Publications

Professor of Neurology, of Pediatrics (Genetics) and, by Courtesy, of Pathology at the Stanford University Medical Center

Publications

  • COMET: Efficacy and safety of avalglucosidase alfa in late-onset Pompe disease participants after 97 weeks of treatment Schoser, B., Kishnani, P., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., Van der Ploeg, A., Berger, K., Clemens, P., Chien, Y., Day, J., Ilarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Thibault, N., Zhou, T., Dimachkie, M., COMET Investigator Grp WILEY. 2022: 59-60
  • Spinal Muscular Atrophy Type 1: Fetal Diagnosis, Prenatal Coordination, and Postnatal Management in the Era of Novel Therapies. NeoReviews Chitkara, R., Chock, V., Davis, A., Rocha, C. T., Day, J. W., Fluharty, B., Hintz, S. 2022; 23 (7): e520-e526

    View details for DOI 10.1542/neo.23-7-e520

    View details for PubMedID 35773512

  • SUNFISH: 3-year efficacy and safety of risdiplam in Types 2 and 3 spinal muscular atrophy Goemans, N., Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Scalco, R., Yeung, W., Mercuri, E., SUNFISH Working Grp WILEY. 2022: 278
  • FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy Deconinck, N., Baranello, G., Boespflug-Tanguy, O., Day, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Dodman, A., Gaki, E., Darras, B., FIREFISH Working Grp WILEY. 2022: 279
  • MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy. Science translational medicine Morelli, K. H., Jin, W., Shathe, S., Madrigal, A. A., Jones, K. L., Schwartz, J. L., Bridges, T., Mueller, J. R., Shankar, A., Chaim, I. A., Day, J. W., Yeo, G. W. 2022; 14 (651): eabn2375

    Abstract

    Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci found early in the maturation of three-dimensional (3D) cortical organoids from DM1 patient-derived induced pluripotent stem cells (iPSCs) cause hyperphosphorylation of CUGBP Elav-like family member 2 (CELF2) protein. Integrative single-cell RNA sequencing and enhanced cross-linking and immunoprecipitation (eCLIP) analysis revealed that reduced CELF2 protein-RNA substrate interactions results in misregulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(y/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-methyl-d-aspartic acid (NMDA) antagonists as potential treatment avenues for neuronal defects in DM1.

    View details for DOI 10.1126/scitranslmed.abn2375

    View details for PubMedID 35767654

  • Scientific rationale for a higher dose of nusinersen. Annals of clinical and translational neurology Finkel, R. S., Ryan, M. M., Pascual Pascual, S. I., Day, J. W., Mercuri, E., De Vivo, D. C., Foster, R., Montes, J., Gurgel-Giannetti, J., MacCannell, D., Berger, Z. 2022

    Abstract

    OBJECTIVE: The long-term favorable safety profile of nusinersen provides an opportunity to consider a higher dose. We report on the relationships between nusinersen cerebrospinal fluid (CSF) exposure, biomarker levels, and clinical efficacy.METHODS: The analyses used data from the CS3A and ENDEAR studies of nusinersen in participants with infantile-onset spinal muscular atrophy (SMA). Steady-state CSF trough (Ctrough ) levels, plasma phosphorylated neurofilament heavy chain (pNF-H) levels, body weight, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores were selected as parameters of interest. A validated population pharmacokinetic (PK) model was applied to predict the nusinersen CSF Ctrough . PK/pharmacodynamic (PK/PD) models used nusinersen CSF Ctrough measurements, which were time-matched with CHOP INTEND scores.RESULTS: Higher nusinersen CSF exposure was associated with a greater decrease in pNF-H levels and greater efficacy, as measured by change in the CHOP INTEND score from baseline. These findings indicate a dose-response relationship between CSF nusinersen levels and treatment response. The higher dose is predicted to lead to approximately a 2.4-fold increase in nusinersen CSF levels with fewer loading doses. PK/PD modeling indicates that a higher concentration of nusinersen may predict an additional 5-point increase in CHOP INTEND score beyond that observed with 12mg.INTERPRETATION: Our data indicate that a higher dose of nusinersen may lead to additional clinically meaningful improvement in efficacy when compared with the currently approved 12-mg dose. The efficacy, safety, and PK of a higher nusinersen dose are currently under investigation in the ongoing phase 2/3 DEVOTE study (NCT04089566).

    View details for DOI 10.1002/acn3.51562

    View details for PubMedID 35567345

  • Major Adverse Dystrophinopathy Event Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy Kaufman, B. D., Garcia, A., He, Z., Buu, M., Tesi-Rocha, C., Day, J. W., Rosenthal, D. N., Gordish-Dressman, H., Almond, C., Duong, T. ELSEVIER SCIENCE INC. 2022: S95
  • Cardiac and pulmonary findings in dysferlinopathy: a 3-year, longitudinal study. Muscle & nerve Moore, U., Fernandez-Torron, R., Jacobs, M., Gordish, H., Diaz-Manera, J., James, M. K., Mayhew, A. G., Harris, E., Guglieri, M., Rufibach, L. E., Feng, J., Blamire, A. M., Carlier, P. G., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Lowes, L. P., Mendell, J. R., Bushby, K., Jain COS Consortium, Bourke, J., Straub, V. 2022

    Abstract

    INTRODUCTION/AIMS: There is debate about whether and to what extent either respiratory or cardiac dysfunction occur in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype.METHODS: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a three-year interval between tests, in 188 genetically confirmed patients aged 11-86years (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG) and echocardiogram (echo).RESULTS: Mean FVC was 90% predicted at baseline, decreasing to 88% at year three. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year three, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population.DISCUSSION: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.

    View details for DOI 10.1002/mus.27524

    View details for PubMedID 35179231

  • Intron Mutations and Early Transcription Termination in Duchenne and Becker muscular dystrophy. Human mutation Waldrop, M. A., Moore, S. A., Mathews, K. D., Darbro, B. W., Medne, L., Finkel, R., Connolly, A. M., Crawford, T. O., Drachman, D., Wein, N., Habib, A. A., Krzesniak-Swinarska, M. A., Zaidman, C. M., Collins, J. J., Jokela, M., Udd, B., Day, J. W., Ortiz-Guerrero, G., Statland, J., Butterfield, R. J., Dunn, D. M., Weiss, R. B., Flanigan, K. M. 2022

    Abstract

    DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription PCR (RT-PCR) or high-throughput RNA sequencing (RNA-Seq) methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/humu.24343

    View details for PubMedID 35165973

  • AT845 gene replacement therapy for late onset Pompe disease: Overview of clinical data from FORTIS, a phase 1/2 open-label clinical study Mozaffar, T., Day, J. W., Longo, N., Manera, J., Straub, V., Maruoka, M., Han, C., Foo, C., Smith, A. R., Bachtell, N. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: S85-S86
  • The avalglucosidase alfa phase 3 COMET trial in late-onset Pompe disease patients: Efficacy and safety results after 97 weeks Kishnani, P., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., van der Ploeg, A. T., Berger, K. I., Clemens, P. R., Chien, Y., Day, J. W., Illarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: S66-S67
  • Brief assessment of cognitive function in myotonic dystrophy: multicenter longitudinal study using computer-assisted evaluation. Muscle & nerve Deutsch, G. K., Hagerman, K. A., Sampson, J., Dent, G., Dekdebrun, J., Parker, D. M., Thornton, C. A., Heatwole, C. R., Subramony, S. H., Mankodi, A. K., Ashizawa, T., Statland, J. M., Arnold, W. D., Moxley, R. T., Day, J. W. 2022

    Abstract

    Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess CNS involvement in multicenter studies have not been determined. This study's primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1.We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at 6 sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3-months and 12-months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and EQ-5D-5L.Based on intra-class correlation coefficients (ICCs), computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (p < 0.0001). Executive function performance improved from baseline to 3-months (p < 0.0001), without further changes over one year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance.Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/mus.27520

    View details for PubMedID 35179228

  • 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. The Lancet. Neurology Mercuri, E., Deconinck, N., Mazzone, E. S., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., 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, C., Fontoura, P., Day, J. W., SUNFISH Study Group, 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., Deconinck, N., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Goemans, N., Casteels, I., De Waele, L., Balikova, I., 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., Oskoui, M., 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., Wen, J., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Servais, L., Boespflug-Tanguy, O., Gidaro, T., Seferian, A., De Lucia, S., 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., 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., Vuillerot, C., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Saidi, M., Kirschner, J., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, E., D'Amico, A., 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, S., 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., Baranello, G., Masson, R., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, R., Mercuri, E., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., 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., Saito, 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., Kostera-Pruszczyk, A., 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., Day, J. W., Beres, S., Duong, T., Gee, R., Dunaway Young, S. 1800; 21 (1): 42-52

    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 randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and -0·19 (-1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs ten [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs five [8%]), rash (20 [17%] vs one [2%]), mouth and aphthous ulcers (eight [7%] vs 0), urinary tract infection (eight [7%] vs 0), and arthralgias (six [5%] vs 0). The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group).INTERPRETATION: Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2-25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam.FUNDING: F Hoffmann-La Roche.

    View details for DOI 10.1016/S1474-4422(21)00367-7

    View details for PubMedID 34942136

  • 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 LANCET NEUROLOGY Mercuri, E., Deconinck, N., Mazzone, E. S., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., 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., Martin, C., Fontoura, P., Day, J. W., SUNFISH Study Grp 2022; 21 (1): 42-52
  • Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach. Frontiers in neurology Mayhew, A. G., James, M. K., Moore, U., Sutherland, H., Jacobs, M., Feng, J., Lowes, L. P., Alfano, L. N., Muni Lofra, R., Rufibach, L. E., Rose, K., Duong, T., Bello, L., Pedrosa-Hernandez, I., Holsten, S., Sakamoto, C., Canal, A., Sanchez-Aguilera Praxedes, N., Thiele, S., Siener, C., Vandevelde, B., DeWolf, B., Maron, E., Gordish-Dressman, H., Hilsden, H., Guglieri, M., Hogrel, J., Blamire, A. M., Carlier, P. G., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz-Manera, J., Pegoraro, E., Mendell, J. R., Straub, V. 2022; 13: 828525

    Abstract

    Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R 2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R 2 0.18). EK scores were strongly associated with PUL (Pseudo R 2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R 2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy.

    View details for DOI 10.3389/fneur.2022.828525

    View details for PubMedID 35359643

  • Correction to: Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug safety Day, J. W., Mendell, J. R., Mercuri, E., Finkel, R. S., Strauss, K. A., Kleyn, A., Tauscher-Wisniewski, S., Tukov, F. F., Reyna, S. P., Chand, D. H. 1800

    View details for DOI 10.1007/s40264-021-01130-7

    View details for PubMedID 34940960

  • Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial LANCET NEUROLOGY Diaz-Manera, J., Kishnani, P. S., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., Van der Ploeg, A. T., Berger, K. I., Clemens, P. R., Chien, Y., Day, J. W., Illarioshkin, S., Roberts, M., Attarian, S., Borges, J., Bouhour, F., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Hug, C., Huynh-Ba, O., Johnson, J., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B., The Comet 2021; 20 (12): 1012-1026
  • Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes. Neuromuscular disorders : NMD Coratti, G., Carmela Pera, M., Montes, J., Scoto, M., Pasternak, A., Bovis, F., Sframeli, M., D'Amico, A., Pane, M., Albamonte, E., Antonaci, L., Lia Frongia, A., Mizzoni, I., Sansone, V. A., Russo, M., Bruno, C., Baranello, G., Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., de Sanctis, R., Stacy Mazzone, E., Milev, E., Rohwer, A., Civitello, M., Darras, B. T., Bertini, E., Day, J., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, E. 1800

    Abstract

    The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.

    View details for DOI 10.1016/j.nmd.2021.10.009

    View details for PubMedID 34980538

  • Correction to: Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Rudnicki, S. A., Andrews, J. A., Duong, T., Cockroft, B. M., Malik, F. I., Meng, L., Wei, J., Wolff, A. A., Genge, A., Johnson, N. E., Tesi-Rocha, C., Connolly, A. M., Darras, B. T., Felice, K., Finkel, R. S., Shieh, P. B., Mah, J. K., Statland, J., Campbell, C., Habib, A. A., Kuntz, N. L., Oskoui, M., Day, J. W. 2021

    View details for DOI 10.1007/s13311-021-01120-8

    View details for PubMedID 34731415

  • Routine practices in use of onasemnogene abeparvovec (OA) in older patients with spinal muscular atrophy (SMA): Early findings from RESTORE Servais, L., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Tizzano, E., Roy, S., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138
  • Real-world treatment patterns and outcomes in patients with spinal muscular atrophy (SMA): Updated findings from the RESTORE Registry Servais, L., Day, J., De Vivo, D., Mercuri, E., Muntoni, F., Shieh, P., Tizzano, E., Desguerre, I., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138-S139
  • Long-term follow-up (LTFU) of onasemnogene abeparvovec gene therapy in spinal muscular atrophy (SMA) Mendell, J., Finkel, R., Mercuri, E., Strauss, K., Day, J., Kleyn, A., Chand, D., Tauscher-Wisniewski, S., Meriggioli, M. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S132-S133
  • Newborn screening (NBS) for spinal muscular atrophy (SMA) in the United States (US): Early findings from the RESTORE registry Servais, L., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Tizzano, E., Roy, S., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138
  • IREFISH Parts 1 and 2: 24-month safety and efficacy of risdiplam in type 1 spinal muscular atrophy (SMA) Masson, R., Boespflug-Tanguy, O., Darras, B., Day, J., Deconinck, N., Klein, A., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., Dodman, A., El-Khairi, M., Gaki, E., Gerber, M., Gorni, K., Kletzl, H., Baranello, G. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S134
  • SUNFISH Part 2: 24-month efficacy and safety of risdiplam in patients with Type 2 or non-ambulant Type 3 spinal muscular atrophy (SMA) Nascimento, A., Day, J., Deconinck, N., Mazzone, E., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Martin, C., Scalco, R., Staunton, H., Yeung, W., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S136
  • Part A results from the ongoing DEVOTE study to explore higher-dose nusinersen in SMA Mercuri, E., Finkel, R., Day, J., Pascual, S., Ryan, M., De Vivo, D., Montes, J., Gurgel-Giannetti, J., Gambino, G., Nuzzo, R., Makepeace, C., Garafalo, S., Berger, Z. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S132
  • Pooled safety data from the risdiplam clinical trial development program Baranello, G., Servais, L., Bertini, E., Chiriboga, C., Darras, B., Day, J., Deconinck, N., Fischer, D., Goemans, N., Kirschner, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Wang, Y., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Scalco, R., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S135
  • Scientific rationale for a higher dose of nusinersen Ryan, M., Finkel, R., Pascual, S., Day, J., Mercuri, E., De Vivo, D., Montes, J., Gurgel-Giannetti, J., MacCannell, D., Berger, Z. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S131
  • The international spinal muscular atrophy registry (ISMAR): baseline characteristics Montes, J., Coratti, G., Scoto, M., Balashkin, J., Pera, M., Samsuddin, S., Martens, W., Bozzardi, A., Rodriguez, A., Civitello, M., Madden, M., Lings, B., Rohwer, A., Hall, S., Zolkipli, Z., Day, J., Darras, B., De Vivo, D., Muntoni, F., Finkel, R., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S126
  • Apitegromab in SMA: an analysis of multiple endpoints and PD relationships to efficacy in the TOPAZ trial Crawford, T., Darras, B., Day, J., Nomikos, G., Song, G., Place, A., Barrett, D., Bilic, S., O'Neil, J., Kertesz, N., Cote, S., Patel, J., Chyung, Y. PERGAMON-ELSEVIER SCIENCE LTD. 2021
  • Quality of life in dysferlinopathy can be good despite poor function Moore, U., James, M., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Yoshimura, M., Bravver, E., Pegoraro, E., Mendell, J., Bushby, K., Straub, V., Mayhew, A. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S104
  • Disease progression in Charcot-Marie-Tooth disease related to MPZ mutations: A longitudinal study using rasch analysis-based weighted CMT examination Fridman, V., Sillau, S., Bockhorst, J., Smith, K., Moroni, I., Pagliano, E., Pisciotta, C., Piscosquito, G., laura, M., Muntoni, F., Bacha, A., Feely, S., Grider, T., Gutmann, L., Shy, R., Wilcox, J., Scherer, S., Herrmann, D., Li, J., Ramchandren, S., Sumner, C., Lloyd, T., Day, J., Siskind, C., Yum, S., Reza, S., Finkel, R., Reilly, M., Pareyson, D., Shy, M. WILEY. 2021: 374
  • Different trajectories in upper limb and gross motor function in spinal muscular atrophy. Muscle & nerve Coratti, G., Pera, M. C., Montes, J., Pasternak, A., Scoto, M., Baranello, G., Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., de Sanctis, R., Mazzone, E. S., Milev, E., Rohwer, A., Civitello, M., Pane, M., Antonaci, L., Frongia, A. L., Sframeli, M., Vita, G. L., D'Amico, A., Mizzoni, I., Albamonte, E., Darras, B. T., Bertini, E., Sansone, V. A., Bovis, F., Day, J., Bruno, C., Muntoni, F., De Vivo, D. C., Finkel, R., Mercuri, E. 2021

    Abstract

    Ref: Different trajectories in upper limb and gross motor function in spinal muscular atrophy INTRODUCTION: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 months.METHODS: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-month changes also included the analysis of concordance between scales with changes grouped as stable (+2 points), improved (>+2) or declined (>-2).RESULTS: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2 the point of slope change was 4.1years for the HFMSE and 5.8 for the RULM, while for type 3 it was 6years for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least 2 assessments at 12-month. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups.DISCUSSION: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.

    View details for DOI 10.1002/mus.27384

    View details for PubMedID 34327716

  • Advances in the therapy of Spinal Muscular Atrophy. The Journal of pediatrics Klotz, J., Rocha, C. T., Young, S. D., Duong, T., Buu, M., Sampson, J., Day, J. W. 2021

    View details for DOI 10.1016/j.jpeds.2021.06.033

    View details for PubMedID 34197889

  • Nusinersen in pediatric and adult patients with type III spinal muscular atrophy. Annals of clinical and translational neurology Pera, M. C., Coratti, G., Bovis, F., Pane, M., Pasternak, A., Montes, J., Sansone, V. A., Dunaway Young, S., Duong, T., Messina, S., Mizzoni, I., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Morando, S., De Sanctis, R., Sframeli, M., Antonaci, L., Frongia, A. L., Rohwer, A., Scoto, M., De Vivo, D. C., Darras, B. T., Day, J., Martens, W., Patanella, K. A., Bertini, E., Muntoni, F., Finkel, R., Mercuri, E., iSMAC group 2021

    Abstract

    OBJECTIVE: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort.METHODS: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83years after nusinersen treatment.RESULTS: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12months on both HFMSE (1.18 points, p=0.004) and RULM scores (0.58 points, p=0.014) but not on the 6MWT (mean difference=6.65m, p=0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT.INTERPRETATION: Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

    View details for DOI 10.1002/acn3.51411

    View details for PubMedID 34165911

  • Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovec. Molecular therapy. Methods & clinical development Day, J. W., Finkel, R. S., Mercuri, E., Swoboda, K. J., Menier, M., van Olden, R., Tauscher-Wisniewski, S., Mendell, J. R. 2021; 21: 76–82

    Abstract

    Spinal muscular atrophy is a progressive, recessively inherited monogenic neurologic disease, the genetic root cause of which is the absence of a functional survival motor neuron 1 gene. Onasemnogene abeparvovec (formerly AVXS-101) is an adeno-associated virus serotype 9 vector-based gene therapy that delivers a fully functional copy of the human survival motor neuron gene. We report anti-adeno-associated virus serotype 9 antibody titers for patients with spinal muscular atrophy when they were screened for eligibility in the onasemnogene abeparvovec clinical trials (intravenous and intrathecal administration) and managed access programs (intravenous). Through December 31, 2019, 196 patients and 155 biologic mothers were screened for anti-adeno-associated virus serotype 9 binding antibodies with an enzyme-linked immunosorbent assay. Of these, 15 patients (7.7%) and 23 biologic mothers (14.8%) had titers >1:50 on their initial screening tests. Eleven patients (5.6%) had elevated titers on their final screening tests. The low percentage of patients with exclusionary antibody titers indicates that most infants with spinal muscular atrophy type 1 should be able to receive onasemnogene abeparvovec. Retesting may identify patients whose antibody titers later decrease to below the threshold for treatment, and retesting should be considered for patients with anti-adeno-associated virus serotype 9 antibody titers >1:50.

    View details for DOI 10.1016/j.omtm.2021.02.014

    View details for PubMedID 33768131

  • Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. The Lancet. Child & adolescent health Finkel, R. S., Chiriboga, C. A., Vajsar, J., Day, J. W., Montes, J., De Vivo, D. C., Bishop, K. M., Foster, R., Liu, Y., Ramirez-Schrempp, D., Schneider, E., Bennett, C. F., Wong, J., Farwell, W. 2021

    Abstract

    BACKGROUND: Nusinersen showed a favourable benefit-risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years.METHODS: This phase 2, open-label, multicentre, dose-escalation study was done in three university hospital sites in the USA and one in Canada. Infants aged between 3 weeks and 6 months with two or three SMN2 gene copies and infantile-onset spinal muscular atrophy were eligible for inclusion. Eligible participants received multiple intrathecal loading doses of 6 mg equivalent nusinersen (cohort 1) or 12 mg dose equivalent (cohort 2), followed by maintenance doses of 12 mg equivalent nusinersen. The protocol amendment on Jan 25, 2016, changed the primary efficacy endpoint from safety and tolerability to reaching motor milestones, assessed using the Hammersmith Infant Neurological Examination section 2 (HINE-2) at the last study visit, in all participants who successfully completed the loading dose period and day 92 assessment. The statistical analysis plan was amended on Feb 10, 2016, to include additional analyses of the subgroup of participants with two SMN2 copies. Adverse events were assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov (NCT01839656).FINDINGS: Between May 3, 2013, and July 9, 2014, 20 symptomatic participants with infantile-onset spinal muscular atrophy (12 boys and 8 girls; median age at diagnosis 78 days [range 0-154]) were enrolled. Median time on study was 36·2 months (IQR 20·6-41·3). The primary endpoint of an incremental improvement in HINE-2 developmental motor milestones was reached by 12 (63%) of 19 evaluable participants. In the 13 participants with two SMN2 copies treated with 12 mg nusinersen, the HINE-2 motor milestone total score increased steadily from a baseline mean of 1·46 (SD 0·52) to 11·86 (6·18) at day 1135, representing a clinically significant change of 10·43 (6·05). At study closure (Aug 21, 2017), 15 (75%) of 20 participants were alive. 101 serious adverse events were reported in 16 (80%) of 20 participants; all five deaths (one in cohort 1 and four in cohort 2) were likely to be related to spinal muscular atrophy disease progression.INTERPRETATION: Our findings are consistent with other trials of nusinersen and show improved survival and attainment of motor milestones over 3 years in patients with infantile-onset spinal muscular atrophy, with a favourable safety profile.FUNDING: Biogen and Ionis Pharmaceuticals.

    View details for DOI 10.1016/S2352-4642(21)00100-0

    View details for PubMedID 34089650

  • Pooled safety data from the risdiplam clinical trial development program Servais, L., Baranello, G., Bertini, E., Chiriboga, C., Darras, B. T., Day, J. W., Deconinck, N., Fischer, D., Goemans, N., Kirschner, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Wang, Y., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Scalco, R. S., Mercuri, E., FIREFISH Study Grp, SUNFISH Study Grp, JEWELFISH Study Grp WILEY. 2021: 397-398
  • Nusinersen Treatment in Adults With Spinal Muscular Atrophy. Neurology. Clinical practice Duong, T., Wolford, C., McDermott, M. P., Macpherson, C. E., Pasternak, A., Glanzman, A. M., Martens, W. B., Kichula, E., Darras, B. T., De Vivo, D. C., Zolkipli-Cunningham, Z., Finkel, R. S., Zeineh, M., Wintermark, M., Sampson, J., Hagerman, K. A., Young, S. D., Day, J. W. 2021; 11 (3): e317-e327

    Abstract

    Objective: To determine changes in motor and respiratory function after treatment with nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability in the USA.Methods: Data were collected prospectively on adult (age >17 years at treatment initiation) SMA participants in the Pediatric Neuromuscular Clinical Research (PNCR) Network. Baseline assessments of SMA outcomes including the Expanded Hammersmith Functional Rating Scale (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) occurred <5 months before treatment, and post-treatment assessments were made up to 24 months after nusinersen initation. Patient-reported experiences, safety laboratory tests and adverse events were monitored. The mean annual rate of change over time was determined for outcome measures using linear mixed effects models.Results: Forty-two adult SMA participants (mean age: 34 years, range 17-66) receiving nusinersen for a mean of 12.5 months (range 3-24 months) were assessed. Several motor and respiratory measures showed improvement distinct from the progressive decline typically seen in untreated adults. Participants also reported qualitative improvements including muscle strength, stamina, breathing and bulbar related outcomes. All participants tolerated nusinersen with normal surveillance labs and no significant adverse events.Conclusions: Trends of improvement emerged in functional motor, patient-reported, and respiratory measures, suggesting nusinersen may be efficacious in adults with SMA. Larger well-controlled studies and additional outcome measures are needed to firmly establish the efficacy of nusinersen in adults with SMA.Classification of Evidence: This study provides Class IV evidence regarding nusinersen tolerability and efficacy based on reported side effects and pulmonary and physical therapy assessments in an adult SMA cohort.

    View details for DOI 10.1212/CPJ.0000000000001033

    View details for PubMedID 34476123

  • FIREFISH Parts 1 and 2: 24-Month Safety and Efficacy of Risdiplam in Type 1 SMA Masson, R., Boespflug-Tanguy, O., Darras, B. T., Day, J. W., Deconinck, N., Klein, A., Mazurkiewicz-Bedziska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., Dodman, A., El-Khairi, M., Gaki, E., Gerber, M., Gorni, K., Kletzl, H., Baranello, G., FIREFISH Working Grp WILEY. 2021: 395-396
  • SUNFISH Part 2: 24-month efficacy and safety of risdiplam in patients with Type 2 or non-ambulant Type 3 SMA Nascimento, A., Day, J. W., Deconinck, N., Mazzone, E., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Scalco, R. S., Staunton, H., Yeung, W., Mercuri, E., SUNFISH Working Grp WILEY. 2021: 187-188
  • Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes. Stem cell reports Chang, A. C., Pardon, G., Chang, A. C., Wu, H., Ong, S., Eguchi, A., Ancel, S., Holbrook, C., Ramunas, J., Ribeiro, A. J., LaGory, E. L., Wang, H., Koleckar, K., Giaccia, A., Mack, D. L., Childers, M. K., Denning, C., Day, J. W., Wu, J. C., Pruitt, B. L., Blau, H. M. 2021

    Abstract

    Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention.

    View details for DOI 10.1016/j.stemcr.2021.04.018

    View details for PubMedID 34019816

  • SUNFISH Part 2: 24-month Efficacy and Safety of Risdiplam in Patients with Type 2 or Non-ambulant Type 3 Spinal Muscular Atrophy (SMA) Oskoui, M., Day, J. W., Deconinck, N., Mazzone, E., Nascimento, A., Saito, K., Vuillerot, C., Baranello, G., Bloespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Scalco, R. S., Staunton, H., Yeung, W., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Results of Double-blind, Placebo-controlled, Dose Range Finding, Crossover Study of Single Day Administration of ERX-963 (IV Flumazenil) in Adults with Myotonic Dystrophy Type 1 Sampson, J., Wang, E., Day, J., Gutmann, L., Mezerhane, E., Seto, A., Ehrich, E. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • A phase I/II open-label gene replacement clinical study for late onset Pompe disease Mozaffar, T., Day, J., Foo, C., Bachtell, N., Conner, E. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Escalating Dose and Randomized, Controlled Study of Nusinersen in Participants With Spinal Muscular Atrophy (SMA); Study Design and Part A Data for the Phase 2/3 DEVOTE (232SM203) Study to Explore High Dose Nusinersen Day, J. W., Pascual, S., Finkel, R. S., Ryan, M. M., Mercuri, E., De Vivo, D. C., Montes, J., Gurgel-Giannetti, J., Gambino, G., Nuzzo, R., Makepeace, C., Berger, Z. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Pooled Safety Data from the Risdiplam Clinical Trial Development Program Servais, L., Baranello, G., Bertini, E., Chiriboga, C., Darras, B. T., Day, J. W., Deconinck, N., Fischer, D., Goemans, N., Kirschner, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Wang, Y., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Scalco, R. S., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Long-Term Follow-Up (LTFU) of Onasemnogene Abeparvovec Gene Therapy in Spinal Muscular Atrophy (SMA) Mendell, J., Finkel, R., Mercuri, E., Strauss, K., Day, J., Kleyn, A., Chand, D., Tauscher-Wisniewski, S., Meriggioli, M. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Efficacy and Safety Results of the Avalglucosidase alfa Phase 3 COMET Trial in Late-Onset Pompe Disease Patients Kushlaf, H., Attarian, S., Borges, J., Bouhour, F., Chien, Y., Choi, Y., Clemens, P., Day, J., Diaz-Manera, J., Erdem-Ozdamar, S., Goker-Alpan, O., Illarioshkin, S., Kishnani, P., Kostera-Pruszczyk, A., Ladha, S., Mozaffar, T., Roberts, M., Straub, V., Toscano, A., van der Ploeg, A., Haack, K., Hug, C., Huynh-Ba, O., Zhou, T., Johnson, J., Dimachkie, M., Schoser, B. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. The Lancet. Neurology Day, J. W., Finkel, R. S., Chiriboga, C. A., Connolly, A. M., Crawford, T. O., Darras, B. T., Iannaccone, S. T., Kuntz, N. L., Pena, L. D., Shieh, P. B., Smith, E. C., Kwon, J. M., Zaidman, C. M., Schultz, M., Feltner, D. E., Tauscher-Wisniewski, S., Ouyang, H., Chand, D. H., Sproule, D. M., Macek, T. A., Mendell, J. R. 2021; 20 (4): 284–93

    Abstract

    BACKGROUND: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.METHODS: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 * 1014 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).FINDINGS: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).INTERPRETATION: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.FUNDING: Novartis Gene Therapies.

    View details for DOI 10.1016/S1474-4422(21)00001-6

    View details for PubMedID 33743238