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3. 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, R., Mazurkiewicz-Bełdzińska, M., Rose, K., Servais, L., Xiong, H., Zanoteli, E., Baranello, Giovanni, Bruno, C., Day, J. W., Deconinck, N., Klein, A., Mercuri, Eugenio Maria, Vlodavets, D., Wang, Y., Dodman, A., El-Khairi, M., Gorni, K., Jaber, B., Kletzl, H., Gaki, E., Fontoura, P., Darras, B. T., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Gerber, M., Khwaja, O., Scalco, R. S., Seabrook, T., Koch, A., Balikova, I., Joniau, I., Accou, G., Tahon, V., Wittevrongel, S., De Vos, E., de Holanda Mendonça, R., Matsui, C., Fornazieri Darcie, A. L., Machado, C., Kiyoko Oyamada, M., Martini, J., Polido, G., Rodrigues Iannicelli, J., Caires de Oliveira Achili Ferreira, J., Hu, C., Zhu, X., Qian, C., Shen, L., Li, H., Shi, Y., Zhou, S., Xiao, Y., Zhou, Z., Wang, S., Sang, T., Wei, C., Dong, H., Cao, Y., Wen, J., Li, W., Qin, L., Barisic, N., Celovec, I., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Tomas, J., Boespflug-Tanguy, O., De Lucia, S., Seferian, A., Barreau, E., Mnafek, N., Peche, H., Grange, A., Trang Nguyen, D., Milascevic, D., Tachibana, S., Pagliano, E., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Dosi, C., Zanin, R., Schembri, V., Brolatti, N., Rao, G., Tassara, E., Morando, S., Tacchetti, P., Pedemonte, M., Priolo, E., Sposetti, L., Baranello G., Mercuri E. (ORCID:0000-0002-9851-5365), Masson, R., Mazurkiewicz-Bełdzińska, M., Rose, K., Servais, L., Xiong, H., Zanoteli, E., Baranello, Giovanni, Bruno, C., Day, J. W., Deconinck, N., Klein, A., Mercuri, Eugenio Maria, Vlodavets, D., Wang, Y., Dodman, A., El-Khairi, M., Gorni, K., Jaber, B., Kletzl, H., Gaki, E., Fontoura, P., Darras, B. T., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Gerber, M., Khwaja, O., Scalco, R. S., Seabrook, T., Koch, A., Balikova, I., Joniau, I., Accou, G., Tahon, V., Wittevrongel, S., De Vos, E., de Holanda Mendonça, R., Matsui, C., Fornazieri Darcie, A. L., Machado, C., Kiyoko Oyamada, M., Martini, J., Polido, G., Rodrigues Iannicelli, J., Caires de Oliveira Achili Ferreira, J., Hu, C., Zhu, X., Qian, C., Shen, L., Li, H., Shi, Y., Zhou, S., Xiao, Y., Zhou, Z., Wang, S., Sang, T., Wei, C., Dong, H., Cao, Y., Wen, J., Li, W., Qin, L., Barisic, N., Celovec, I., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Tomas, J., Boespflug-Tanguy, O., De Lucia, S., Seferian, A., Barreau, E., Mnafek, N., Peche, H., Grange, A., Trang Nguyen, D., Milascevic, D., Tachibana, S., Pagliano, E., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Dosi, C., Zanin, R., Schembri, V., Brolatti, N., Rao, G., Tassara, E., Morando, S., Tacchetti, P., Pedemonte, M., Priolo, E., Sposetti, L., Baranello G., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. Methods: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural his

Published
2022

4. 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 Maria, Deconinck, N., Mazzone, Elena Stacy, Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, Giovanni, Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, Craig, Fontoura, P., Day, J. W., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Casteels, I., De Waele, L., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., Mcdonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Gidaro, T., Seferian, A., De Lucia, Sara Sofia, Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J. -B., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, Enrico Silvio, D'Amico, Adele, Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, Serafino, Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Masson, R., Bianchi Marzoli, Stefania, Santarsiero, Rocco Domenico, Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, Renata, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Beres, S., Duong, T., Gee, R., Dunaway Young, S., Mercuri E. (ORCID:0000-0002-9851-5365), Mazzone E. S., Baranello G., Martin C., De Lucia S., Bertini E., D'Amico A., Corti S., Bianchi Marzoli S., Santarsiero D., Zanin R., Amorelli G. M., D'Amico G., Orazi L., Coratti G. (ORCID:0000-0001-6666-5628), Mercuri, Eugenio Maria, Deconinck, N., Mazzone, Elena Stacy, Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, Giovanni, Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, Craig, Fontoura, P., Day, J. W., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Casteels, I., De Waele, L., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., Mcdonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Gidaro, T., Seferian, A., De Lucia, Sara Sofia, Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J. -B., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, Enrico Silvio, D'Amico, Adele, Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, Serafino, Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Masson, R., Bianchi Marzoli, Stefania, Santarsiero, Rocco Domenico, Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, Renata, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Beres, S., Duong, T., Gee, R., Dunaway Young, S., Mercuri E. (ORCID:0000-0002-9851-5365), Mazzone E. S., Baranello G., Martin C., De Lucia S., Bertini E., D'Amico A., Corti S., Bianchi Marzoli S., Santarsiero D., Zanin R., Amorelli G. M., D'Amico G., Orazi L., and Coratti G. (ORCID:0000-0001-6666-5628)

Abstract

Background: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. Methods: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2–25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing. Findings: Between Oct 9, 2017, and Sept 4, 2018, 180 patients were rand

Published
2022

9. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders

Author

Miller, D T, Shen, Y, Weiss, L A, Korn, J, Anselm, I, Bridgemohan, C, Cox, G F, Dickinson, H, Gentile, J, Harris, D J, Hegde, V, Hundley, R, Khwaja, O, Kothare, S, Luedke, C, Nasir, R, Poduri, A, Prasad, K, Raffalli, P, Reinhard, A, Smith, S E, Sobeih, M M, Soul, J S, Stoler, J, Takeoka, M, Tan, W-H, Thakuria, J, Wolff, R, Yusupov, R, Gusella, J F, Daly, M J, and Wu, B-L

Published
2009
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11. The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: Results from trials in healthy adults and patients with spinal muscular atrophy.

Author

Kletzl, H, Marquet, A, Günther, A, Tang, W, Heuberger, J, Groeneveld, Gj, Birkhoff, W, Mercuri, E, Lochmüller, H, Wood, C, Fischer, D, Gerlach, I, Heinig, K, Bugawan, T, Dziadek, S, Kinch, R, Czech, C, Khwaja, O., Mercuri E (ORCID:0000-0002-9851-5365), Kletzl, H, Marquet, A, Günther, A, Tang, W, Heuberger, J, Groeneveld, Gj, Birkhoff, W, Mercuri, E, Lochmüller, H, Wood, C, Fischer, D, Gerlach, I, Heinig, K, Bugawan, T, Dziadek, S, Kinch, R, Czech, C, Khwaja, O., and Mercuri E (ORCID:0000-0002-9851-5365)

Abstract

Spinal muscular atrophy (SMA) is a rare genetic and progressively debilitating neuromuscular disease. It is the leading genetic cause of death among infants. In SMA, low levels of survival of motor neuron (SMN) protein lead to motor neuron death and muscle atrophy as the SMN protein is critical to motor neuron survival. SMA is caused by mutations in, or deletion of, the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein due to alternative splicing which excludes exon 7 from most transcripts, generating truncated, rapidly degraded SMN protein. Patients with SMA rely on limited expression of functional SMN full-length protein from the SMN2 gene, but insufficient levels are generated. RG7800 is an oral, selective SMN2 splicing modifier designed to modulate alternative splicing of SMN2 to increase the levels of functional SMN protein. In two trials, oral administration of RG7800 increased in blood full-length SMN2 mRNA expression in healthy adults and SMN protein levels in SMA patients by up to two-fold, which is expected to provide clinical benefit. Copyright © 2018 Elsevier B.V. All rights reserved. KEYWORDS: Neuromuscular disease; SMN protein; SMN2 splicing modifier; Spinal muscular atrophy; Survival of motor neuron

Published
2019

14. P.063 SUNFISH Part 1 results and Part 2 trial design in patients with type 2/3 spinal muscular atrophy (SMA) receiving risdiplam (RG7916)

Author

Campbell, C, primary, Mercuri, E, additional, Baranello, G, additional, Kirschner, J, additional, Servais, L, additional, Goemans, N, additional, Pera, M, additional, Buchbjerg, J, additional, Yeung, W, additional, Kletzl, H, additional, Gerber, M, additional, Czech, C, additional, Cleary, Y, additional, Gorni, K, additional, and Khwaja, O, additional

Published
2019
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15. P.064 FIREFISH Part 1: 1-year results on motor function in infants with Type 1 spinal muscular atrophy (SMA) receiving risdiplam (RG7916)

Author

Seabrook, TJ, primary, Baranello, G, additional, Servais, L, additional, Day, JW, additional, Deconinck, N, additional, Mercuri, E, additional, Klein, A, additional, Darras, B, additional, Masson, R, additional, Kletzl, H, additional, Cleary, Y, additional, El-Khairi, M, additional, Czech, C, additional, Gerber, M, additional, Nguyen, C, additional, Gelblin, K, additional, Gorni, K, additional, Khwaja, O, additional, and Cabalteja, C, additional

Published
2019
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16. 209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands

Author

Finkel, R, Bertini, Enrico Silvio, Muntoni, F, Mercuri, Eugenio Maria, Chen, K, Kirschner, J, De Lemus, M, Hogrel, Jy, Khwaja, O, Main, M, Mazzone, E, Montes, J, Ramsey, D, Sejersen, T, Sumner, C, Swoboda, K, Tiziano, Francesco Danilo, Tseng, B, Van Der Pol, L, Villerot, C, Wirth, B, Witchen, A, Yeh, Ws, and Zittersteijn, A.

Subjects
Gerontology, medicine.medical_specialty, business.industry, education, Outcome measures, Spinal muscular atrophy, Outcome assessment, Settore MED/03 - GENETICA MEDICA, medicine.disease, humanities, Child health, Clinical trial, Neurology, Family medicine, Pediatrics, Perinatology and Child Health, inglese, medicine, Neurology (clinical), Pediatric Neurology, business, Genetics (clinical)
Abstract

209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands Richard Finkel *, Enrico Bertini , Francesco Muntoni , Eugenio Mercuri d on behalf of the ENMC SMA Workshop Study Group 1 a Nemours Children’s Hospital, Orlando, USA b UCL Institute of Child Health, Dubowitz Neuromuscular Centre, London, UK c Bambino Gesu Children’s Research Hospital, Rome, Italy d Pediatric Neurology Unit, Catholic University, Rome, Italy Received 2 March 2015

Published
2015

17. SMA THERAPIES II AND BIOMARKERS

Author

Baranello, G., primary, Servais, L., additional, Day, J., additional, Deconinck, N., additional, Mercuri, E., additional, Klein, A., additional, Darras, B., additional, Masson, R., additional, Kletzl, H., additional, Cleary, Y., additional, Armstrong, G., additional, Seabrook, T., additional, Czech, C., additional, Gerber, M., additional, Gelblin, K., additional, Gorni, K., additional, and Khwaja, O., additional

Published
2018
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18. SMA THERAPIES II AND BIOMARKERS

Author

Mercuri, E., primary, Baranello, G., additional, Kirschner, J., additional, Servais, L., additional, Goemans, N., additional, Carmela Pera, M., additional, Buchbjerg, J., additional, Armstrong, G., additional, Kletzl, H., additional, Gerber, M., additional, Czech, C., additional, Cleary, Y., additional, Gorni, K., additional, and Khwaja, O., additional

Published
2018
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19. SMA THERAPIES II AND BIOMARKERS

Author

Kletzl, H., primary, Czech, C., additional, Cleary, Y., additional, Sturm, S., additional, Günther, A., additional, Baranello, G., additional, Mercuri, E., additional, Servais, L., additional, Day, J., additional, Deconinck, N., additional, Klein, A., additional, Darras, B., additional, Masson, R., additional, Kirschner, J., additional, Goemans, N., additional, Pera, M., additional, Chiriboga, C., additional, Fischer, D., additional, Gorni, K., additional, and Khwaja, O., additional

Published
2018
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20. SMA THERAPIES II AND BIOMARKERS

Author

Bertini, E., primary, Day, J., additional, Al Muhaizea, M., additional, Xiong, H., additional, Servais, L., additional, Prufer, A., additional, Buchbjerg, J., additional, Armstrong, G., additional, Gorni, K., additional, and Khwaja, O., additional

Published
2018
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21. SMA THERAPIES II AND BIOMARKERS

Author

Chiriboga, C., primary, Mercuri, E., additional, Fischer, D., additional, Kraus, D., additional, Thompson, N., additional, Armstrong, G., additional, Kletzl, H., additional, Gerber, M., additional, Cleary, Y., additional, Bergauer, T., additional, Gorni, K., additional, and Khwaja, O., additional

Published
2018
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22. Innovative home activity monitoring in non-ambulant patients with spinal muscular atrophy: a multicenter observational trial

Author

Gargaun, E., primary, Seferian, A., additional, Quicke, G., additional, Moraux, A., additional, Gidaro, T., additional, Gasnier, E., additional, Daron, A., additional, Péréon, Y., additional, Cances, C., additional, Vuillerot, C., additional, Cuisset, J., additional, Toledano, E., additional, Hermosilla, R., additional, Khwaja, O., additional, Czech, C., additional, Chabanon, A., additional, Annoussamy, M., additional, Vissiere, D., additional, and Servais, L., additional

Published
2017
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23. A series of case reports from JEWELFISH, an open-label study to investigate the safety, tolerability, and pharmacokinetics/ pharmacodynamics of RG7916 in adult and pediatric patients with spinal muscular atrophy who previously participated in a study with another SMN2-targeting therapy

Author

Chiriboga, C., primary, Mercuri, E., additional, Fischer, D., additional, Marquet, A., additional, Kraus, D., additional, Alexander, M., additional, Cho, A., additional, Armstrong, G., additional, Kletzl, H., additional, Czech, C., additional, Seabrook, T., additional, Abdallah, H., additional, Mueller, L., additional, Gorni, K., additional, and Khwaja, O., additional

Published
2017
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24. Clinical studies of RG7916 in patients with spinal muscular atrophy: SUNFISH part 1 study update

Author

Mercuri, E., primary, Kirschner, J., additional, Baranello, G., additional, Servais, L., additional, Goemans, N., additional, Pera, M., additional, Marquet, A., additional, Seabrook, T., additional, Sturm, S., additional, Armstrong, G., additional, Kletzl, H., additional, Czech, C., additional, Kraus, D., additional, Abdallah, H., additional, Mueller, L., additional, Gorni, K., additional, and Khwaja, O., additional

Published
2017
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25. Longitudinal data of the European prospective natural history study of patients with type 2 and 3 spinal muscular atrophy

Author

Chabanon, A., primary, Annoussamy, M., additional, Daron, A., additional, Pereon, Y., additional, Cances, C., additional, Vuillerot, C., additional, Goemans, N., additional, Cuisset, J., additional, Laugel, V., additional, Schara, U., additional, Gargaun, E., additional, Gidaro, T., additional, Seferian, A., additional, Lowes, L., additional, Carlier, P., additional, Hogrel, J., additional, Czech, C., additional, Hermosilla, R., additional, Khwaja, O., additional, and Servais, L., additional

Published
2017
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28. Callosal dysgenesis in fetuses with ventriculomegaly: levels of agreement between imaging modalities and postnatal outcome

Author

Li, Y, Estroff, JA, Khwaja, O, Mehta, TS, Poussaint, TY, Robson, CD, Feldman, HA, Ware, J, and Levine, D

Subjects
Adult, Pregnancy, Pregnancy Outcome, Humans, Female, Prospective Studies, Agenesis of Corpus Callosum, Magnetic Resonance Imaging, Article, Statistics, Nonparametric, Ultrasonography, Prenatal, Cerebral Ventricles
Abstract

To assess neurodevelopmental outcome of fetuses diagnosed with callosal abnormalities after referral for ventriculomegaly.This sub-analysis of a prospective study of 430 fetuses, which were referred for ventriculomegaly and underwent sonography and magnetic resonance imaging (MRI), included those fetuses with a diagnosis of corpus callosal abnormalities after recruitment into the main study. Between three and six radiologists independently reviewed ultrasound and MR images and recorded central nervous system (CNS) abnormalities, with final diagnoses being decided by consensus. Postnatal outcomes of fetuses with callosal abnormalities were compared between those with and those without other abnormalities.Callosal abnormalities were detected in 13% (58/430) of the fetuses referred with ventriculomegaly. Callosal dysgenesis was isolated in 24% (14/58) of these cases, with the remainder complicated by CNS, karyotypic or other major abnormalities. Five fetuses diagnosed prenatally as having isolated callosal abnormalities had additional CNS findings on postnatal assessment. Preconference kappa for callosal abnormalities was 0.76 for ultrasound and 0.78 for MRI, indicating that these investigations had a similar level of operator dependence. Neurodevelopmental outcome was normal or showed only mild delay that resolved in 67% (8/12) children with isolated callosal abnormalities compared to 7% (2/27) in those with non-isolated callosal abnormalities (P = 0.003).Callosal abnormalities are present in a significant proportion of fetuses with a diagnosis of ventriculomegaly. Isolated callosal abnormalities are associated with normal neurodevelopmental outcome in approximately two-thirds of fetuses.

Published
2012

31. P.1.g.041 RG1662, a new negative allosteric modulator of the gamma-aminobutyric acid Aα5 receptor subtype, does not show convulsions at relevant doses

Author

Wandel, C., primary, Thomas, A., additional, Hernandez, M.C., additional, Ballard-Yardy, T., additional, Knoflach, F., additional, Trube, G., additional, Rothfuss, A., additional, Husar, E., additional, Lennon-Chrimes, S., additional, Bentley, D., additional, d'Ardhuy, X. Liogier, additional, Squassante, L., additional, Noeldeke, J., additional, and Khwaja, O., additional

Published
2015
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32. P.7.d.011 Results from a phase I proof-of-mechanism study with a vasopressin 1A receptor antagonist in autism spectrum disorder

Author

Del Valle Rubido, M., primary, Umbricht, D., additional, Shic, F., additional, McCracken, J.T, additional, Scahill, L., additional, Khwaja, O., additional, Squassante, L., additional, Boak, L., additional, Bolognani, F., additional, Fontoura, P., additional, Wall, C., additional, Jou, R., additional, Loomis, R., additional, Lyons, M., additional, Gavaletz, A., additional, Cowen, J., additional, Apelian, T., additional, Jeste, S., additional, Ferretti, C., additional, Taylor, B., additional, Berlin, G., additional, Noone, R., additional, Antar, L., additional, and Hollander, E., additional

Published
2015
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33. P.376 - A series of case reports from JEWELFISH, an open-label study to investigate the safety, tolerability, and pharmacokinetics/ pharmacodynamics of RG7916 in adult and pediatric patients with spinal muscular atrophy who previously participated in a study with another SMN2-targeting therapy

Author

Chiriboga, C., Mercuri, E., Fischer, D., Marquet, A., Kraus, D., Alexander, M., Cho, A., Armstrong, G., Kletzl, H., Czech, C., Seabrook, T., Abdallah, H., Mueller, L., Gorni, K., and Khwaja, O.

Published
2017
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38. T.P.7 Small molecule compounds correct alternative splicing of the SMN2 gene and restore SMN protein expression and function

Author

Naryshkin, N., primary, Narasimhan, J., additional, Dakka, A., additional, Gabbeta, V., additional, Haley, M., additional, Jung, S., additional, Crona, J., additional, Vazirani, P., additional, Furia, B., additional, Qi, H., additional, Woll, M., additional, Lee, S., additional, Choi, S., additional, Koyama, H., additional, Yang, T., additional, Chen, G., additional, Zhang, S., additional, Zhang, N., additional, Huang, S., additional, Li, C., additional, Turpoff, A., additional, Hedrick, J., additional, Zhao, X., additional, Mollin, A., additional, Zadel, M., additional, Letinski, S., additional, Paushkin, S., additional, Kobayashi, D., additional, McCarthy, K., additional, Chen, K., additional, Metzger, F., additional, Ratni, H., additional, Gerlach, I., additional, Khwaja, O., additional, Trifillis, P., additional, Colacino, J., additional, Babiak, J., additional, Almstead, N., additional, Peltz, S., additional, Karp, G., additional, Weetall, M., additional, and Welch, E., additional

Published
2012
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42. Clinical severity and quality of life in children and adolescents with Rett syndrome

Author

Lane, J. B., primary, Lee, H.- S., additional, Smith, L. W., additional, Cheng, P., additional, Percy, A. K., additional, Glaze, D. G., additional, Neul, J. L., additional, Motil, K. J., additional, Barrish, J. O., additional, Skinner, S. A., additional, Annese, F., additional, McNair, L., additional, Graham, J., additional, Khwaja, O., additional, Barnes, K., additional, and Krischer, J. P., additional

Published
2011
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43. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders

Author

Miller, D T, primary, Shen, Y, additional, Weiss, L A, additional, Korn, J, additional, Anselm, I, additional, Bridgemohan, C, additional, Cox, G F, additional, Dickinson, H, additional, Gentile, J, additional, Harris, D J, additional, Hegde, V, additional, Hundley, R, additional, Khwaja, O, additional, Kothare, S, additional, Luedke, C, additional, Nasir, R, additional, Poduri, A, additional, Prasad, K, additional, Raffalli, P, additional, Reinhard, A, additional, Smith, S E, additional, Sobeih, M M, additional, Soul, J S, additional, Stoler, J, additional, Takeoka, M, additional, Tan, W-H, additional, Thakuria, J, additional, Wolff, R, additional, Yusupov, R, additional, Gusella, J F, additional, Daly, M J, additional, and Wu, B-L, additional

Published
2008
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47. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Author

Khwaja, O. S., Ho, E., Barnes, K. V., O, H. M., Pereira, Luis Marcelo, Finkelstein, Y., Nelson, Charles A., Vogel-Farley, V., DeGregorio, G., Holm, Ingrid Adele, Khatwa, Umakanth A., Kapur, Kush, Alexander, Mark Edward, Finnegan, D. M., Cantwell, N. G., Walco, A. C., Rappaport, Leonard Allan, Gregas, M., Fichorova, Raina Nakova, Shannon, M. W., Sur, M., and Kaufmann, Walter E

Abstract

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Published
2014
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48. Artificial Intelligence versus Statistical Modeling and Optimization of Cholesterol Oxidase Production by using Streptomyces Sp.

Author

Lakshmi Pathak, Vineeta Singh, Ram Niwas, Khwaja Osama, Saif Khan, Shafiul Haque, C K M Tripathi, and B N Mishra

Subjects
Medicine, Science
Abstract

Cholesterol oxidase (COD) is a bi-functional FAD-containing oxidoreductase which catalyzes the oxidation of cholesterol into 4-cholesten-3-one. The wider biological functions and clinical applications of COD have urged the screening, isolation and characterization of newer microbes from diverse habitats as a source of COD and optimization and over-production of COD for various uses. The practicability of statistical/ artificial intelligence techniques, such as response surface methodology (RSM), artificial neural network (ANN) and genetic algorithm (GA) have been tested to optimize the medium composition for the production of COD from novel strain Streptomyces sp. NCIM 5500. All experiments were performed according to the five factor central composite design (CCD) and the generated data was analysed using RSM and ANN. GA was employed to optimize the models generated by RSM and ANN. Based upon the predicted COD concentration, the model developed with ANN was found to be superior to the model developed with RSM. The RSM-GA approach predicted maximum of 6.283 U/mL COD production, whereas the ANN-GA approach predicted a maximum of 9.93 U/mL COD concentration. The optimum concentrations of the medium variables predicted through ANN-GA approach were: 1.431 g/50 mL soybean, 1.389 g/50 mL maltose, 0.029 g/50 mL MgSO4, 0.45 g/50 mL NaCl and 2.235 ml/50 mL glycerol. The experimental COD concentration was concurrent with the GA predicted yield and led to 9.75 U/mL COD production, which was nearly two times higher than the yield (4.2 U/mL) obtained with the un-optimized medium. This is the very first time we are reporting the statistical versus artificial intelligence based modeling and optimization of COD production by Streptomyces sp. NCIM 5500.

Published
2015
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50. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.

Author

Darras, B. T., Masson, R., Mazurkiewicz-Bełdzińska, M., Rose, K., Xiong, H., Zanoteli, E., Baranello, G., Bruno, C., Vlodavets, D., Wang, Y., El-Khairi, M., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Fontoura, P., and Servais, L.

Subjects
*SPINAL muscular atrophy, *INFANTS, *BRONCHIOLITIS, *RNA splicing, *NEUROMUSCULAR diseases, *CHILDREN'S hospitals
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<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure. CONCLUSIONS: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482. opens in new tab.). [ABSTRACT FROM AUTHOR]

Published
2021
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