Publications

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

Publications

  • 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
  • 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

  • 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

  • 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 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. M., 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
  • Exome testing most useful for people with recessive CMT Siskind, C., Sampson, J., Goyal, N., Rocha, A., Day, J. WILEY. 2021: 141–42
  • Efficacy and safety results of the avalglucosidase alfa phase 3 COMET trial in late-onset Pompe disease patients Kishnani, P. S., Attarian, S., Borges, J., Bouhourd, F., Chien, Y., Choi, Y., Clemens, P., Day, J., Diaz-Manera, J., Erdem-Ozdamar, S., Goker-Alpan, O., Illarioshkin, S., Kostera-Pruszczyk, A., Kushlaf, H., Ladha, S., Mozaffar, T., Roberts, M., Straub, V., Toscano, A., van der Ploeg, A., Haack, K., Huynh-Ba, O., Zhou, T., Dimachkie, M., Schoser, B. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S57
  • A phase I/II open-label gene replacement clinical study for late onset Pompe disease Day, J. W., Mozaffar, T., Foo, C., Bachtell, N., Conner, E. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S32
  • Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease. Neuromuscular disorders : NMD Moore, U., Gordish, H., Diaz-Manera, J., James, M. K., Mayhew, A. G., Guglieri, M., Fernandez-Torron, R., 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., Straub, V., Jain COS Consortium 2021

    Abstract

    This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments.

    View details for DOI 10.1016/j.nmd.2021.01.009

    View details for PubMedID 33610434

  • Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study. Brain : a journal of neurology Pipis, M., Feely, S. M., Polke, J. M., Skorupinska, M., Perez, L., Shy, R. R., Laura, M., Morrow, J. M., Moroni, I., Pisciotta, C., Taroni, F., Vujovic, D., Lloyd, T. E., Acsadi, G., Yum, S. W., Lewis, R. A., Finkel, R. S., Herrmann, D. N., Day, J. W., Li, J., Saporta, M., Sadjadi, R., Walk, D., Burns, J., Muntoni, F., Ramchandren, S., Horvath, R., Johnson, N. E., Zuchner, S., Pareyson, D., Scherer, S. S., Rossor, A. M., Shy, M. E., Reilly, M. M., Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN) 2021

    Abstract

    Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84±2.42; two-tailed paired t-test P=0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97±1.77; two-tailed paired t-test P=0.003) and the CMTESv2-R (mean change 1.21±2.52; two-tailed paired t-test P=0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24±3.09; two-tailed paired t-test P=0.009) and over 2 years (mean change 4.00±3.79; two-tailed paired t-test P=0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

    View details for DOI 10.1093/brain/awaa323

    View details for PubMedID 33415332

  • Transcriptome alterations in myotonic dystrophy frontal cortex. Cell reports Otero, B. A., Poukalov, K. n., Hildebrandt, R. P., Thornton, C. A., Jinnai, K. n., Fujimura, H. n., Kimura, T. n., Hagerman, K. A., Sampson, J. B., Day, J. W., Wang, E. T. 2021; 34 (3): 108634

    Abstract

    Myotonic dystrophy (DM) is caused by expanded CTG/CCTG repeats, causing symptoms in skeletal muscle, heart, and central nervous system (CNS). CNS issues are debilitating and include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Here, we generate RNA-seq transcriptomes from DM and unaffected frontal cortex and identify 130 high-confidence splicing changes, most occurring only in cortex, not skeletal muscle or heart. Mis-spliced exons occur in neurotransmitter receptors, ion channels, and synaptic scaffolds, and GRIP1 mis-splicing modulates kinesin association. Optical mapping of expanded CTG repeats reveals extreme mosaicism, with some alleles showing >1,000 CTGs. Mis-splicing severity correlates with CTG repeat length across individuals. Upregulated genes tend to be microglial and endothelial, suggesting neuroinflammation, and downregulated genes tend to be neuronal. Many gene expression changes strongly correlate with mis-splicing, suggesting candidate biomarkers of disease. These findings provide a framework for mechanistic and therapeutic studies of the DM CNS.

    View details for DOI 10.1016/j.celrep.2020.108634

    View details for PubMedID 33472074

  • Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen. Neuromuscular disorders : NMD Coratti, G., Pane, M., Lucibello, S., Pera, M. C., Pasternak, A., Montes, J., Sansone, V. A., Duong, T., Dunaway Young, S., Messina, S., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Tacchetti, P., Carnicella, S., Sframeli, M., Antonaci, L., Frongia, A. L., De Vivo, D. C., Darras, B. T., Day, J., Bertini, E., Muntoni, F., Finkel, R., Mercuri, E. 2021

    Abstract

    Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.

    View details for DOI 10.1016/j.nmd.2021.03.012

    View details for PubMedID 34099377

  • 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. n., Cockroft, B. M., Malik, F. I., Meng, L. n., Wei, J. n., Wolff, A. A., Genge, A. n., Johnson, N. E., Tesi-Rocha, C. n., Connolly, A. M., Darras, B. T., Felice, K. n., Shieh, P. B., Mah, J. K., Statland, J. n., Campbell, C. n., Habib, A. A., Kuntz, N. L., Oskoui, M. n., Day, J. W. 2021

    Abstract

    This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

    View details for DOI 10.1007/s13311-020-01004-3

    View details for PubMedID 33624184

  • Risdiplam in Type 1 Spinal Muscular Atrophy. The New England journal of medicine Baranello, G. n., Darras, B. T., Day, J. W., Deconinck, N. n., Klein, A. n., Masson, R. n., Mercuri, E. n., Rose, K. n., El-Khairi, M. n., Gerber, M. n., Gorni, K. n., Khwaja, O. n., Kletzl, H. n., Scalco, R. S., Seabrook, T. n., Fontoura, P. n., Servais, L. n. 2021

    Abstract

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

    View details for DOI 10.1056/NEJMoa2009965

    View details for PubMedID 33626251

  • Assessing Dysferlinopathy Patients Over Three Years With A New Motor Scale. Annals of neurology Jacobs, M. n., James, M. K., Lowes, L. P., Alfano, L. N., Eagle, M. n., Lofra, R. M., Moore, U. n., Feng, J. n., Rufibach, L. E., Rose, K. n., Duong, T. n., Bello, L. n., Pedrosa-Hernández, I. n., Holsten, S. n., Sakamoto, C. n., Canal, A. n., Práxedes, N. S., Thiele, S. n., Siener, C. n., Vandevelde, B. n., DeWolf, B. n., Maron, E. n., Guglieri, M. n., Hogrel, J. Y., Blamire, A. M., Carlier, P. G., Spuler, S. n., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E. n., Pestronk, A. n., Walter, M. C., Paradas, C. n., Stojkovic, T. n., Mori-Yoshimura, M. n., Bravver, E. n., Díaz-Manera, J. n., Pegoraro, E. n., Mendell, J. R., Mayhew, A. G., Straub, V. n. 2021

    Abstract

    Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD.We collected a longitudinal series of functional assessments from 187 dysferlinopathy patients over three years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and non-ambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories.The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3-8 years post symptom onset at baseline.The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinics practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.26044

    View details for PubMedID 33576057

  • Author Correction: Humanizing the mdx mouse model of DMD: the long and the short of it. NPJ Regenerative medicine Yucel, N., Chang, A. C., Day, J. W., Rosenthal, N., Blau, H. M. 2020; 5 (1): 25

    View details for DOI 10.1038/s41536-020-00112-0

    View details for PubMedID 33349636

  • Deep phenotypic dissection and natural history of a large multicentre CMT2A cohort Pipis, M., Feely, S., Skorupinska, M., Polke, J., Quiros, L., Laura, M., Moroni, I., Pisciotta, C., Vujovic, D., Lloyd, T., Acsadi, G., Yum, S., Lewis, R., Finkel, R., Herrmann, D., Day, J., Li, J., Saporta, M., Sadjadi, R., Walk, D., Burns, J., Ramchandren, S., Horvath, R., Johnson, N., Zuchner, S., Pareyson, D., Scherer, S., Rossor, A., Shy, M., Reilly, M. WILEY. 2020: 559
  • Development and Validation of the Pediatric CMT Quality of Life Outcome Measure. Annals of neurology Ramchandren, S., Wu, T. T., Finkel, R. S., Siskind, C. E., Feely, S. M., Burns, J., Reilly, M. M., Estilow, T., Shy, M. E., Childhood CMT Study Group, Bacon, C. J., Shy, R. R., Cornett, K., Muntoni, F., Day, J. W., Lloyd, T., Sumner, C. J., Herrmann, D. N., Kirk, C., Yum, S. W. 2020

    Abstract

    OBJECTIVE: Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL), especially in children. Defining QOL in pediatric CMT can help physicians monitor disease burden clinically and in trials. We identified items pertaining to QOL in children with CMT and conducted validation studies to develop a pediatric CMT-specific QOL outcome measure (pCMT-QOL).METHODS: Development and validation of the pCMT-QOL patient-reported outcome measure was iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing. Testing was conducted in children with CMT seen at participating sites from the USA, United Kingdom, and Australia.RESULTS: We conducted systematic literature reviews and analysis of generic QOL measures to identify six domains relevant to QOL in children with CMT. 60 items corresponding to those domains were developed de novo, or identified from literature review and CMT-specific modification of items from the pediatric Neuro-QOL measures. The draft version underwent prospective feasibility and face content validity assessments to develop a working version of the pCMT-QOL measure. From 2010-2016, the pCMT-QOL working version was administered to 398 children ages 8-18 seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test-retest reliability, internal consistency, convergent validity, IRT analysis, and longitudinal analysis, to develop the final pCMT-QOL patient-reported outcome measure.INTERPRETATION: The pCMT-QOL patient-reported outcome measure is a reliable, valid, and sensitive measure of health-related QOL for children with CMT. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.25966

    View details for PubMedID 33222249

  • Respiratory trajectories in type 2 and non-ambulant 3 Spinal muscular atrophy in the iSMAC cohort study. Neurology Trucco, F., Ridout, D., Scoto, M., Coratti, G., Main, M. L., Lofra, R. M., Mayhew, A. G., Montes, J., Pane, M., Sansone, V., Albamonte, E., D'Amico, A., Bertini, E., Messina, S., Bruno, C., Parasuraman, D., Childs, A., Gowda, V., Willis, T., Ong, M., Marini-Bettolo, C., De Vivo, D. C., Darras, B. T., Day, J., Kichula, E. A., Mayer, O. H., Navas Nazario, A. A., Finkel, R. S., Mercuri, E., Muntoni, F., international SMA consortium (iSMAc) 2020

    Abstract

    OBJECTIVE: To describe the respiratory trajectories and their correlation with motor function in an international paediatric cohort of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA).METHODS: Eight-year retrospective observational study of patients in the iSMAc natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC% predicted (FVC%P.), Non-Invasive ventilation (NIV) requirement. Hammersmith functional motor scale (HFMS) and Revised performance of upper limb (RULM) were correlated with respiratory function. We excluded patients in interventional clinical trials and on Nusinersen commercial therapy.RESULTS: There were 437 patients with SMA: 348 type 2, 89 non-ambulant type 3. Mean age at first visit was 6.9(±4.4) and 11.1(±4) years. In SMA type 2 FVC%P declined by 4.2%/year from 5 to 13 years, followed by a slower decline (1.0%/year). In type 3 FVC%P declined by 6.3%/year between 8 and 13 years, followed by a slower decline (0.9%/year). 39% SMA type 2 and 9% type 3 required NIV at median age 5.0(1.8-16.6) and 15.1(13.8-16.3) years. 84% SMA type 2 and 80% type 3 had scoliosis, 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM in both subtypes.CONCLUSIONS: In SMA type 2 and non-ambulant type 3 lung function declines differently, with a common levelling after age 13 years. Lung and motor function correlated in both subtypes. Our data further defines the milder SMA phenotypes and provides novel information to benchmark the long-term efficacy of new treatments for SMA.

    View details for DOI 10.1212/WNL.0000000000011051

    View details for PubMedID 33067401

  • Switching between disease-modifying therapies in patients with spinal muscular atrophy: real-world data collected from the RESTORE Registry Servais, L., Day, J., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, O., Shah, A., Anderson, F., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S97
  • One-time administration of AVXS-101 intrathecal (IT) for spinal muscular atrophy in the phase 1 study (STRONG): safety report Chand, D., Finkel, R., Day, J., Darris, B., Kuntz, N., Connolly, A., Zaidman, C., Crawford, T., Butterfield, R., Shieh, P., Tennekoon, G., Brandesma, J., Iannaccone, S., Meriggioli, M., Tauscher-Wisniewski, S., Shoffner, J., Ogrinc, F., Kavanagh, S., Feltner, D., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S120
  • Escalating dose and randomized, controlled study of high-dose nusinersen in SMA; study design and updated enrollment for the DEVOTE Study Finkel, R., Day, J., Ryan, M., Mercuri, E., De Vivo, D., Pascual, S., Montes, J., Gurgel-Giannetti, J., Mitchell-Sweeney, N., Foster, R., Sun, P., Ramirez-Schrempp, D., Kandinov, B., Farwell, W. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S124
  • SUNFISH Part 1: 24-month safety and exploratory outcomes of risdiplam (RG7916) treatment in patients with Type 2 or 3 spinal muscular atrophy (SMA) Day, J., Baranello, G., Boespflug-Tanguy, O., Borell, S., Goemans, N., Kirschner, J., Masson, R., Pera, M., Servais, L., Fuhrer, S., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Scalco, R., Staunton, H., Yeung, W., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S123
  • FIREFISH Part 1: 24-month safety and exploratory outcomes of risdiplam (RG7916) in infants with Type 1 spinal muscular atrophy (SMA) Baranello, G., Bloespflug-Tanguy, O., Darras, B., Day, J., Deconinck, N., Klein, A., Masson, R., Mercuri, E., Dodman, A., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Scalco, R., Servais, L. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S122
  • Nusinersen in adolescents and young adults with SMA: Longitudinal experience from an expanded cohort of CS2/CS12 and SHINE participants Darras, B., Day, J., Swoboda, K., Chiriboga, C., Iannaccone, S., De Vivo, D., Deconinck, N., Finkel, R., Tulinius, M., Saito, K., Montes, J., Foster, R., Ramirez-Schrempp, D., Kandinov, B., Wong, J., Farwell, W. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S120
  • FIREFISH Parts 1 and 2: 12-month pooled safety and efficacy outcomes of risdiplam (RG7916) in infants with Type 1 spinal muscular atrophy (SMA) Servais, L., Bloespflug-Tanguy, O., Darras, B., Day, J., Deconinck, N., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Vlodavets, D., Xiong, H., Zanoteli, E., Dodman, A., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Scalco, R., Baranello, G. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S126
  • Analysis of Cobb angle and clinical characteristics in children with spinal muscular atrophy who enrolled in CHERISH and SHINE Young, S., Montes, J., Glanzman, A., Gee, R., Day, J., Finkel, R., Darras, B., De Vivo, D., Gambino, G., Foster, R., Wong, J., Kandinov, B., Berger, Z. PERGAMON-ELSEVIER SCIENCE LTD. 2020: S70
  • Clinical variability in spinal muscular atrophy type III. Annals of neurology Coratti, G., Messina, S., Lucibello, S., Pera, M. C., Montes, J., Pasternak, A., Stat, F. B., Escudero, J. E., Mazzone, E. S., Mayhew, A., Glanzman, A. M., Young, S. D., Salazar, R., Duong, T., Lofra, R. M., de Sanctis, R., Carnicella, S., Milev, E., Civitello, M., Pane, M., Scoto, M., Bettolo, C. M., Antonaci, L., Frongia, A., Sframeli, M., Vita, G. L., D'Amico, A., van den Hauwe, M., Albamonte, E., Goemans, N., Darras, B. T., Bertini, E., Sansone, V., Day, J., Osorio, A. N., Bruno, C., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, E. 2020

    Abstract

    OBJECTIVE: We report natural history data in a large cohort of 199 spinal muscular atrophy (SMA) type III patients assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number and functional status.METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments.RESULTS: A break point at age 7 was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type and ambulatory status were significantly associated with changes in mean HFMSE score while sex and SMN2 copy number were not. The increase in response before the break point of age 7 is significant only for SMA IIIA (beta=1.79, p<.0001). After the break point the change in the rate of HFMSE score significantly decrease for both SMA IIIA (beta=1.15, p<.0001) and IIIB (beta=0.69, p=0.002).INTERPRETATION: Our findings contribute to the understanding of the natural history of type III SMA and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.25900

    View details for PubMedID 32926458

  • Cobblestone Malformation in LAMA2 Congenital Muscular Dystrophy (MDC1A). Journal of neuropathology and experimental neurology Jayakody, H., Zarei, S., Nguyen, H., Dalton, J., Chen, K., Hudgins, L., Day, J., Withrow, K., Pandya, A., Teasley, J., Dobyns, W. B., Mathews, K. D., Moore, S. A. 2020

    Abstract

    Congenital muscular dystrophy type 1A (MDC1A) is caused by recessive variants in laminin alpha2 (LAMA2). Patients have been found to have white matter signal abnormalities on magnetic resonance imaging (MRI) but rarely structural brain abnormalities. We describe the autopsy neuropathology in a 17-year-old with white matter signal abnormalities on brain MRI. Dystrophic pathology was observed in skeletal muscle, and the sural nerve manifested a mild degree of segmental demyelination and remyelination. A diffuse, bilateral cobblestone appearance, and numerous points of fusion between adjacent gyri were apparent on gross examination of the cerebrum. Brain histopathology included focal disruptions of the glia limitans associated with abnormal cerebral cortical lamination or arrested cerebellar granule cell migration. Subcortical nodular heterotopia was present within the cerebellar hemispheres. Sampling of the centrum semiovale revealed no light microscopic evidence of leukoencephalopathy. Three additional MDC1A patients were diagnosed with cobblestone malformation on brain MRI. Unlike the autopsied patient whose brain had a symmetric distribution of cobblestone pathology, the latter patients had asymmetric involvement, most severe in the occipital lobes. These cases demonstrate that cobblestone malformation may be an important manifestation of the brain pathology in MDC1A and can be present even when patients have a structurally normal brain MRI.

    View details for DOI 10.1093/jnen/nlaa062

    View details for PubMedID 32827036

  • Procedural Patterns and Safety of Atrial Fibrillation Ablation: Findings from Get with The Guidelines-Atrial Fibrillation. Circulation. Arrhythmia and electrophysiology Loring, Z., Holmes, D. N., Matsouaka, R. A., Curtis, A. B., Day, J. D., Desai, N., Ellenbogen, K. A., Feld, G. K., Fonarow, G. C., Frankel, D. S., Hurwitz, J. L., Knight, B. P., Joglar, J. A., Russo, A. M., Sidhu, M. S., Turakhia, M. P., Lewis, W. R., Piccini, J. P. 2020

    Abstract

    Background - Catheter ablation is an increasingly utilized treatment for symptomatic atrial fibrillation (AF). However, there are limited prospective, nationwide data on patient selection and procedural characteristics. This study describes patient characteristics, techniques, treatment patterns, and safety outcomes of patients undergoing AF ablation. Methods - A total of 3,139 patients undergoing AF ablation between 2016-2018 in the Get With The Guidelines-Atrial Fibrillation registry from 24 US centers were included. Patient demographics, medical history, procedural details and complications were abstracted. Differences between paroxysmal and persistent AF patients were compared using Pearson's Chi-square and Wilcoxon rank-sum tests. Results - Patients undergoing AF ablation were predominantly male (63.9%) and Caucasian (93.2%) with a median age of 65. Hypertension was the most common comorbidity (67.6%) and persistent AF patients had more comorbidities than paroxysmal AF patients. Drug refractory, paroxysmal AF was the most common ablation indication (Class I, 53.6%) followed by drug refractory, persistent AF (Class I, 41.8%). Radiofrequency (RF) ablation with contact force (CF) sensing was the most common ablation modality (70.5%); 23.7% of patients underwent cryoballoon ablation. Pulmonary vein isolation (PVI) was performed in 94.6% of de novo ablations; the most common adjunctive lesions included left atrial roof or posterior/inferior lines, and cavotricuspid isthmus ablation. Complications were uncommon (5.1%), and were life-threatening in 0.7% of cases. Conclusions - More than 98% of AF ablations among participating sites are performed for Class I or Class IIA indications. CF-guided RF ablation is the dominant technique and PVI the principal lesion set. In-hospital complications are uncommon and rarely life-threatening.

    View details for DOI 10.1161/CIRCEP.119.007944

    View details for PubMedID 32703018

  • Gain and loss of abilities in type II SMA: A 12-month natural history study. Neuromuscular disorders : NMD Coratti, G., Lucibello, S., Pera, M. C., Duong, T., Muni Lofra, R., Civitello, M., D'Amico, A., Goemans, N., Darras, B. T., Bruno, C., Sansone, V. A., Day, J., Nascimento Osorio, A., Muntoni, F., Montes, J., Sframeli, M., Finkel, R., Mercuri, E., ISMAC group 2020

    Abstract

    The advent of clinical trials in spinal muscular atrophy (SMA) has highlighted the need to define patterns of progression using functional scales. It has recently been suggested that the analysis of abilities gained or lost applied to functional scales better reflects meaningful changes. We defined as "gain" a positive change between scores from 0 to either 1 or 2 and as "loss" a negative change from either 2 or 1 to 0. The aim of this study was to describe, over 12 months, which abilities on the Hammersmith Functional Motor Scale Expanded (HFMSE) were more frequently lost or gained in patients with SMA II. The cohort included 614 12-month assessments from 243 patients (age range: 30 months - 63 years; mean 9.94, SD ±7.91). The peak of abilities gained occurred before the age of 5 years while the highest number of lost abilities was found in the group 5-13 years. A correlation between the HFMSE baseline score and the ordinal number of the items was found for both lost (p<0.001) or gained (p<0.001) activities. No correlation was found with SMN2 copy number. These findings will have implications for clinical trial design and for the interpretation of real-world data using new therapeutic approaches.

    View details for DOI 10.1016/j.nmd.2020.07.004

    View details for PubMedID 32893082

  • Determining An Appropriate Cardiopulmonary Exercise Testing Protocol For Individuals With Neuromuscular Disease Duong, T., Day, J., Dunaway-Young, S., Stevens, V. LIPPINCOTT WILLIAMS & WILKINS. 2020: 640
  • Diagnosis of Myotonic Dystrophy Based on Resting State fMRI Using Convolutional Neural Networks. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Kamali, T., Hagerman, K. A., Day, J. W., Sampson, J., Lim, K. O., Mueller, B. A., Wozniak, J. 2020; 2020: 1714–17

    Abstract

    Myotonic dystrophies (DM) are neuromuscular conditions that cause widespread effects throughout the body. There are brain white matter changes on MRI in patients with DM that correlate with neuropsychological functional changes. How these brain alterations causally relate to the presence and severity of cognitive symptoms remains largely unknown. Deep neural networks have significantly improved the performance of image classification of huge datasets. However, its application in brain imaging is limited and not well described, due to the scarcity of labeled training data. In this work, we propose an approach for the diagnosis of DM based on a spatio-temporal deep learning paradigm. The obtained accuracy (73.71%) and sensitivities and specificities showed that the implemented approach based on 4-D convolutional neural networks leads to a compact, discriminative, and fast computing DM-based clinical medical decision support system.Clinical relevance- Many adults with DM experience cognitive and neurological effects impacting their quality of life, and ability to maintain employment. A robust and reliable DM-based clinical decision support system may help reduce the long diagnostic delay common to DM. Furthermore, it can help neurologists better understand the pathophysiology of the disease and analyze effects of new drugs that aim to address the neurological symptoms of DM.

    View details for DOI 10.1109/EMBC44109.2020.9176455

    View details for PubMedID 33018327

  • Descriptive analysis of varying real-world treatment patterns and outcomes in patients with spinal muscular atrophy collected from the RESTORE registry Finkel, R. S., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, C., Shah, A., Khan, F., Anderson, F. A., Servais, L. WILEY. 2020: 620–21
  • SUNFISH Part 2: Efficacy and safety of risdiplam (RG7916) in patients with Type 2 or non-ambulant Type 3 spinal muscular atrophy (SMA) Mercuri, E., Barisic, N., Boespflug-Tanguy, O., Day, J. W., Deconinck, N., Kostera-Pruszczyk, A., Masson, R., Mazzone, E., Nascimento, A., Saito, K., Vlodavets, D., Fuerst-Recktenwald, S., Fuhrer, S., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Yeung, W. Y., Vuillerot, C. WILEY. 2020: 869
  • Real-World Treatment Patterns and Outcomes in Patients with Spinal Muscular Atrophy Collected from the RESTORE Registry Servais, L., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, O., Shah, A., Khan, F., Anderson, F. A., Finkel, R. S. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • SUNFISH Part 2: Efficacy and Safety of Risdiplam (RG7916) in Patients with Type 2 or Non-Ambulant Type 3 Spinal Muscular Atrophy (SMA) Mercuri, E., Barisic, N., Boespflug-Tanguy, O., Deconinck, N., Kostera-Pruszczyk, A., Masson, R., Mazzone, E., Nascimento, A., Saito, K., Vlodavets, D., Vuillerot, C., Fuerst-Recktenwald, S., Fuhrer, S., Gerber, M., Gorni, K., Kletzl, H., Martin, C., Yeung, W., Day, J. W., SUNFISH Study Grp LIPPINCOTT WILLIAMS & WILKINS. 2020
  • One-Time Intrathecal (IT) Administration of AVXS-101 IT Gene-Replacement Therapy for Spinal Muscular Atrophy: Phase 1 Study (STRONG) Finkel, R. S., Day, J. W., Darras, B. T., Kuntz, N. L., Connolly, A. M., Crawford, T., Butterfield, R. J., Shieh, P. B., Tennekoon, G., Iannaccone, S. T., Meriggioli, M., Tauscher-Wisniewski, S., Shoffner, J., Ogrinc, F. G., Kavanagh, S., Kernbauer, E., Whittle, J., Sproule, D. M., Feltner, D. E., Mendell, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • JEWELFISH: Safety and Pharmacodynamic Data in Non-Naive Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam (RG7916) Chiriboga, C., Bruno, C., Day, J. W., Duong, T., Fischer, D., Kirschner, J., Muntoni, F., Fuerst-Recktenwald, S., Gerber, M., Gorni, K., Kletzl, H., Warren, F., Yeung, W., Mercuri, E., JEWELFISH Study Grp LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Pooled Safety Data from the Risdiplam (RG7916) Clinical Trial Development Program 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., Servais, L., Wang, Y., Fuerst-Recktenwald, S., Gerber, M., Gorni, K., Jaber, B., McIver, T., Scalco, R., Eugenio Mercuri FIREFISH, SUNFISH, JEWELFISH Study Grp LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Onasemnogene Abeparvovec-xioi Gene-Replacement Therapy for Spinal Muscular Atrophy Type 1 (SMA1): Phase 3 US Study (STR1VE) Update Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Shieh, P. B., Smith, E. C., Schultz, M., Feltner, D. E., Tauscher-Wisniewski, S., Ogrinc, F. G., Shah, A., Ouyang, H., Macek, T., Kernbauer, E., Sproule, D. M., Mendell, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Escalating Dose and Randomized, Controlled Study of Nusinersen in Participants with Spinal Muscular Atrophy; Study Design of the Phase 2/3 DEVOTE (232SM203) Study to Explore High Dose Nusinersen Finkel, R. S., Day, J. W., Mitchell-Sweeney, N., Foster, R., Sun, P., Bhan, I., Kandinov, B., Farwell, W. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Longer-term Experience with Nusinersen in Teenagers and Young Adults with Spinal Muscular Atrophy: Results from the CS2/CS12 and SHINE Studies Day, J. W., Swoboda, K. J., Darras, B. T., Chiriboga, C. A., Iannaccone, S. T., De Vivo, D. C., Deconinck, N., Finkel, R. S., Tulinius, M., Saito, K., Montes, J., Sun, P., Bhan, I., Kandinov, B., Wong, J., Farwell, W. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • RESTORE: A Prospective Multinational Registry of Patients with Genetically Confirmed Spinal Muscular Atrophy - Rationale and Study Design. Journal of neuromuscular diseases Finkel, R. S., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, O., Khan, F., Renault, L., Anderson, F. A., Servais, L. 2020

    Abstract

    BACKGROUND: Dramatic improvements in spinal muscular atrophy (SMA) treatment have changed the prognosis for patients with this disease, leading to important new questions. Gathering representative, real-world data about the long-term efficacy and safety of emerging SMA interventions is essential to document their impact on patients and caregivers.OBJECTIVES: This registry will assess outcomes in patients with genetically confirmed SMA and provide information on the effectiveness and long-term safety of approved and emerging treatments.DESIGN AND METHODS: RESTORE is a prospective, multicenter, multinational observational registry. Patients will be managed according to usual clinical practice. Both newly recruitedSMAtreatment centers and sites involved in existing SMA registries, including iSMAC, Treat-NMD, French SMA Assistance Publique- Hopitaux de Paris (AP-HP), Cure-SMA, SMArtCARE, will be eligible to participate; de novo; sites already participating in another registry may be included via consortium agreements. Data from patients enrolled in partnering registries will be shared with the RESTORE Registry and data for newly diagnosed patients will be added upon enrollment. Patients will be enrolled over a 5-year period and followed for 15 years or until death. Assessments will include SMA history and treatment, pulmonary, nutritional, and motor milestones, healthcare resource utilization, work productivity, activity impairment, adverse events, quality of life, caregiver burden, and survival.Status:Recruitment started in September 2018. As of January 3, 2020, 64 patients were enrolled at 25 participating sites.CONCLUSIONS: The RESTORE Registry has begun recruiting recently diagnosed patients with genetically confirmed SMA, enabling assessment of both short- and long-term patient outcomes.

    View details for DOI 10.3233/JND-190451

    View details for PubMedID 32039859

  • Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. Journal of neuromuscular diseases Glascock, J., Sampson, J., Connolly, A. M., Darras, B. T., Day, J. W., Finkel, R., Howell, R. R., Klinger, K. W., Kuntz, N., Prior, T., Shieh, P. B., Crawford, T. O., Kerr, D., Jarecki, J. 2020

    View details for DOI 10.3233/JND-190468

    View details for PubMedID 32007960