evgenia, Leppenen, Natalya, Yupatova, Nataliya, Monakhova, Anastasya, Papina, Yulia, Shidlovsckaia, Olga, Milic Rasic, Vedrana, Brankovic, Vesna, Kosac, Ana, Djokic, Olivera, Jakšic, Vesna, Pepic, Ana, Martinovic, Jelena, Munell Casadesus, Francina, Tizzano, Eduardo, Martín Begué, Nieves, Wolley Dod, Charlotte, Subira, Olaia, Planas Pascual, Bernat, Toro Tamargo, Esther, Madruga Garrido, Marcos, Medina Romero, José David, Salinas, Marta Peña, Nascimento Osorio, Andrés, Díaz Cortés, Ana, Jiménez Gañan, Enrique, Suh, Simone Dowon, Medina Cantillo, Julita, Moya, Obdulia, Padros, Nuria, Urraca, Sandra Roca, Valdivia, Hugo Gonzalez, Pascual Pascual, Samuel, de Manuel, Sofía, Martin, Susana Noval, Burnham, Paul, Espinosa, Sandra, Moreno, Mercedes Martinez, Topaloglu, Haluk, Oncel, Ibrahim, Eroglu Ertugru, Nesibe, Konuskan, Bahadir, Eldem, Bora, Kadayifçilar, Sibel, Alemdaroglu, Ipek, Karaduman, Aynur Ayse, Yilmaz, Oznur Tunca, Bilgin, Neslihan, Sari, Seher, Chiriboga, Claudia, Lee, John J., Rome-Martin, Donnielle, Day, John W., Beres, Shannon, Duong, Tina, Gee, Richard, Dunaway Young, Sally, Fuerst-Recktenwald, Sabine, Marquet, Anne, Muelhardt, Nicoletta, Trundell, Dylan, Mazzone, Elena S, Nascimento, Andres, Gerber, Marianne, Gorni, Ksenija, Khwaja, Omar, Kletzl, Heidemarie, Scalco, Renata S, Staunton, Hannah, Yeung, Wai Yin, Martin, Carmen, Fontoura, Paulo, and Day, John W

Published
2022
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8. Progress in Understanding and Treating SCN2A-Mediated Disorders.

Author

Sanders, Stephan J, Campbell, Arthur J, Cottrell, Jeffrey R, Moller, Rikke S, Wagner, Florence F, Auldridge, Angie L, Bernier, Raphael A, Catterall, William A, Chung, Wendy K, Empfield, James R, George, Alfred L, Hipp, Joerg F, Khwaja, Omar, Kiskinis, Evangelos, Lal, Dennis, Malhotra, Dheeraj, Millichap, John J, Otis, Thomas S, Petrou, Steven, Pitt, Geoffrey, Schust, Leah F, Taylor, Cora M, Tjernagel, Jennifer, Spiro, John E, and Bender, Kevin J

Subjects
Animals, Humans, NAV1.2 Voltage-Gated Sodium Channel, Neurodevelopmental Disorders, Na(V)1.2, autism spectrum disorder, developmental delay, epilepsy, intellectual disability, neurodevelopment, neurodevelopmental disorder, sodium channel, Neurodegenerative, Brain Disorders, Neurosciences, Genetics, Mental Health, Intellectual and Developmental Disabilities (IDD), Autism, 2.1 Biological and endogenous factors, Aetiology, Neurological, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.

Published
2018

9. Exploring Social Biomarkers in High-Functioning Adults with Autism and Asperger's Versus Healthy Controls: A Cross-Sectional Analysis

Author

Del Valle Rubido, Marta, Hollander, Eric, McCracken, James T., Shic, Frederick, Noeldeke, Jana, Boak, Lauren, and Khwaja, Omar

Subjects
Pervasive developmental disorders -- Diagnosis -- Risk factors, Biological markers -- Social aspects -- Analysis, Health
Abstract

Biomarkers for autism spectrum disorder (ASD) are lacking but would facilitate drug development for the core deficits of the disorder. We evaluated markers proposed for characterization of differences in social communication and interaction in adults with ASD versus healthy controls (HC) for utility as biomarkers. Data pooled from an observational study and baseline data from a placebo-controlled study were analyzed. Between-group differences were observed in eye-tracking tasks for activity monitoring, biomotion, human activity preference, composite score (p = 0.0001-0.037) and pupillometry (various tasks, p = 0.017-0.05). Impaired olfaction was more common in the ASD sample versus HC (p = 0.018). Our preliminary results suggest the potential use for stratification and response sub-analyses outcome-prediction of specific eye-tracking tasks, pupillometry and olfaction tests in ASD trials, Author(s): Marta Del Valle Rubido [sup.1] , Eric Hollander [sup.2] , James T. McCracken [sup.3] , Frederick Shic [sup.4] [sup.5] , Jana Noeldeke [sup.1] [sup.7] , Lauren Boak [sup.6] , [...]

Published
2020
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13. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial

Author

Masson, Riccardo, primary, Mazurkiewicz-Bełdzińska, Maria, additional, Rose, Kristy, additional, Servais, Laurent, additional, Xiong, Hui, additional, Zanoteli, Edmar, additional, Baranello, Giovanni, additional, Bruno, Claudio, additional, Day, John W, additional, Deconinck, Nicolas, additional, Klein, Andrea, additional, Mercuri, Eugenio, additional, Vlodavets, Dmitry, additional, Wang, Yi, additional, Dodman, Angela, additional, El-Khairi, Muna, additional, Gorni, Ksenija, additional, Jaber, Birgit, additional, Kletzl, Heidemarie, additional, Gaki, Eleni, additional, Fontoura, Paulo, additional, Darras, Basil T, additional, Volpe, Joseph J, additional, Posner, John, additional, Kellner, Ulrich, additional, Quinlivan, Rosaline, additional, Gerber, Marianne, additional, Khwaja, Omar, additional, Scalco, Renata S, additional, Seabrook, Timothy, additional, Koch, Armin, additional, Balikova, Irina, additional, Joniau, Inge, additional, Accou, Geraldine, additional, Tahon, Valentine, additional, Wittevrongel, Sylvia, additional, De Vos, Elke, additional, de Holanda Mendonça, Rodrigo, additional, Matsui Jr, Ciro, additional, Fornazieri Darcie, Ana Letícia, additional, Machado, Cleide, additional, Kiyoko Oyamada, Maria, additional, Martini, Joyce, additional, Polido, Graziela, additional, Rodrigues Iannicelli, Juliana, additional, Caires de Oliveira Achili Ferreira, Juliana, additional, Hu, Chaoping, additional, Zhu, Xiaomei, additional, Qian, Chen, additional, Shen, Li, additional, Li, Hui, additional, Shi, Yiyun, additional, Zhou, Shuizhen, additional, Xiao, Ying, additional, Zhou, Zhenxuan, additional, Wang, Sujuan, additional, Sang, Tian, additional, Wei, Cuijie, additional, Dong, Hui, additional, Cao, Yiwen, additional, Wen, Jing, additional, Li, Wenzhu, additional, Qin, Lun, additional, Barisic, Nina, additional, Celovec, Ivan, additional, Galiot Delic, Martina, additional, Ivkic, Petra Kristina, additional, Vukojevic, Nenad, additional, Kern, Ivana, additional, Najdanovic, Boris, additional, Skugor, Marin, additional, Tomas, Josipa, additional, Boespflug-Tanguy, Odile, additional, De Lucia, Silvana, additional, Seferian, Andrea, additional, Barreau, Emmanuel, additional, Mnafek, Nabila, additional, Peche, Helene, additional, Grange, Allison, additional, Trang Nguyen, Diem, additional, Milascevic, Darko, additional, Tachibana, Shotaro, additional, Pagliano, Emanuela, additional, Bianchi Marzoli, Stefania, additional, Santarsiero, Diletta, additional, Garcia Sierra, Myriam, additional, Tremolada, Gemma, additional, Arnoldi, Maria Teresa, additional, Vigano, Marta, additional, Dosi, Claudia, additional, Zanin, Riccardo, additional, Schembri, Veronica, additional, Brolatti, Noemi, additional, Rao, Giuseppe, additional, Tassara, Elisa, additional, Morando, Simone, additional, Tacchetti, Paola, additional, Pedemonte, Marina, additional, Priolo, Enrico, additional, Sposetti, Lorenza, additional, Comi, Giacomo Pietro, additional, Govoni, Alessandra, additional, Osnaghi, Silvia Gabriella, additional, Minorini, Valeria, additional, Abbati, Francesca, additional, Fassini, Federica, additional, Foa, Michaela, additional, Lopopolo, Amalia, additional, Pane, Marika, additional, Palermo, Concetta, additional, Pera, Maria Carmela, additional, Amorelli, Giulia Maria, additional, Barresi, Costanza, additional, D'Amico, Guglielmo, additional, Orazi, Lorenzo, additional, Coratti, Giorgia, additional, Leone, Daniela, additional, Laura, Antonaci, additional, De Sanctis, Roberto, additional, Berti, Beatrice, additional, Kimura, Naoki, additional, Takeshima, Yasuhiro, additional, Shimomura, Hideki, additional, Lee, Tomoko, additional, Gomi, Fumi, additional, Morimatsu, Takanobu, additional, Furukawa, Toru, additional, Stodolska-Koberda, Urszula, additional, Waskowska, Agnieszka, additional, Kolendo, Jagoda, additional, Sobierajska-Rek, Agnieszka, additional, Modrzejewska, Sandra, additional, Lemska, Anna, additional, Melnik, Evgenia, additional, Artemyeva, Svetlana, additional, Leppenen, Natalya, additional, Yupatova, Nataliya, additional, Monakhova, Anastasya, additional, Papina, Yulia, additional, Shidlovsckaia, Olga, additional, Litvinova, Elena, additional, Enzmann, Cornelia, additional, Galiart, Elea, additional, Gugleta, Konstantin, additional, Wondrusch Haschke, Christine, additional, Topaloglu, Haluk, additional, Oncel, Ibrahim, additional, Ertugrul, Nesibe Eroglu, additional, Konuskan, Bahadir, additional, Eldem, Bora, additional, Kadayifçilar, Sibel, additional, Alemdaroglu, Ipek, additional, Sari, Seher, additional, Bilgin, Neslihan, additional, Karaduman, Aynur Ayse, additional, Sarikaya, Fatma Gokcem Yildiz, additional, Graham, Robert J, additional, Ghosh, Partha, additional, Casavant, David, additional, Levine, Alexis, additional, Titus, Rachael, additional, Engelbrekt, Amanda, additional, Ambrosio, Lucia, additional, Fulton, Anne, additional, Baglieri, Anna Maria, additional, Dias, Courtney, additional, Maczek, Elizabeth, additional, Pasternak, Amy, additional, Beres, Shannon, additional, Duong, Tina, additional, Gee, Richard, additional, and Young, Sally, additional

Published
2022
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14. Weight Status in the First 2 Years of Life and Neurodevelopmental Impairment in Extremely Low Gestational Age Newborns

Author

Lee, Kathleen, McGovern, Anne, Gambardella, Jill, Ursprung, Susan, Kristen Ecklund, Ruth Blomquist, Bassan, Haim, Butler, Samantha, Duplessis, Adré, Hahn, Cecil, Limperopoulos, Catherine, Khwaja, Omar, Soul, Janet S., Shah, Bhavesh, Christianson, Karen, Hampf, Frederick, Gilmore, Herbert, McQuiston, Susan, Martin, Camilia R., Hallisey, Colleen, Hurley, Caitlin, Creixell, Miren, Share, Jane, Van Marter, Linda J., Durfee, Sara, Insoft, Robert M., Wilson, Jennifer G., Pimental, Maureen, Westra, Sjirk J., Krishnamoorthy, Kalpathy, Cole, Cynthia, Fiascone, John M., Madden, Janet, Nylen, Ellen, Furey, Anne, McCauley, Roy, Church, Paige T., Keller, Cecelia, Miller, Karen J., Bednarek, Francis, Naples, Mary, Powers, Beth, Wellman, Jacqueline, Adair, Robin, Bream, Richard, Miller, Alice, Scheiner, Albert, Stine, Christy, Ehrenkranz, Richard, Williams, Joanne, Romano, Elaine, Miller, Cindy, Close, Nancy, O'Shea, T. Michael, Gordon, Debbie, Harold, Teresa, Specter, Barbara, Allred, Deborah, Dillard, Robert, Goldstein, Don, Hiatt, Deborah, Hounshell, Gail, Waldrep, Ellen, Washburn, Lisa, Welch, Cherrie D., Engelke, Stephen C., Moseley, Sherry, Pare, Linda, Smart, Donna, Wilson, Joan, Adler, Ira, Buckwald, Sharon, Helms, Rebecca, Kerkering, Kathyrn, MacGilvray, Scott S., Resnik, Peter, Bose, Carl, Bose, Gennie, Fordham, Lynn A., Bostic, Lisa, Marshall, Diane, Milowic, Kristi, Wereszczak, Janice, Poortenga, Mariel, Sutton, Dinah, Betz, Bradford W., Bezinque, Steven L., Junewick, Joseph, Burdo-Hartman, Wendy, Fagerman, Lynn, Lohr, Kim, Pastyrnak, Steve, Solomon, Carolyn, Cavenagh, Ellen, Caine, Victoria J., Olomu, Nicholas, Price, Joan, Paneth, Nigel, Karna, Padmani, Lenski, Madeleine, Schreiber, Michael D., Yoon, Grace, Feinstein, Kate, Caldarelli, Leslie, O'Connor, Sunila E., Msall, Michael, Plesha-Troyke, Susan, Batton, Daniel, Kring, Beth, Brooklier, Karen, Oca, Melisa J., Solomon, Katherine M., Belfort, Mandy B., Kuban, Karl C.K., Allred, Elizabeth N., Ehrenkranz, Richard A., and Leviton, Alan

Published
2016
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16. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Author

Khwaja, Omar S., Ho, Eugenia, Barnes, Katherine V., O'Leary, Heather M., Pereira, Luis M., Finkelstein, Yaron, Nelson, Charles A., Vogel-Farley, Vanessa, DeGregorio, Geneva, Holm, Ingrid A., Khatwa, Umakanth, Kapur, Kush, Alexander, Mark E., Finnegan, Deirdre M., Cantwell, Nicole G., Walco, Alexandra C., Rappaport, Leonard, Gregas, Matt, Fichorova, Raina N., Shannon, Michael W., Sur, Mriganka, and Kaufmann, Walter E.

Published
2014

18. Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial

Author

Richardson, R, Van Laar, Amber, Thompson, Marin, Fine, Elisabeth, Khwaja, Omar, Li, Chunming, Liang, Grace, Meier, Andreas, Roberts, Eiry, Pfau, Madeline, Rodman, Josh, Bankiewicz, Krystof, Larson, Paul, and Christine, Chadwick

Abstract

BACKGROUND AND OBJECTIVES: To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations. METHODS: PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg. RESULTS: No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinsons Disease Rating Scale III off-medication and on-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinsons Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts. DISCUSSIONS: VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years. TRIAL REGISTRATION INFORMATION: NCT01973543. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Published
2022

19. Additional file 11 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Subjects
carbohydrates (lipids), sense organs, skin and connective tissue diseases
Abstract

Additional file 11. Co-morbid Symptoms: Change from Baseline at 6months. Table summarizing Conner���s, ADAMS and CSHQ data.

Published
2022
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20. Additional file 7 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Subjects
humanities
Abstract

Additional file 7. Quantitative EEG. Figures showing further analysis of EEG to support the EEG data in the main manuscript.

Published
2022
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21. Additional file 2 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Subjects
Data_FILES
Abstract

Additional file 2. Study design.

Published
2022
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22. Additional file 5 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Abstract

Additional file 5. Percent of Participants with Relevant Improvements for each Assessment of the Composite Endpoint by Age Group at 3 and 6 months. A table showing percent of participants with above-threshold improvements for each assessment by age group and time point.

Published
2022
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23. Additional file 4 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Abstract

Additional file 4. EEG supplementary methods. Provides detailed methodology.

Published
2022
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24. Additional file 9 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Subjects
sense organs, skin and connective tissue diseases
Abstract

Additional file 9. Diastolic and systolic blood pressure. Table summarizing the change from baseline data at 2 weeks, 3 months and 6 months.

Published
2022
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25. Additional file 3 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Abstract

Additional file 3. Primary and secondary assessment scales. Provides more detailed information on the scales, including the DS-CGI-I.

Published
2022
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26. Additional file 8 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Subjects
digestive, oral, and skin physiology
Abstract

Additional file 8 Estimated Receptor Occupancy and Pharmacokinetics: Table 1: Estimated Receptor Occupancy from Geomean Trough Basmisanil Plasma Concentrations (ng/mL) by Age Group and Dose. Table showing trough concentrations and estimated receptor occupancy by age group and dose. Table 2: Geomean Trough Basmisanil Plasma Concentration (ng/mL) and Receptor Occupancy by dose. Table showing trough concentrations and estimated receptor occupancy by dose. Table 3: Geomean Trough Basmisanil Plasma Concentrations (ng/mL) in Adolescents and Adults by visit and dose. Table showing trough concentrations by age group, dose, and timepoint.

Published
2022
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27. Additional file 6 of A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-��5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, and d���Ardhuy, Xavier Liogier

Abstract

Additional file 6. VABS-II: Change from baseline at 6 months. Figure showing VABS-II data: composite and individual scores for socialization, communication, and daily living skills.

Published
2022
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28. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author

Mercuri, Eugenio, primary, Deconinck, Nicolas, additional, Mazzone, Elena S, additional, Nascimento, Andres, additional, Oskoui, Maryam, additional, Saito, Kayoko, additional, Vuillerot, Carole, additional, Baranello, Giovanni, additional, Boespflug-Tanguy, Odile, additional, Goemans, Nathalie, additional, Kirschner, Janbernd, additional, Kostera-Pruszczyk, Anna, additional, Servais, Laurent, additional, Gerber, Marianne, additional, Gorni, Ksenija, additional, Khwaja, Omar, additional, Kletzl, Heidemarie, additional, Scalco, Renata S, additional, Staunton, Hannah, additional, Yeung, Wai Yin, additional, Martin, Carmen, additional, Fontoura, Paulo, additional, Day, John W, additional, Volpe, Joseph J., additional, Posner, John, additional, Kellner, Ulrich, additional, Quinlivan, Rosaline, additional, Daron, Aurore, additional, Delstanche, Stéphanie, additional, Bruninx, Romain, additional, Dal Farra, Fabian, additional, Schneider, Olivier, additional, Balikova, Irina, additional, Delbeke, Patricia, additional, Joniau, Inge, additional, Tahon, Valentine, additional, Wittevrongel, Sylvia, additional, De Vos, Elke, additional, Casteels, Ingele, additional, De Waele, Liesbeth, additional, Cassiman, Catherine, additional, Prové, Lies, additional, Kinoo, David, additional, Vancampenhout, Lisa, additional, Van Den Hauwe, Marleen, additional, Van Impe, Annelies, additional, Prufer de Queiroz Campos Araujo, Alexandra, additional, Chacon Pereira, Aline, additional, Nardes, Flávia, additional, Haefeli, Lorena, additional, Rossetto, Julia, additional, Ferreira Rebel, Marcos, additional, Almeida Pereira, Jaqueline, additional, Campbell, Craig, additional, Sharan, Sapna, additional, McDonald, Wendy, additional, Scholtes, Cheryl, additional, Mah, Jean, additional, Sframeli, Maria, additional, Chiu, Angela, additional, Hagel, Jane, additional, Beneish, Raquel, additional, Cariou-Palmer, Gaela, additional, Pham, Connie, additional, Toffoli, Daniela, additional, Arpin, Stephanie, additional, Turgeon Desilets, Sarah, additional, Wang, Yi, additional, Hu, Chaoping, additional, Huan, Jianfeng, additional, Qian, Chen, additional, Shen, Li, additional, Xiao, Ying, additional, Zhou, Zhenxuan, additional, Li, Hui, additional, Wang, Sujuan, additional, Xiong, Hui, additional, Chang, Xingzhi, additional, Dong, Hui, additional, Liu, Ying, additional, Sang, Tian, additional, Wei, Cuijie, additional, Wen, Jing, additional, Cao, Yiwen, additional, Ly, Xingyao, additional, Zhao, Jingjing, additional, Li, Wenzhu, additional, Qin, Lun, additional, Barisic, Nina, additional, Galiot Delic, Martina, additional, Ivkic, Petra Kristina, additional, Vukojevic, Nenad, additional, Kern, Ivana, additional, Najdanovic, Boris, additional, Skugor, Marin, additional, Gidaro, Teresa, additional, Seferian, Andreea, additional, De Lucia, Silvana, additional, Barreau, Emmanuel, additional, Mnafek, Nabila, additional, Momtchilova, Marta Milkova, additional, Peche, Helene, additional, Valherie, Carole, additional, Grange, Allison, additional, Lilien, Charlotte, additional, Milascevic, Darko, additional, Tachibana, Shotaro, additional, Ravelli, Claudia, additional, Cardas, Ruxandra, additional, Taytard, Jessica, additional, Aubertin, Guillaume, additional, Vanden Brande, Laure, additional, Davion, Jean-Baptiste, additional, Coopman, Stephanie, additional, Bouacha, Ikram, additional, Debruyne, Philippe, additional, Defoort, Sabine, additional, Derlyn, Gilles, additional, Leroy, Florian, additional, Danjoux, Loïc, additional, Guilbaud, Julie, additional, Desguerre, Isabelle, additional, Barnérias, Christine, additional, Semeraro, Michaela, additional, Bremond-Gignac, Dominique, additional, Bruere, Lenaic, additional, Rateaux, Maxence, additional, Deladrière, Élodie, additional, Germa, Virginie, additional, Pereon, Yann, additional, Mercie, Sandra, additional, Billaud, Fanny, additional, Le Goff, Lucie, additional, Letellier, Guy, additional, Portefaix, Aurélie, additional, De-Montferrand, Camille, additional, Le-Goff, Laure, additional, Fontaine, Stephanie, additional, Saidi, Manel, additional, Bouzid, Nabil, additional, Barriere, Aurélie, additional, Tinat, Marie, additional, Dreesbach, Michelle, additional, Lagréze, Wolf, additional, Michaelis, Bettina, additional, Molnar, Fanni, additional, Seger, Dorina, additional, Vogt, Sibylle, additional, Bertini, Enrico, additional, D'Amico, Adele, additional, Petroni, Sergio, additional, Bonetti, Anna Maria, additional, Carlesi, Adelina, additional, Mizzoni, Irene, additional, Bruno, Claudio, additional, Priolo, Enrico, additional, Rao, Giuseppe, additional, Morando, Simone, additional, Tacchetti, Paola, additional, Zuffi, Ambra, additional, Comi, Giacomo Pietro, additional, Brusa, Roberta, additional, Corti, Stefania, additional, Daniele, Velardo, additional, Govoni, Alessandra, additional, Magri, Francesca, additional, Minorini, Valeria, additional, Osnaghi, Silvia Gabriella, additional, Abbati, Francesca, additional, Fassini, Federica, additional, Foa, Michaela, additional, Lopopolo, Amaqlia, additional, Meneri, Megi, additional, Zoppas, Francesca, additional, Parente, Valeria, additional, Masson, Riccardo, additional, Bianchi Marzoli, Stefania, additional, Santarsiero, Diletta, additional, Garcia Sierra, Myriam, additional, Tremolada, Gemma, additional, Arnoldi, Maria Teresa, additional, Vigano, Marta, additional, Zanin, Riccardo, additional, Mercuri, Eugenio, additional, Antonaci, Laura, additional, de Sanctis, Roberto, additional, Pane, Marika, additional, Pera, Maria Carmela, additional, Amorelli, Giulia Maria, additional, Barresi, Costanza, additional, D'Amico, Gugliemo, additional, Orazi, Lorenzo, additional, Coratti, Giorgia, additional, Haginoya, Kazuhiro, additional, Kato, Atsuko, additional, Morishita, Yuko, additional, Kira, Ryutaro, additional, Akiyama, Kiyomu, additional, Goto, Miwako, additional, Mori, Yujiro, additional, Okamoto, Misato, additional, Tsutsui, Saki, additional, Takatsuji, Yuta, additional, Tanaka, Aya, additional, Komaki, Hirofumi, additional, Omori, Miina, additional, Suzuki, Ippei, additional, Takeuchi, Mizuki, additional, Todoroki, Daisuke, additional, Watanabe, Seji, additional, Matsubayashi, Tomoko, additional, Inakazu, Emi, additional, Nagura, Hiroe, additional, Suzuki, Akira, additional, Usui, Manami, additional, Ishikawa, Nobutsune, additional, Harada, Yousuke, additional, Fudeyasu, Kenishi, additional, Hirata, Kazuhiko, additional, Michiue, Kana, additional, Ueda, Kazuyuki, additional, Fujitani, Junko, additional, Arakawa, Reiko, additional, Takano, Kozue, additional, Yashiro, Shigeko, additional, Seki, Maiko, additional, Sano, Nozomi, additional, Fukuyama, Koji, additional, Matsumoto, Yuki, additional, Miyazaki, Hirofumi, additional, Shibata, Minoru, additional, Kobayashi, Kyoko, additional, Nakamura, Yukie, additional, Takeshima, Yasuhiro, additional, Kuma, Moe, additional, Fraczek, Anna, additional, Jedrzejowska, Maria, additional, Lusakowska, Anna, additional, Czeszyk-Piotrowicz, Agnieszka, additional, Hautz, Wojciech, additional, Rakusiewicz, Klaudia, additional, Burlewicz, Malgorzata, additional, Gierlak-Wojcicka, Zuzanna, additional, Kepa, Malwina, additional, Sikorski, Adam, additional, Sobieraj, Marcin, additional, Mazurkiewicz-Beldzinska, Maria, additional, Lemska, Anna, additional, Modrzejewska, Sandra, additional, Koberda, Mateusz, additional, Stodolska-Koberda, Urszula, additional, Waskowska, Agnieszka, additional, Kolendo, Jagoda, additional, Sobierajska-Rek, Agnieszka, additional, Steinborn, Barbara, additional, Dalz, Magdalena, additional, Grabowska, Julia, additional, Hajduk, Wojciech, additional, Janasiewicz-Karachitos, Justyna, additional, Klimas, Monika, additional, Stopa, Marcin, additional, Gajewska, Ewa, additional, Pusz, Beata, additional, Vlodavets, Dmitry, additional, Melnik, Evgenia, additional, Leppenen, Natalya, additional, Yupatova, Nataliya, additional, Monakhova, Anastasya, additional, Papina, Yulia, additional, Shidlovsckaia, Olga, additional, Milic Rasic, Vedrana, additional, Brankovic, Vesna, additional, Kosac, Ana, additional, Djokic, Olivera, additional, Jakšic, Vesna, additional, Pepic, Ana, additional, Martinovic, Jelena, additional, Munell Casadesus, Francina, additional, Tizzano, Eduardo, additional, Martín Begué, Nieves, additional, Wolley Dod, Charlotte, additional, Subira, Olaia, additional, Planas Pascual, Bernat, additional, Toro Tamargo, Esther, additional, Madruga Garrido, Marcos, additional, Medina Romero, José David, additional, Salinas, Marta Peña, additional, Nascimento Osorio, Andrés, additional, Díaz Cortés, Ana, additional, Jiménez Gañan, Enrique, additional, Suh, Simone Dowon, additional, Medina Cantillo, Julita, additional, Moya, Obdulia, additional, Padros, Nuria, additional, Urraca, Sandra Roca, additional, Valdivia, Hugo Gonzalez, additional, Pascual Pascual, Samuel, additional, de Manuel, Sofía, additional, Martin, Susana Noval, additional, Burnham, Paul, additional, Espinosa, Sandra, additional, Moreno, Mercedes Martinez, additional, Topaloglu, Haluk, additional, Oncel, Ibrahim, additional, Eroglu Ertugru, Nesibe, additional, Konuskan, Bahadir, additional, Eldem, Bora, additional, Kadayifçilar, Sibel, additional, Alemdaroglu, Ipek, additional, Karaduman, Aynur Ayse, additional, Yilmaz, Oznur Tunca, additional, Bilgin, Neslihan, additional, Sari, Seher, additional, Chiriboga, Claudia, additional, Lee, John J., additional, Rome-Martin, Donnielle, additional, Day, John W., additional, Beres, Shannon, additional, Duong, Tina, additional, Gee, Richard, additional, Dunaway Young, Sally, additional, Fuerst-Recktenwald, Sabine, additional, Marquet, Anne, additional, Muelhardt, Nicoletta, additional, and Trundell, Dylan, additional

Published
2022
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29. Efficacy of a vectorized anti‐tau antibody using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies

Author

Liu, Wencheng, primary, Holth, Jerrah, additional, Paranjpe, Maneesha, additional, Ren, Xiao‐Qin, additional, Shu, Yanqun, additional, Murlidharan, Giridhar, additional, Chung, Charlotte, additional, Powers, Alex, additional, Peterson, Emalee, additional, Ecker, Abigail, additional, Hameedi, Usman, additional, Grant, Kyle, additional, Kurella, Vinodh, additional, Kavanagh, Dillon, additional, Khwaja, Omar, additional, Hou, Jay, additional, Paul, Steven M., additional, Bales, Kelly R., additional, and Carter, Todd, additional

Published
2021
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30. Convergent Cerebrospinal Fluid Proteomes and Metabolic Ontologies in Humans and Animal Models of Rett Syndrome

Author

Zlatic, Stephanie A., primary, Duong, Duc, additional, Gadalla, Kamal K.E., additional, Murage, Brenda, additional, Ping, Lingyan, additional, Shah, Ruth, additional, Khwaja, Omar, additional, Swanson, Lindsay C., additional, Sahin, Mustafa, additional, Rayaprolu, Sruti, additional, Kumar, Prateek, additional, Rangaraju, Srikant, additional, Bird, Adrian, additional, Tarquinio, Daniel, additional, Cobb, Stuart, additional, and Faundez, Victor, additional

Published
2021
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31. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls

Author

Darras, Basil T, Masson, Riccardo, Mazurkiewicz-Bełdzińska, Maria, Rose, Kristy, Xiong, Hui, Zanoteli, Edmar, Baranello, Giovanni, Bruno, Claudio, Vlodavets, Dmitry, Wang, Yi, El-Khairi, Muna, Gerber, Marianne, Gorni, Ksenija, Khwaja, Omar, Kletzl, Heidemarie, Scalco, Renata S, Fontoura, Paulo, Servais, Laurent, Joseph J, Volpe, John, Posner, Armin, Koch, Ulrich, Kellner, Rosaline, Quinlivan, Nicolas, Deconinck, Irina, Balikova, Patricia, Delbeke, Inge, Joniau, Valentine, Tahon, Sylvia, Wittevrongel, Elke De Vos, Rodrigo de Holanda Mendonça, Ciro Matsui Jr, Ana Letícia Fornazieri Darcie, Cleide, Machado, Maria Kiyoko Oyamada, Daniel de Souza Costa, Joyce, Martini, Graziela, Polido, Juliana Rodrigues Iannicelli, Juliana Caires de Oliveira Achili Ferreira, Chaoping, Hu, Yiyun, Shi, Shuizhen, Zhou, Xiaomei, Zhu, Chen, Qian, Shen, Li, Ying, Xiao, Zhenxuan, Zhou, Hui, Li, Sujuan, Wang, Tian, Sang, Cuijie, Wei, Jing, Wen, Yiwen, Cao, Wenzhu, Li, Lun, Qin, Nina, Barisic, Ivan, Celovec, Martina, Martina, Galiot, Delic, Petra Kristina Ivkić, Nenad, Vukojević, Ivana, Kern, Boris, Najdanovic, Marin, Skugor, Odile, Boespflug-Tanguy, Teresa, Gidaro, Andrea, Seferian, Emmanuel, Barreau, Elodie Da Cunha, Céline, Lambotin, Nabila, Mnafek, Helene, Peche, Stephanie, Gilabert, Allison, Grange, Charlotte, Lilien, Darko, Milascevic, Ariadna, Perticari, Shotaro, Tachibana, Emanuela, Pagliano, Stefania Bianchi Marzoli, Diletta, Santarsiero, Myriam Garcia Sierra, Gemma, Tremolada, Maria Teresa Arnoldi, Marta, Vigano, Riccardo, Zanin, Noemi, Brolatti, Marina, Pedemonte, Enrico, Priolo, Giuseppe, Rao, Enrica, Spaletra, Lorenza, Sposetti, Elisa, Tassara, Simone, Morando, Paola, Tacchetti, Giacomo Pietro Comi, Alessandra, Govoni, Silvia Gabriella Osnaghi, Valeria, Minorini, Francesca, Abbati, Federica, Fassini, Michaela, Foa, Amalia, Lopopolo, Elisa, Minuti, Mercuri, Eugenio Maria, Pane, Marika, Concetta, Palermo, Pera, Maria Carmela, Amorelli, Giulia Maria, Costanza, Barresi, Gugliemo, D'Amico, Orazi, Lorenzo, Coratti, Giorgia, De Sanctis, Roberto, Yasuhiro, Takeshima, Fumi, Gomi, Naoki, Kimura, Takanobu, Morimatsu, Mana, Okamoto, Toru, Furukawa, Mateusz, Koberda, Natalia, Kubiak, Urszula, Stodolska-Koberda, Agnieszka, Waśkowska, Jagoda, Kolendo, Agnieszka, Sobierajska-Rek, Svetlana, Artemyeva, Evgenia, Melnik, Natalya, Leppenen, Nataliya, Yupatova, Elena, Litvinova, Anastasya, Monakhova, Yulia, Papina, Olga, Shidlovsckaia, Andrea, Klein, Cornelia, Enzmann, Elea, Galiart, Konstantin, Gugleta, Patricia, Siems, Verena, Kreiliger, Christine Wondrusch Haschke, Haluk, Topaloglu, Ibrahim, Oncel, Didem, Ardicli, Nesibe Eroglu Ertugrul, Hizal, Gharibzadeh, Ceren, Gunbey, Bahadir, Konuskan, Selen Serel Arslan, Elams Ebru Yalcin, Fatma Gokcem Yildiz Sarikaya, Bora, Eldem, Sibel, Kadayıfçılar, Ipek, Alemdaroglu, Aynur Ayse Karaduman, Oznur Tunca Yilmaz, Robert, J Graham, Partha, Ghosh, David, Casavant, Brian, Snyder, Alexis, Levine, Rachael, Titus, Amanda, Engelbrekt, Lucia, Ambrosio, Anne, Fulton, Anna Maria Baglieri, Courtney, Dias, Elizabeth, Maczek, Elizabeth, Mirek, Amy, Pasternak, John, W Day, Shannon, Beres, Tina, Duong, Richard, Gee, Sally, Young, Darras, Basil T, Masson, Riccardo, Mazurkiewicz-Bełdzińska, Maria, Rose, Kristy, Xiong, Hui, Zanoteli, Edmar, Baranello, Giovanni, Bruno, Claudio, Vlodavets, Dmitry, Wang, Yi, El-Khairi, Muna, Gerber, Marianne, Gorni, Ksenija, Khwaja, Omar, Kletzl, Heidemarie, Scalco, Renata S, Fontoura, Paulo, Servais, Laurent, and Ambrosio, Lucia

Subjects
Male, medicine.medical_specialty, Neuromuscular disease, Risdiplam, Type 1 Spinal Muscular Atrophy, treated infants, historical controls, MEDLINE, Spinal Muscular Atrophies of Childhood, Severity of Illness Index, Text mining, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Internal medicine, Severity of illness, medicine, Humans, Progression-free survival, 610 Medicine & health, business.industry, Historically Controlled Study, Infant, General Medicine, Spinal muscular atrophy, SMA, medicine.disease, Progression-Free Survival, Settore MED/26 - NEUROLOGIA, Pyrimidines, Neuromuscular Agents, Motor Skills, Female, business, Azo Compounds
Abstract

BACKGROUND Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P

Published
2021

34. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls

Author

Darras, Basil T., primary, Masson, Riccardo, additional, Mazurkiewicz-Bełdzińska, Maria, additional, Rose, Kristy, additional, Xiong, Hui, additional, Zanoteli, Edmar, additional, Baranello, Giovanni, additional, Bruno, Claudio, additional, Vlodavets, Dmitry, additional, Wang, Yi, additional, El-Khairi, Muna, additional, Gerber, Marianne, additional, Gorni, Ksenija, additional, Khwaja, Omar, additional, Kletzl, Heidemarie, additional, Scalco, Renata S., additional, Fontoura, Paulo, additional, and Servais, Laurent, additional

Published
2021
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35. In Search of Biomarkers for Autism Spectrum Disorder

Author

Del Valle Rubido, Marta, McCracken, James T., Hollander, Eric, Shic, Frederick, Noeldeke, Jana, Boak, Lauren, Khwaja, Omar, Sadikhov, Shamil, Fontoura, Paulo, and Umbricht, Daniel

Subjects
Adult, Male, genetic structures, Eye Movements, Autism Spectrum Disorder, Intelligence, social cognition, Neuropsychological Tests, behavioral disciplines and activities, Severity of Illness Index, mental disorders, Humans, Interpersonal Relations, eye movement, Research Articles, Intelligence Tests, Communication, Reproducibility of Results, Recognition, Psychology, Olfactory Perception, olfactory, Treatment, biomarker, Female, Biomarkers, Research Article
Abstract

Autism Spectrum Disorder (ASD) lacks validated measures of core social functions across development stages suitable for clinical trials. We assessed the concurrent validity between ASD clinical measures and putative biomarkers of core deficits, and their feasibility of implementation in human studies. Datasets from two adult ASD studies were combined (observational study [n = 19] and interventional study baseline data [n = 19]). Potential biomarkers included eye-tracking, olfaction, and auditory and visual emotion recognition assessed via the Affective Speech Recognition test (ASR) and Reading-the-Mind-in-the-Eyes Test (RMET). Current functioning was assessed with intelligence quotient (IQ), adaptive skill testing, and behavioral ratings. Autism severity was determined by the Autism Diagnostic Observation Scale-2 and Social Communication Interaction Test (SCIT). Exploratory measures showed varying significant associations across ASD severity, adaptive skills, and behavior. Eye tracking endpoints showed little relationship to adaptive ability but correlated with severity and behavior. ASR scores significantly correlated with most adaptive behavior domains, as well as severity. Olfaction predicted visual and auditory emotion recognition. SCIT scores related moderately to multiple severity domains, and was the only measure not related with IQ. RMET accuracy was less related to ASD features. Eye tracking, SCIT, and ASR showed high test-retest reliability. We documented associations of proximal biomarkers of social functioning with multiple ASD dimensions. With the exception of SCIT, most correlations were modest, limiting utility as proxy measures of social communication. Feasibility and reliability were high for eye-tracking, ASR, and SCIT. Overall, several novel experimental paradigms showed potential as social biomarkers or surrogate markers in ASD. Autism Research 2018, 11: 1567-1579. © 2018 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: More accurate measurements of treatment effects are needed to help the development of new drug treatments for autism spectrum disorders (ASD). This study evaluates the relationship between assessments designed to measure behaviors associated with social communication and cognition in ASD with clinical and diagnostic assessments of symptom severity as well as their implementation. The assessments including eye-tracking, auditory and visual social stimuli recognition, and olfaction identification showed potential for use in the evaluation of treatments for social difficulties in ASD.

Published
2018

36. Risdiplam in Type 1 Spinal Muscular Atrophy

Author

Baranello, Giovanni, Darras, Basil T, Day, John W, Deconinck, Nicolas, Klein, Andrea, Masson, Riccardo, Mercuri, Eugenio Maria, Rose, Kristy, El-Khairi, Muna, Gerber, Marianne, Gorni, Ksenija, Khwaja, Omar, Kletzl, Heidemarie, Scalco, Renata S, Seabrook, Timothy, Fontoura, Paulo, Servais, Laurent, FIREFISH Working Group: Joseph, J Volpe, John, Posner, Armin, Koch, Ulrich, Kellner, Rosaline, Quinlivan, Irina, Balikova, Patricia, Delbeke, Inge, Joniau, Valentine, Tahon, Sylvia, Wittevrongel, Elke De Vos, Edmar, Zanoteli, Rodrigo de Holanda Mendonça, Ciro Matsui Jr, Ana Letícia Fornazieri Darcie, Cleide, Machado, Maria Kiyoko Oyamada, Daniel de Souza Costa, Joyce, Martini, Graziela, Polido, Juliana Rodrigues Iannicelli, Juliana Caires de Oliveira Achili Ferreira, Wang, Yi, Chaoping, Hu, Yiyun, Shi, Shuizhen, Zhou, Xiaomei, Zhu, Chen, Qian, Shen, Li, Ying, Xiao, Zhenxuan, Zhou, Hui, Li, Sujuan, Wang, Hui, Xiong, Tian, Sang, Cuijie, Wei, Jing, Wen, Yiwen, Cao, Wenzhu, Li, Lun, Qin, Nina, Barisic, Ivan, Celovec, Martina Galiot Delic, Petra Kristina Ivkić, Nenad, Vukojević, Ivana, Kern, Boris, Najdanovic, Marin, Skugor, Odile, Boespflug-Tanguy, Teresa, Gidaro, Andrea, Seferian, Emmanuel, Barreau, Elodie Da Cunha, Céline, Lambotin, Nabila, Mnafek, Helene, Peche, Stephanie, Gilabert, Allison, Grange, Charlotte, Lilien, Darko, Milascevic, Ariadna, Perticari, Shotaro, Tachibana, Emanuela, Pagliano, Bianchi Marzoli, Stefania, Diletta, Santarsiero, Myriam Garcia Sierra, Gemma, Tremolada, Maria Teresa Arnoldi, Marta, Vigano, Riccardo, Zanin, Bissoli, Claudio Bruno, Noemi, Brolatti, Marina, Pedemonte, Enrico, Priolo, Giuseppe, Rao, Enrica, Spaletra, Lorenza, Sposetti, Elisa, Tassara, Simone, Morando, Paola, Tacchetti, Giacomo Pietro Comi, Alessandra, Govoni, Silvia Gabriella Osnaghi, Valeria, Minorini, Francesca, Abbati, Federica, Fassini, Michaela, Foa, Amalia, Lopopolo, Elisa, Minuti, Pane, Marika, Concetta, Palermo, Pera, Maria Carmela, Amorelli, Giulia Maria, Costanza, Barresi, Gugliemo, D'Amico, Orazi, Lorenzo, Coratti, Giorgia, De Sanctis, Roberto, Yasuhiro, Takeshima, Fumi, Gomi, Naoki, Kimura, Takanobu, Morimatsu, Mana, Okamoto, Toru, Furukawa, Maria, Mazurkiewicz-Bełdzińska, Mateusz, Koberda, Natalia, Kubiak, Urszula, Stodolska-Koberda, Agnieszka, Waśkowska, Jagoda, Kolendo, Agnieszka, Sobierajska-Rek, Dmitry, Vlodavets, Svetlana, Artemyeva, Evgenia, Melnik, Natalya, Leppenen, Nataliya, Yupatova, Elena, Litvinova, Anastasya, Monakhova, Yulia, Papina, Olga, Shidlovsckaia, Cornelia, Enzmann, Elea, Galiart, Konstantin, Gugleta, Patricia, Siems, Verena, Kreiliger, Christine Wondrusch Haschke, Haluk, Topaloglu, Ibrahim, Oncel, Didem, Ardicli, Nesibe Eroglu Ertugrul, Hizal, Gharibzadeh, Ceren, Gunbey, Bahadir, Konuskan, Selen Serel Arslan, Elams Ebru Yalcin, Fatma Gokcem Yildiz Sarikaya, Bora, Eldem, Sibel, Kadayıfçılar, Ipek, Alemdaroglu, Aynur Ayse Karaduman, Oznur Tunca Yilmaz, Lucia, Ambrosio, Anne, Fulton, Anna Maria Baglieri, Courtney, Dias, Elizabeth, Maczek, Elizabeth, Mirek, Amy, Pasternak, Shannon, Beres, Tina, Duong, Richard, Gee, Sally, Young, Giovanni, Baranello, Basil T, Darra, John W, Day, Nicolas, Deconinck, Andrea, Klein, Riccardo, Masson, Eugenio, Mercuri, Kristy, Rose, Muna, El-Khairi, Marianne, Gerber, Ksenija, Gorni, Omar, Khwaja, Heidemarie, Kletzl, Renata S, Scalco, Timothy, Seabrook, Paulo, Fontoura, Laurent, Servai, and Ambrosio, Lucia

Subjects
Male, Oral, Neuromuscular disease, RNA Splicing, Administration, Oral, 030204 cardiovascular system & hematology, Spinal Muscular Atrophies of Childhood, Bioinformatics, Dose-Response Relationship, 03 medical and health sciences, 0302 clinical medicine, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, medicine, Humans, Risdiplam, Type 1 Spinal Muscular Atrophy, 030212 general & internal medicine, Progression-free survival, 610 Medicine & health, Respiratory Tract Infections, Dose-Response Relationship, Drug, business.industry, Infant, Survival of motor neuron, General Medicine, Spinal muscular atrophy, medicine.disease, Survival of Motor Neuron 1 Protein, Progression-Free Survival, Clinical trial, Dose–response relationship, Settore MED/26 - NEUROLOGIA, Pyrimidines, nervous system, Neuromuscular Agents, RNA splicing, Administration, Female, Drug, business, Respiratory Insufficiency, Azo Compounds
Abstract

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Published
2021

37. Haematological effects of oral administration of bitopertin, a glycine transport inhibitor, in patients with non‐transfusion‐dependent β‐thalassaemia

Author

Taher, Ali T., primary, Viprakasit, Vip, additional, Cappellini, Maria Domenica, additional, Kraus, Dominik, additional, Cech, Patrick, additional, Volz, Dietmar, additional, Winter, Erica, additional, Nave, Stephane, additional, Dukart, Juergen, additional, Khwaja, Omar, additional, Koerner, Annette, additional, Hermosilla, Ricardo, additional, and Brugnara, Carlo, additional

Published
2021
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38. Risdiplam in Type 1 Spinal Muscular Atrophy

Author

Baranello, Giovanni, primary, Darras, Basil T., additional, Day, John W., additional, Deconinck, Nicolas, additional, Klein, Andrea, additional, Masson, Riccardo, additional, Mercuri, Eugenio, additional, Rose, Kristy, additional, El-Khairi, Muna, additional, Gerber, Marianne, additional, Gorni, Ksenija, additional, Khwaja, Omar, additional, Kletzl, Heidemarie, additional, Scalco, Renata S., additional, Seabrook, Timothy, additional, Fontoura, Paulo, additional, and Servais, Laurent, additional

Published
2021
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41. Weight Status in the First 2 Years of Life and Neurodevelopmental Impairment in Extremely Low Gestational Age Newborns

Author

Belfort, Mandy B., Kuban, Karl C.K., OʼShea, Michael T., Allred, Elizabeth N., Ehrenkranz, Richard A., Engelke, Stephen C., Leviton, Alan, Lee, Kathleen, McGovern, Anne, Gambardella, Jill, Ursprung, Susan, Ecklund, Ruth Blomquist Kristen, Bassan, Haim, Butler, Samantha, Duplessis, Adré, Hahn, Cecil, Limperopoulos, Catherine, Khwaja, Omar, Soul, Janet S., Shah, Bhavesh, Christianson, Karen, Hampf, Frederick, Gilmore, Herbert, McQuiston, Susan, Martin, Camilia R., Hallisey, Colleen, Hurley, Caitlin, Creixell, Miren, Share, Jane, Van Marter, Linda J., Durfee, Sara, Insoft, Robert M., Wilson, Jennifer G., Pimental, Maureen, Westra, Sjirk J., Krishnamoorthy, Kalpathy, Cole, Cynthia, Fiascone, John M., Madden, Janet, Nylen, Ellen, Furey, Anne, McCauley, Roy, Church, Paige T., Keller, Cecelia, Miller, Karen J., Bednarek, Francis, Naples, Mary, Powers, Beth, Wellman, Jacqueline, Adair, Robin, Bream, Richard, Miller, Alice, Scheiner, Albert, Stine, Christy, Ehrenkranz, Richard, Williams, Joanne, Romano, Elaine, Miller, Cindy, Close, Nancy, OʼShea, Michael T., Gordon, Debbie, Harold, Teresa, Specter, Barbara, Allred, Deborah, Dillard, Robert, Goldstein, Don, Hiatt, Deborah, Hounshell, Gail, Waldrep, Ellen, Washburn, Lisa, Welch, Cherrie D., Engelke, Stephen C., Moseley, Sherry, Pare, Linda, Smart, Donna, Wilson, Joan, Adler, Ira, Buckwald, Sharon, Helms, Rebecca, Kerkering, Kathyrn, MacGilvray, Scott S., Resnik, Peter, Bose, Carl, Bose, Gennie, Fordham, Lynn A., Bostic, Lisa, Marshall, Diane, Milowic, Kristi, Wereszczak, Janice, Poortenga, Mariel, Sutton, Dinah, Betz, Bradford W., Bezinque, Steven L., Junewick, Joseph, Burdo-Hartman, Wendy, Fagerman, Lynn, Lohr, Kim, Pastyrnak, Steve, Solomon, Carolyn, Cavenagh, Ellen, Caine, Victoria J., Olomu, Nicholas, Price, Joan, Paneth, Nigel, Karna, Padmani, Lenski, Madeleine, Schreiber, Michael D., Yoon, Grace, Feinstein, Kate, Caldarelli, Leslie, OʼConnor, Sunila E., Msall, Michael, Plesha-Troyke, Susan, Batton, Daniel, Kring, Beth, Brooklier, Karen, Oca, Melisa J., and Solomon, Katherine M.

Published
2016
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42. Copy number variation plays an important role in clinical epilepsy

Author

Olson, Heather, Shen, Yiping, Avallone, Jennifer, Sheidley, Beth R., Pinsky, Rebecca, Bergin, Ann M., Berry, Gerard T., Duffy, Frank H., Eksioglu, Yaman, Harris, David J., Hisama, Fuki M., Ho, Eugenia, Irons, Mira, Jacobsen, Christina M., James, Philip, Kothare, Sanjeev, Khwaja, Omar, Lipton, Jonathan, Loddenkemper, Tobias, Markowitz, Jennifer, Maski, Kiran, Megerian, Thomas J., Neilan, Edward, Raffalli, Peter C., Robbins, Michael, Roberts, Amy, Roe, Eugene, Rollins, Caitlin, Sahin, Mustafa, Sarco, Dean, Schonwald, Alison, Smith, Sharon E., Soul, Janet, Stoler, Joan M., Takeoka, Masanori, Tan, Wen-Han, Torres, Alcy R., Tsai, Peter, Urion, David K., Weissman, Laura, Wolff, Robert, Wu, Bai-Lin, Miller, David T., and Poduri, Annapurna

Published
2014
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43. A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome.

Author

Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar, Lennon-Chrimes, Sian, Noeldeke, Jana, Pellicer, Sabine, Squassante, Lisa, Visootsak, Jeannie, Wandel, Christoph, Fontoura, Paulo, d'Ardhuy, Xavier Liogier, Clematis Study Group, De La Torre Fornell, Rafael, Glue, Paul, and Hoover-Fong, Julie

Subjects
DOWN syndrome, INTELLECTUAL disabilities, EXECUTIVE function, YOUNG adults, COGNITIVE ability, ADULTS
Abstract

Background: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. Methods: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12–13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. Results: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. Conclusions: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. Trial registration: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789. [ABSTRACT FROM AUTHOR]

Published
2022
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48. Severity Assessment in CDKL5 Deficiency Disorder

Author

Demarest, Scott, primary, Pestana-Knight, Elia M., additional, Olson, Heather E., additional, Downs, Jenny, additional, Marsh, Eric D., additional, Kaufmann, Walter E., additional, Partridge, Carol-Anne, additional, Leonard, Helen, additional, Gwadry-Sridhar, Femida, additional, Frame, Katheryn Elibri, additional, Cross, J. Helen, additional, Chin, Richard F.M., additional, Parikh, Sumit, additional, Panzer, Axel, additional, Weisenberg, Judith, additional, Utley, Karen, additional, Jaksha, Amanda, additional, Amin, Sam, additional, Khwaja, Omar, additional, Devinsky, Orrin, additional, Neul, Jeffery L., additional, Percy, Alan K., additional, and Benke, Tim A., additional

Published
2019
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50. Update from SUNFISH Part 1: Safety, Tolerability and PK/PD from the Dose-Finding Study, Including Exploratory Efficacy Data in Patients with Type 2 or 3 Spinal Muscular Atrophy (SMA) Treated with Risdiplam (RG7916) (S25.007)

Author

Mercuri, Eugenio, primary, Baranello, Giovanni, additional, Kirschner, Janbernd, additional, Servais, Laurent, additional, Goemans, Nathalie, additional, Pera, Maria Carmela, additional, Buchbjerg, Jeppe, additional, Yeung, Wai Yin, additional, Kletzl, Heidemarie, additional, Gerber, Marianne, additional, Czech, Christian, additional, Cleary, Yumi, additional, Gorni, Ksenija, additional, and Khwaja, Omar, additional

Published
2019
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