Publications

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

Publications

  • Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study. Neurology Crawford, T. O., Darras, B. T., Day, J. W., Dunaway Young, S., Duong, T., Nelson, L. L., Barrett, D., Song, G., Bilic, S., Cote, S., Sadanowicz, M., Iarrobino, R., Xu, T. J., O'Neil, J., Rossello, J., Place, A., Kertesz, N., Nomikos, G., Chyung, Y. 2024; 102 (5): e209151

    Abstract

    Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA.In this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants ≥2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points.Fifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported.Apitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA.This trial is registered with ClinicalTrials.gov (NCT03921528).This study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

    View details for DOI 10.1212/WNL.0000000000209151

    View details for PubMedID 38330285

  • Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3. Journal of neuromuscular diseases Wolfe, A., Stimpson, G., Ramsey, D., Coratti, G., Dunaway Young, S., Mayhew, A., Pane, M., Rohwer, A., Muni Lofra, R., Duong, T., O'Reilly, E., Milev, E., Civitello, M., Sansone, V. A., D'Amico, A., Bertini, E., Messina, S., Bruno, C., Albamonte, E., Mazzone, E., Main, M., Montes, J., Glanzman, A. M., Zolkipli-Cunningham, Z., Pasternak, A., Marini-Bettolo, C., Day, J. W., Darras, B. T., De Vivo, D. C., Baranello, G., Scoto, M., Finkel, R. S., Mercuri, E., Muntoni, F. 2024

    Abstract

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS).In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019).We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient.RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex.This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

    View details for DOI 10.3233/JND-230211

    View details for PubMedID 38427497

  • Real-World Outcomes in Patients with Spinal Muscular Atrophy Treated with Onasemnogene Abeparvovec Monotherapy: Findings from the RESTORE Registry. Journal of neuromuscular diseases Servais, L., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Proud, C. M., Shieh, P. B., Tizzano, E. F., Quijano-Roy, S., Desguerre, I., Saito, K., Faulkner, E., Benguerba, K. M., Raju, D., LaMarca, N., Sun, R., Anderson, F. A., Finkel, R. S. 2024

    Abstract

    BACKGROUND: Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials.OBJECTIVE: We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting.METHODS: RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources.RESULTS: Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0-6) month and at onasemnogene abeparvovec infusion was 3 (1-10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related.CONCLUSION: These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

    View details for DOI 10.3233/JND-230122

    View details for PubMedID 38250783

  • Adeno-associated virus serotype 9 antibody seroprevalence for patients in the United States with spinal muscular atrophy. Molecular therapy. Methods & clinical development Day, J. W., Mendell, J. R., Burghes, A. H., van Olden, R. W., Adhikary, R. R., Dilly, K. W. 2023; 31: 101117

    Abstract

    Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (AAV9) vector-based gene therapy for spinal muscular atrophy (SMA). Patients with elevated titers of anti-AAV9 antibodies (AAV9-Ab) should not receive onasemnogene abeparvovec because of potential safety and efficacy implications. We conducted a retrospective study to describe the seroprevalence of anti-AAV9 binding antibodies for pediatric patients with SMA in the United States. At initial testing, 13.0% (115 of 882) of patients (mean [SD] age, 26.29 [33.66] weeks) had elevated AAV9-Ab titers. The prevalence of elevated titers decreased as age increased, with 18.2% (92 of 507) of patients ≤3 months old but only 1.1% (1 of 92) of patients ≥21 months old having elevated titers. This suggests transplacental maternal transfer of antibodies. No patterns of geographic variations in AAV9-Ab prevalence were confirmed. Elevated AAV9-Ab titers in children <6 weeks old decreased in all circumstances. Lower magnitudes of elevated titers declined more rapidly than greater magnitudes. Retesting was completed at the discretion of the treating clinician, so age at testing and time between tests varied. AAV9-Ab retesting should be considered when patients have elevated titers, and elevations at a young age are not a deterrent to eventual onasemnogene abeparvovec administration. Early disease-modifying treatment for SMA leads to optimal outcomes.

    View details for DOI 10.1016/j.omtm.2023.101117

    View details for PubMedID 37822718

    View details for PubMedCentralID PMC10562739

  • Assessing the Assisted Six-Minute Cycling Test as a Measure of Endurance in Non-Ambulatory Patients with Spinal Muscular Atrophy (SMA). Journal of clinical medicine Tang, W. J., Gu, B., Montalvo, S., Dunaway Young, S., Parker, D. M., de Monts, C., Ataide, P., Ni Ghiollagain, N., Wheeler, M. T., Tesi Rocha, C., Christle, J. W., He, Z., Day, J. W., Duong, T. 2023; 12 (24)

    Abstract

    Assessing endurance in non-ambulatory individuals with Spinal Muscular Atrophy (SMA) has been challenging due to limited evaluation tools. The Assisted 6-Minute Cycling Test (A6MCT) is an upper limb ergometer assessment used in other neurologic disorders to measure endurance. To study the performance of the A6MCT in the non-ambulatory SMA population, prospective data was collected on 38 individuals with SMA (13 sitters; 25 non-sitters), aged 5 to 74 years (mean = 30.3; SD = 14.1). The clinical measures used were A6MCT, Revised Upper Limb Module (RULM), Adapted Test of Neuromuscular Disorders (ATEND), and Egen Klassifikation Scale 2 (EK2). Perceived fatigue was assessed using the Fatigue Severity Scale (FSS), and effort was assessed using the Rate of Perceived Exertion (RPE). Data were analyzed for: (1) Feasibility, (2) Clinical discrimination, and (3) Associations between A6MCT with clinical characteristics and outcomes. Results showed the A6MCT was feasible for 95% of the tested subjects, discriminated between functional groups (p = 0.0086), and was significantly associated with results obtained from RULM, ATEND, EK2, and Brooke (p < 0.0001; p = 0.029; p < 0.001; p = 0.005). These findings indicate the A6MCT's potential to evaluate muscular endurance in non-ambulatory SMA individuals, complementing clinician-rated assessments. Nevertheless, further validation with a larger dataset is needed for broader application.

    View details for DOI 10.3390/jcm12247582

    View details for PubMedID 38137651

    View details for PubMedCentralID PMC10743820

  • Sunfish parts 1 and 2: 4-year efficacy and safety data of risdiplam in types 2 and 3 spinal muscular atrophy (SMA) Oskoui, M., Deconinck, N., Mazzone, E. S., Nascimento, A., Day, J. W., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschnero, J., Kostera-Pruszczyk, A., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Yeung, W., Scalco, R. S., Mercuri, E. ELSEVIER. 2023
  • Cerebrospinal Fluid Proteomic Changes after Nusinersen in Patients with Spinal Muscular Atrophy. Journal of clinical medicine Beaudin, M., Kamali, T., Tang, W., Hagerman, K. A., Dunaway Young, S., Ghiglieri, L., Parker, D. M., Lehallier, B., Tesi-Rocha, C., Sampson, J. B., Duong, T., Day, J. W. 2023; 12 (20)

    Abstract

    Disease-modifying treatments have transformed the natural history of spinal muscular atrophy (SMA), but the cellular pathways altered by SMN restoration remain undefined and biomarkers cannot yet precisely predict treatment response. We performed an exploratory cerebrospinal fluid (CSF) proteomic study in a diverse sample of SMA patients treated with nusinersen to elucidate therapeutic pathways and identify predictors of motor improvement. Proteomic analyses were performed on CSF samples collected before treatment (T0) and at 6 months (T6) using an Olink panel to quantify 1113 peptides. A supervised machine learning approach was used to identify proteins that discriminated patients who improved functionally from those who did not after 2 years of treatment. A total of 49 SMA patients were included (10 type 1, 18 type 2, and 21 type 3), ranging in age from 3 months to 65 years. Most proteins showed a decrease in CSF concentration at T6. The machine learning algorithm identified ARSB, ENTPD2, NEFL, and IFI30 as the proteins most predictive of improvement. The machine learning model was able to predict motor improvement at 2 years with 79.6% accuracy. The results highlight the potential application of CSF biomarkers to predict motor improvement following SMA treatment. Validation in larger datasets is needed.

    View details for DOI 10.3390/jcm12206696

    View details for PubMedID 37892834

  • Assessment of maximal effort for weaker individuals with NMD during the assisted six-minute cycling test Blumberg, Y., De Monts, C., Tang, W., Montalvo, S., Ataide, P., Young, S., Wheeler, M., Ashley, E., Myers, J., Day, J., Christle, J., Duong, T. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S187
  • Quality of life in adults with dysferlinopathy: international clinical outcome study of dysferlinopathy Hilsden, H., James, M., Dressman, H., Day, J., Mendell, J., Torron, R., Harms, M., Pestronk, A., Vissing, J., Desai, U., Yoshimura, M., Shin, J., Mozaffar, T., Stojkovic, T., Pegoraro, E., Raivas, J., Olive, M., Paradas, C., Straub, V., Mayhew, A. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S113
  • Topline data analysis of the phase 1/2 clinical trial evaluating AOC 1001 in adult patients with myotonic dystrophy type 1: MARINA Johnson, N., Day, J., Hamel, J., Thornton, C., Subramony, S., Soltanzadeh, P., Statland, J., Wicklund, M., Arnold, W., Freimer, M., DiTrapani, K., Heusner, C., Chen, C., Cho, H., McEvoy, B., Zhu, Y., Tai, L., Ackermann, E. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S72
  • Topline safety and efficacy data analysis of phase 1/2 clinical trial evaluating AOC 1001 in adults with myotonic dystrophy type 1: MARINA ™ Johnson, N., Day, J., Hamel, J., Thornton, C., Subramony, S., Soltanzadeh, P., Statland, J., Wicklund, M., Arnold, W., Freimer, M., DiTrapani, K., Heusner, C., Chen, C., McEvoy, B., Zhu, Y., Tai, L., Ackermann, E. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S190-S191
  • Safety update: Risdiplam clinical trial program for spinal muscular atrophy (SMA) Baranello, G., Chiriboga, C., Servais, L., Darras, B., Day, J., Deconinck, N., Farrar, M., Finkel, R., Bertini, E., Kirschner, J., Rasson, M., Mazurkiewicz-Beldzinska, M., Vlodavets, D., Bader-Weder, S., Gorni, K., Jaber, B., Yeung, W., Papp, G., Scalco, R., Mercuri, E., FIREFISH SUNFISH JEWELFISH RAINBOW PERGAMON-ELSEVIER SCIENCE LTD. 2023: S92-S93
  • Effect of Apitegromab on pedi-cat and promis-fatigue questionnaire at 36-months in patients with spinal muscular atrophy Crawford, T., Darras, B., Day, J., Krueger, J., Mercuri, E., Nascimento, A., Pasternak, A., Duong, T., Liu, L., Sadanowicz, M., Baver, S., Topaz Study Team PERGAMON-ELSEVIER SCIENCE LTD. 2023: S93-S94
  • More prevalent comorbidities, healthcare costs, and service utilization in male Myotonic Dystrophy (DM) patients and female patients Day, J., Munoz, K., Chen, C., Brook, R., Kleinman, N., Cho, H., McEvoy, B., Stahl, M., Tai, L. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S157
  • Effect of apitegromab on motor function at 36 months in patients with nonambulatory spinal muscular atrophy aged 2-12 years old Crawford, T., Darras, B., Day, J., De Vivo, D., Mercuri, E., Nascimento, A., Mazzone, E., Waugh, A., Song, G., Evans, R., Marantz, J., TOPAZ Study Team PERGAMON-ELSEVIER SCIENCE LTD. 2023: S91
  • Assisted Six Minute Cycle Test (A6MCT): A Feasible and Valid Measurement of Functional and Fatigue Changes in Individuals with Spinal Muscular Atrophy Tang, W., Montalvo, S., De Monts, C., Young, S., Ataide, P., Ghiollagain, N., Stevens, V., Parker, D., He, Z., Rocha, C., Day, J., Duong, T. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S135
  • Intravenous and intrathecal onasemnogene abeparvovec gene therapy in symptomatic and presymptomatic spinal muscular atrophy (SMA): long-term follow-up study Darras, B., Mercuri, E., Strauss, K., Day, J., Chien, Y., Masson, R., Wigderson, M., Alecu, I., Ballarini, N., Mehl, L., Marra, J., Connolly, A. PERGAMON-ELSEVIER SCIENCE LTD. 2023: S87
  • Generation of two induced pluripotent stem cell lines from Duchenne muscular dystrophy patients. Stem cell research Liu, W., Zeng, W., Kong, X., Htet, M., Yu, R., Wheeler, M., Day, J. W., Wu, J. C. 2023; 72: 103207

    Abstract

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that leads to death in early adulthood. Patients with DMD have null mutations leading to loss of functional dystrophin protein. Here we generated two DMD induced pluripotent stem cell (iPSC) lines, one with deletion of exon 51 and the other with a single nucleotide nonsense mutation (c.10171C > T). Both lines expressed high levels of pluripotency markers, had the capability of differentiating into derivatives of the three germ layers, and possessed normal karyotypes. These iPSC lines can serve as powerful tools to model DMD in vitro and as a platform for therapeutic development.

    View details for DOI 10.1016/j.scr.2023.103207

    View details for PubMedID 37740996

  • Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function. Journal of clinical medicine Dunaway Young, S., Montes, J., Glanzman, A. M., Gee, R., Day, J. W., Finkel, R. S., Darras, B. T., De Vivo, D. C., Gambino, G., Foster, R., Wong, J., Garafalo, S., Berger, Z. 2023; 12 (15)

    Abstract

    Nusinersen has been shown to improve or stabilize motor function in individuals with spinal muscular atrophy (SMA). We evaluated baseline scoliosis severity and motor function in nusinersen-treated non-ambulatory children with later-onset SMA. Post hoc analyses were conducted on 95 children initiating nusinersen treatment in the CHERISH study or SHINE long-term extension trial. Participants were categorized by baseline Cobb angle (first nusinersen dose): ≤10°, >10° to ≤20°, and >20° to <40° (no/mild/moderate scoliosis, respectively). Outcome measures included the Hammersmith Functional Motor Score-Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Regression analysis determined the relationships between baseline scoliosis severity and later motor function. For children with no, mild, and moderate scoliosis, the mean increase in HFMSE from baseline to Day 930 was 6.0, 3.9, and 0.7 points, and in RULM was 6.1, 4.6, and 2.3 points. In the linear model, a 10° increase in baseline Cobb angle was significantly associated with a -1.4 (95% CI -2.6, -0.2) point decrease in HFMSE (p = 0.02) and a -1.2 (95% CI -2.1, -0.4) point decrease in RULM (p = 0.006) at Day 930. Treatment with nusinersen was associated with improvements/stabilization in motor function in all groups, with greater response in those with no/mild scoliosis at baseline.

    View details for DOI 10.3390/jcm12154901

    View details for PubMedID 37568304

  • ADAPTations to low load blood flow restriction exercise versus conventional heavier load resistance exercise in UK military personnel with persistent knee pain: protocol for the ADAPT study, a multi-centre randomized controlled trial BMC MUSCULOSKELETAL DISORDERS Cassidy, R. P., Lunt, K. M., Coppack, R. J., Bennett, A. N., Bilzon, J. J., Mcguigan, M., Egginton, N., Sellon, E., Day, J., Ladlow, P. 2023; 24 (1): 580

    Abstract

    Muscle atrophy, muscle weakness and localised pain are commonly reported following musculoskeletal injury (MSKI). To mitigate this risk and prepare individuals to return to sport or physically demanding occupations, resistance training (RT) is considered a vital component of rehabilitation. However, to elicit adaptations in muscle strength, exercise guidelines recommend lifting loads ≥ 70% of an individual's one repetition maximum (1-RM). Unfortunately, individuals with persistent knee pain are often unable to tolerate such high loads and this may negatively impact the duration and extent of their recovery. Low load blood flow restriction (LL-BFR) is an alternative RT technique that has demonstrated improvements in muscle strength, hypertrophy, and pain in the absence of high mechanical loading. However, the effectiveness of high-frequency LL-BFR in a residential rehabilitation environment remains unclear. This study will compare the efficacy of high frequency LL-BFR to 'conventional' heavier load resistance training (HL-RT) on measures of physical function and pain in adults with persistent knee pain.This is a multicentre randomised controlled trial (RCT) of 150 UK service personnel (aged 18-55) admitted for a 3-week residential rehabilitation course with persistent knee pain. Participants will be randomised to receive: a) LL-BFR delivered twice daily at 20% 1-RM or b) HL-RT three-times per week at 70% 1-RM. Outcomes will be recorded at baseline (T1), course discharge (T2) and at three-months following course (T3). The primary outcome will be the lower extremity functional scale (LEFS) at T2. Secondary outcomes will include patient reported perceptions of pain, physical and occupational function and objective measures of muscle strength and neuromuscular performance. Additional biomechanical and physiological mechanisms underpinning both RT interventions will also be investigated as part of a nested mechanistic study.LL-BFR is a rehabilitation modality that has the potential to induce positive clinical adaptations in the absence of high mechanical loads and therefore could be considered a treatment option for patients suffering significant functional deficits who are unable to tolerate heavy load RT. Consequently, results from this study will have a direct clinical application to healthcare service providers and patients involved in the rehabilitation of physically active adults suffering MSKI.ClinicalTrials.org reference number, NCT05719922.

    View details for DOI 10.1186/s12891-023-06693-3

    View details for Web of Science ID 001032457700001

    View details for PubMedID 37461024

    View details for PubMedCentralID PMC10351180

  • Correction to: Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study. Neurology and therapy Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Mercuri, E., Kirschner, J., Kostera-Pruszczyk, A., Jaber, B., Gorni, K., Kletzl, H., Carruthers, I., Martin, C., Warren, F., Scalco, R. S., Wagner, K. R., Muntoni, F., JEWELFISH Study Group, Deconinck, N., Balikova, I., Joniau, I., Tahon, V., Wittevrongel, S., Goemans, N., Cassiman, C., Prove, L., Vancampenhout, L., van den Hauwe, M., Van Impe, A., Cances, C., Soler, V., De La Morandais, L. M., Vovan, D., Cintas, P., Auriol, F., Mus, M., Alphonsa, G., Bellio, V., Gil Mato, O., Flamein, F., Evrard, C., Ziouche, A., Bouacha-Allou, I., Debruyne, P., Derlyn, G., Defoort, S., Leroy, F., Danjoux, L., Desguerre, I., Bremond-Gignac, D., Rateuax, M., Deladriere, E., Vuillerot, C., Veillerot, Q., Sibille-Dabadi, B., Barriere, A., Tinat, M., Saidi, M., Fontaine, S., De Montferrand, C., Le-Goff, L., Portefaix, A., Louvier, U. W., Duval, P., Caradec, P., Touati, S., Herranz, A. Z., Kirschner, J., Bollig, J., Molnar, F., Vogt, S., Pechmann, A., Schorling, D., Wider, S., Kolbel, H., Schara, U., Braun, F., Gangfuss, A., Hagenacker, T., Eckstein, A., Dekowski, D., Oeverhaus, M., Stoehr, M., Andres, B., Smuda, K., Bertini, E., D'Amico, A., Petroni, S., Valente, P., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Pedemonte, M., Brolatti, N., Priolo, E., Rao, G., Sposetti, L., Morando, S., Comi, G., Osnaghi, S., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, M. A., Magri, F., Govoni, A., Meneri, M., Parente, V., Mercuri, E., Antonaci, L., Pera, M. C., Pane, M., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., De Sanctis, R., Vita, G., Sframeli, M., Vita, G. L., Aragona, P., Inferrera, L., Postorino, E. I., Montanini, D., Di Bella, V., Donato, C., Cala, E., Van der Pol, L., Aalbers, J., de Boer, J., Imhof, S., Cooijmans, P., Ruyten, T., Van Der Woude, D., Kostera-Pruszczyk, A., Klimaszewska, B., Romanczak, D., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Lusakowska, A., Kierdaszuk, B., Czeczko, K., Fischer, D., Henzi, B., Gugleta, K., Kusnyerik, A., Siems, P., Akos, S., Frei, N., Seppi, C., Haschke, C. W., Guglieri, M., Straub, V., Bell, R., Nassar, M., Page, S., Clarke, M. P., Regan, A., Mayhew, A., Lofra, R. M., Parasuraman, D., Bruschi, S., Ghauri, A., Castle, A., Naqvi, S., Patt, N., Scoto, M., Trucco, F., Henderson, R. H., Kukadia, R., Moore, W., Milev, E., Rye, C., Selby, V., Wolfe, A., Darras, B., Baglieri, A. M., Fulton, A., Lucken, C., Maczek, E., Pasternak, A., Chiriboga, C. A., Kane, S., Bautista, M. E., Frommer, E., Pensec, N., Salazar, R., Yochai, C., Rodrigues-Torres, R., Chawla, M., Day, J., Beres, S., Gee, R., Young, S. D., Finkel, R., Nazario, A. N., Fasiuddin, A., Wells, J. A., Wilson, J., Berry, D., Rizzo, V., Duke, J., Monduy, M., Collado, J. 2023

    View details for DOI 10.1007/s40120-023-00503-7

    View details for PubMedID 37395990

  • Learning Spectral Fractional Anisotropy and Mean Diffusivity Features as Neuroimaging Biomarkers for Tracking White Matter Integrity Changes in Myotonic Dystrophy Type 1 Patients using Deep 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., Day, J. W., Deutsch, G. K., Sampson, J. B., Murad, A., Chaufty, J., Parker, D., Wozniak, J. R. 2023; 2023: 1-4

    Abstract

    Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular progressive multisystem disease that results in a broad spectrum of clinical central nervous system (CNS) involvement, including problems with memory, attention, executive functioning, and social cognition. Fractional anisotropy and mean diffusivity along-tract data calculated using diffusion tensor imaging techniques play a vital role in assessing white matter microstructural changes associated with neurodegeneration caused by DM1. In this work, a novel spectrogram-based deep learning method is proposed to characterize white matter network alterations in DM1 with the goal of building a deep learning model as neuroimaging biomarkers of DM1. The proposed method is evaluated on fractional anisotropies and mean diffusivities along-tract data calculated for 25 major white matter tracts of 46 DM1 patients and 96 unaffected controls. The evaluation data consists of a total of 7100 spectrogram images. The model achieved 91% accuracy in identifying DM1, a significant improvement compared to previous methods.Clinical relevance- Clinical care of DM1 is particularly challenging due to DM1 multisystem involvement and the disease variability. Patients with DM1 often experience neurological and psychological symptoms, such as excessive sleepiness and apathy, that greatly impact their quality of life. Some of DM1 CNS symptoms may be responsive to treatment. The goal of this research is to gain a deeper understanding of the impact of DM1 on the CNS and to develop a deep learning model that can serve as a biomarker for the disease, with the potential to be used in future clinical trials as an outcome measure.

    View details for DOI 10.1109/EMBC40787.2023.10340468

    View details for PubMedID 38083393

  • DEVOTE Study Exploring Higher Dose of Nusinersen in Spinal Muscular Atrophy: Study Design and Part A Results. Journal of neuromuscular diseases Finkel, R. S., Day, J. W., Pascual, S. I., Ryan, M. M., Mercuri, E., De Vivo, D. C., Montes, J., Gurgel-Giannetti, J., Monine, M., Gambino, G., Makepeace, C., Foster, R., Berger, Z., DEVOTE Study Group 2023

    Abstract

    BACKGROUND: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose.OBJECTIVE: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A.METHODS: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to higher doses.RESULTS: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1-12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing.CONCLUSIONS: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen.

    View details for DOI 10.3233/JND-221667

    View details for PubMedID 37393513

  • Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants. Brain : a journal of neurology Record, C. J., Skorupinska, M., Laura, M., Rossor, A. M., Pareyson, D., Pisciotta, C., Feely, S. M., Lloyd, T. E., Horvath, R., Sadjadi, R., Herrmann, D. N., Li, J., Walk, D., Yum, S. W., Lewis, R. A., Day, J., Burns, J., Finkel, R. S., Saporta, M. A., Ramchandren, S., Weiss, M. D., Acsadi, G., Fridman, V., Muntoni, F., Poh, R., Polke, J. M., Zuchner, S., Shy, M. E., Scherer, S. S., Reilly, M. M., Inherited Neuropathies Consortium - Rare Disease Clinical Research Network, Abreu, L., Anderson, K. A., Baratta, S., Berry, D., Blake, J., Cavalca, E., Cornett, K., Cortese, A., Donlevy, G., Dragon, A., Dudziec, M., Estilow, K. E., Ferment, V., Grant, N., Grider, T., Hyslop, E., Jones, T., Kressin, N., Leon, W., Magri, S., McCray, B., Menezes, M., Milev, E., Parrott, L., Patel, P., Pires, C. B., Prada, V., Ramdharry, G., Saveri, P., Schirinzi, G., Shy, R., Siskind, C., Sowden, J., Stork, S., Sumner, C. J., Taroni, F., Thomas, S., Twachtman-Bassett, J., Villalpando, N., Vujovic, D., Wells, J., Wood, E., Zuccarino, R. 2023

    Abstract

    Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterised by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and 3 benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness (change in CMTES (DeltaCMTES) = 1.3 ± 2.6, p = 0.00016, SRM = 0.50). Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year DeltaCMTES = 2.3 ± 2.5, p = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

    View details for DOI 10.1093/brain/awad187

    View details for PubMedID 37284795

  • COMPARATIVE REAL-WORLD RETROSPECTIVE DATA ANALYSIS OF COMORBID CONDITIONS AND HEALTHCARE UTILIZATION FOR PATIENTS WITH MYOTONIC DYSTROPHY OVER A 5-YEAR TIMEFRAME Day, J. W., Chen, C. Y., Munoz, K., Brook, R. A., Kleinman, N. L., McEvoy, B., Cho, H., Stahl, M., Tai, L. J. ELSEVIER SCIENCE INC. 2023: S393
  • FIREFISH Parts 1 and 2: 4-year efficacy and safety of risdiplam in Type 1 spinal muscular atrophy (SMA) Mazurkiewicz-Beldzinska, M., Baranello, G., Boespflug-Tanguy, O., Day, J., Deconinck, N., Klein, A., Masson, R., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Palfreeman, L., Dodman, A., Darras, B. WILEY. 2023: 196
  • COMET: Patient-reported outcome measures in patients with late-onset Pompe disease after 145 weeks' avalglucosidase alfa Toscano, A., Kishnani, P., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Van der Ploeg, A., Clemens, P., Day, J., Illarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Huynh-Ba, O., Tammireddy, S., Thibault, N., Zhou, T., Dimachkie, M., Schoser, B., Comet Invest Grp WILEY. 2023: 209-210
  • Apitegromab in SMA: An Analysis of Additional Efficacy Endpoints in the TOPAZ Study at 36 Months Crawford, T., Darras, B., Day, J., Mercuri, E., Nascimento, A., Mazzone, E., Waugh, A., Song, G., Bilic, S., Marantz, J., Topaz Study Team WILEY. 2023: 192
  • SUNFISH Parts 1 and 2: 4-year efficacy and safety data of risdiplam in Types 2 and 3 spinal muscular atrophy (SMA) Kostera-Pruszczyk, A., Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Yeung, W., Scalco, R., Mercuri, E. WILEY. 2023: 194
  • Choroid plexus mis-splicing and altered cerebrospinal fluid composition in myotonic dystrophy type 1. Brain : a journal of neurology Nutter, C. A., Kidd, B. M., Carter, H. A., Hamel, J. I., Mackie, P. M., Kumbkarni, N., Davenport, M. L., Tuyn, D. M., Gopinath, A., Creigh, P. D., Sznajder, Ł. J., Wang, E. T., Ranum, L. P., Khoshbouei, H., Day, J. W., Sampson, J. B., Prokop, S., Swanson, M. S. 2023

    Abstract

    Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knockin model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knockin mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from donors without neurologically unaffected (two females, three males; ages 50-70) and myotonic dystrophy type 1 donors (one female, three males; ages 50-70). To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55) and non-myotonic dystrophy patients (three females, four males; ages 26-51) and Western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knockin mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knockin mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output, and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.

    View details for DOI 10.1093/brain/awad148

    View details for PubMedID 37143315

  • A Human PBMC Assay of Type 1 Interferon Responses to Closely Related AAV Vectors Hamilton, B. A., Patil, R., Kim, S., Day, J. W., Wright, J. CELL PRESS. 2023: 76
  • Intravenous and Intrathecal Onasemnogene Abeparvovec Gene Therapy in Symptomatic and Presymptomatic Spinal Muscular Atrophy: Long-Term Follow-Up Study Darras, B., Mercuri, E., Strauss, K., Day, J., Chien, Y., Masson, R., Wigderson, M., Alecu, I., Ballarini, N., Mehl, L., Marra, J., Connolly, A. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Preliminary Assessment of the Phase 1/2 Clinical Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AOC 1001 Administered Intravenously to Adult Patients with Myotonic Dystrophy Type 1 (DM1) (MARINA) Johnson, N., Day, J., Hamel, J., Thornton, C., Subramony, S., Soltanzadeh, P., Statland, J., Arnold, W., Wicklund, M., Ditrapani, K., Heusner, C., Chen, C., McEvoy, B., Zhu, Y., Tai, L., Ackermann, E. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Motor Outcomes to Validate Evaluations in Facioscapulohumeral muscular dystrophy (MOVE FSHD): Preliminary Baseline Characteristics Walker, M., Butterfield, R., Day, J., Eichinger, K., Elsheikh, B., Friedman, S., Genge, A., Higgs, K., Johnson, N., Jones, P., Leung, D., Lewis, L., Lochmuller, H., O'Ferrall, E., Martens, W., Shaw, D., Shieh, P., Subramony, S., Trivedi, J., Wang, L., Wicklund, M., Tawil, A., Statland, J. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • SUNFISH Parts 1 and 2: 4-year Efficacy and Safety Data of Risdiplam in Types 2 and 3 Spinal Muscular Atrophy (SMA) Servais, L., Oskoui, M., Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Braid, J., Papp, G., Gorni, K., Martin, C., Scalco, R., Yeung, W., Mercuri, E. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Integrated Analyses of Data from Clinical Trials of Delandistrogene Moxeparvovec (SRP-9001) in Duchenne Muscular Dystrophy (DMD) Proud, C., Zaidman, C., Shieh, P., McDonald, C., Day, J., Mason, S., Guridi, M., Han, L., Yu, L., Reid, C., Darton, E., Wandel, C., Richardson, J., Malhotra, J., Singh, T., Rodino-Klapac, L., Mendell, J. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy (SMA) Darras, B., Baranello, G., Boespflug-Tanguy, O., Day, J., Deconinck, N., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Palfreeman, L., Dodman, A., Servais, L. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • A Multimodal Neuroimaging Feature Extraction Framework for Biomarker Discovery in Myotonic Dystrophies Kamali, T., Day, J., Sampson, J., Murad, A., Chaufty, J. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Correction to: Two‑year efficacy and safety of risdiplam in patients with type 2 or non‑ambulant type 3 spinal muscular atrophy (SMA). Journal of neurology Oskoui, M., Day, J. W., Deconinck, N., Mazzone, E. S., Nascimento, A., Saito, K., Vuillerot, C., Baranello, G., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Papp, G., Gorni, K., Kletzl, H., Martin, C., McIver, T., Scalco, R. S., Staunton, H., Yeung, W. Y., Fontoura, P., Mercuri, E., SUNFISH Working Group 2023

    View details for DOI 10.1007/s00415-023-11658-6

    View details for PubMedID 37071150

  • Generation of two induced pluripotent stem cell lines from spinal muscular atrophy type 1 patients carrying no functional copies of SMN1 gene. Stem cell research Zeng, W., Kong, X., Alamana, C., Liu, Y., Guzman, J., Pang, P. D., Day, J. W., Wu, J. C. 2023; 69: 103095

    Abstract

    Spinal muscular atrophy (SMA) is a severe neurodegenerative muscular disease caused by the homozygous loss of survival of motor neuron 1 (SMN1) genes. SMA patients exhibit marked skeletal muscle (SKM) loss, eventually leading to death. Here we generated two iPSC lines from two SMA type I patients with homozygous SMN1 mutations and validated the pluripotency and the ability to differentiate into three germ layers. The iPSC lines can be applied to generate skeletal muscles to model muscle atrophy of SMA that persists after treatment of motor neurons and will serve as a complementary platform for drug screening in vitro.

    View details for DOI 10.1016/j.scr.2023.103095

    View details for PubMedID 37087898

  • Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial. JAMA neurology Kishnani, P. S., Diaz-Manera, J., Toscano, A., Clemens, P. R., Ladha, S., Berger, K. I., Kushlaf, H., Straub, V., Carvalho, G., Mozaffar, T., Roberts, M., Attarian, S., Chien, Y. H., Choi, Y. C., Day, J. W., Erdem-Ozdamar, S., Illarioshkin, S., Goker-Alpan, O., Kostera-Pruszczyk, A., van der Ploeg, A. T., An Haack, K., Huynh-Ba, O., Tammireddy, S., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B. 2023

    Abstract

    In the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA (COMET) trial, avalglucosidase alfa treatment for 49 weeks showed clinically meaningful improvements in upright forced vital capacity (FVC) percent predicted and 6-minute walk test (6MWT) compared with alglucosidase alfa.To report avalglucosidase alfa treatment outcomes during the COMET trial extension.This phase 3 double-blind randomized clinical trial with crossover in the extension period enrolled patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff at February 10, 2021. Data were analyzed from May to June 2021.Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week.The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed.Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched.In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment and, to a lesser extent, patients who switched from alglucosidase alfa. No new safety concerns were observed.ClinicalTrials.gov Identifier: NCT02782741.

    View details for DOI 10.1001/jamaneurol.2023.0552

    View details for PubMedID 37036722

    View details for PubMedCentralID PMC10087094

  • Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG). Journal of neuromuscular diseases Finkel, R. S., Darras, B. T., Mendell, J. R., Day, J. W., Kuntz, N. L., Connolly, A. M., Zaidman, C., Crawford, T. O., Butterfield, R. J., Shieh, P. B., Tennekoon, G., Brandsema, J. F., Iannaccone, S. T., Shoffner, J., Kavanagh, S., Macek, T. A., Tauscher-Wisniewski, S. 2023

    Abstract

    Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing.STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients.Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls.Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P <  0.01).Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

    View details for DOI 10.3233/JND-221560

    View details for PubMedID 36911944

  • Expanding the muscle imaging spectrum in dysferlinopathy: description of an outlier population from the classical MRI pattern. Neuromuscular disorders : NMD Llansó, L., Moore, U., Bolano-Diaz, C., James, M., Blamire, A. M., Carlier, P. G., Rufibach, L., Gordish-Dressman, H., Boyle, G., Hilsden, H., 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., Mendell, J. R., Straub, V., Díaz-Manera, J. 2023; 33 (4): 349-357

    Abstract

    Dysferlinopathy is a muscle disease characterized by a variable clinical presentation and is caused by mutations in the DYSF gene. The Jain Clinical Outcome Study for Dysferlinopathy (COS) followed the largest cohort of patients (n=187) with genetically confirmed dysferlinopathy throughout a three-year natural history study, in which the patients underwent muscle function tests and muscle magnetic resonance imaging (MRI). We previously described the pattern of muscle pathology in this population and established a series of imaging criteria for diagnosis. In this paper, we describe the muscle imaging and clinical features of a subgroup of COS participants whose muscle imaging results did not completely meet the diagnostic criteria. We reviewed 184 T1-weighted (T1w) muscle MRI scans obtained at the baseline visit of the COS study, of which 106 were pelvic and lower limb only and 78 were whole-body scans. We identified 116 of the 184 patients (63%) who did not meet at least one of the established imaging criteria. The highest number found of unmet criteria was four per patient. We identified 24 patients (13%) who did not meet three or more of the nine established criteria and considered them as "outliers". The most common unmet criterion (27.3% of cases) was the adductor magnus being equally or more affected than the adductor longus. We compared the genetic, demographic, clinical and muscle function data of the outlier patients with those who met the established criteria and observed that the outlier patients had an age of disease onset that was significantly older than the whole group (29.3 vs 20.5 years, p=0.0001). This study expands the phenotypic muscle imaging spectrum of patients with dysferlinopathy and can help to guide the diagnostic process in patients with limb girdle weakness of unknown origin.

    View details for DOI 10.1016/j.nmd.2023.02.007

    View details for PubMedID 36972667

  • Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial LANCET NEUROLOGY Thornton, C. A., Iii, R., Eichinger, K., Heatwole, C., Mignon, L., Arnold, W., Ashizawa, T., Day, J. W., Dent, G., Tanner, M. K., Duong, T., Greene, E. P., Herbelin, L., Johnson, N. E., King, W., Kissel, J., Leung, D. G., Lott, D. J., Norris, D. A., Pucillo, E. M., Schell, W., Statland, J. M., Stinson, N., Subramony, S. H., Xia, S., Bishop, K. M., Bennett, C. 2023; 22 (3): 218-228
  • Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial. The Lancet. Neurology Thornton, C. A., Moxley, R. T., Eichinger, K., Heatwole, C., Mignon, L., Arnold, W. D., Ashizawa, T., Day, J. W., Dent, G., Tanner, M. K., Duong, T., Greene, E. P., Herbelin, L., Johnson, N. E., King, W., Kissel, J. T., Leung, D. G., Lott, D. J., Norris, D. A., Pucillo, E. M., Schell, W., Statland, J. M., Stinson, N., Subramony, S. H., Xia, S., Bishop, K. M., Bennett, C. F. 2023; 22 (3): 218-228

    Abstract

    Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA.In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete.Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose.Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed.Ionis Pharmaceuticals, Biogen.

    View details for DOI 10.1016/S1474-4422(23)00001-7

    View details for PubMedID 36804094

  • 2-Year Change in Revised Hammersmith Scale Scores in a Large Cohort of Untreated Paediatric Type 2 and 3 SMA Participants. Journal of clinical medicine Stimpson, G., Ramsey, D., Wolfe, A., Mayhew, A., Scoto, M., Baranello, G., Muni Lofra, R., Main, M., Milev, E., Coratti, G., Pane, M., Sansone, V., D'Amico, A., Bertini, E., Messina, S., Bruno, C., Albamonte, E., Mazzone, E. S., Montes, J., Glanzman, A. M., Zolkipli-Cunningham, Z., Pasternak, A., Duong, T., Dunaway Young, S., Civitello, M., Marini-Bettolo, C., Day, J. W., Darras, B. T., De Vivo, D. C., Finkel, R. S., Mercuri, E., Muntoni, F. 2023; 12 (5)

    Abstract

    The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

    View details for DOI 10.3390/jcm12051920

    View details for PubMedID 36902710

  • Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study. Neurology and therapy Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Mercuri, E., Kirschner, J., Kostera-Pruszczyk, A., Jaber, B., Gorni, K., Kletzl, H., Carruthers, I., Martin, C., Warren, F., Scalco, R. S., Wagner, K. R., Muntoni, F. 2023

    Abstract

    Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam.Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment.A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles.The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients.

    View details for DOI 10.1007/s40120-023-00444-1

    View details for PubMedID 36780114

  • Validation of the Parent-Proxy Pediatric Charcot-Marie-Tooth Disease Quality of Life Outcome Measure. Journal of the peripheral nervous system : JPNS Wu, T. T., Finkel, R. S., Siskind, C. E., Feely, S. M., Burns, J., Reilly, M. M., Muntoni, F., Estilow, T., Shy, M. E., Ramchandren, S., Childhood CMT Study Group of the Inherited Neuropathy Consortium, Bacon, C. J., Shy, R. R., Cornett, K., Laura, M., Milev, E., Day, J. W., Lloyd, T., Sumner, C. J., Herrmann, D. N., Kirk, C., Yum, S. W. 2023

    Abstract

    OBJECTIVE: Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL) in children. We have previously developed and validated the English and Italian versions of the pediatric CMT-specific QOL outcome measure (pCMT-QOL) for children aged 8-18. There is currently no parent-proxy CMT QOL outcome measure for use in clinical trials, which could provide complementary information in these children and adolescents. This study describes the validation studies conducted to develop the parent-proxy version of the pCMT-QOL outcome measure for children aged 8-18years old.METHODS: Development and validation of the parent-proxy version of the pCMT-QOL outcome measure for children aged 8-18years old was iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing, conducted on parents of children with CMT seen at participating sites from the USA, United Kingdom, and Australia.RESULTS: We utilized previously described methods to develop a working parent-proxy version of the pCMT-QOL measure. From 2010-2016, the parent-proxy pCMT-QOL working version was administered to 358 parents of children with CMT aged 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 parent-proxy version of the pCMT-QOL outcome measure for children aged 8-18years old.INTERPRETATION: The parent-proxy version of the pCMT-QOL outcome measure is a reliable, valid, and sensitive proxy measure of health-related QOL for children aged 8-18 with CMT.

    View details for DOI 10.1111/jns.12538

    View details for PubMedID 36748295

  • Assessing Bulbar Function in Spinal Muscular Atrophy Using Patient-Reported Outcomes. Journal of neuromuscular diseases Young, S. D., Pasternak, A., Duong, T., McGrattan, K. E., Stranberg, S., Maczek, E., Dias, C., Tang, W., Parker, D., Levine, A., Rohan, A., Wolford, C., Martens, W., McDermott, M. P., Darras, B. T., Day, J. W. 2023

    Abstract

    Novel Spinal Muscular Atrophy (SMA) treatments have demonstrated improvements on motor measures that are clearly distinct from the natural history of progressive decline. Comparable measures are needed to monitor bulbar function, which is affected in severe SMA.To assess bulbar function with patient-reported outcome measures (PROs) and determine their relationships with clinical characteristics.We recruited 47 non-ambulatory participants (mean (SD) age = 29.8 (13.7) years, range = 10.3-73.2) with SMA. PROs including Voice Handicap Index (VHI) and Eating Assessment Tool-10 (EAT-10) were collected alongside clinical characteristics and standardized motor assessments. Associations were assessed using Spearman correlation coefficients and group comparisons were performed using Wilcoxon rank sum tests.A majority of the 47 participants were SMA type 2 (70.2%), non-sitters (78.7%), 3 copies of SMN2 (77.5%), and using respiratory support (66.0%). A majority (94%) reported voice issues primarily in 8/30 VHI questions. Problems included: difficulty understanding me in a noisy room (87.2%); difficult for people to hear me (74.5%); and people ask me to repeat when speaking face-to-face (72.3%). A majority (85.1%) reported swallowing issues primarily in 3/10 EAT-10 questions: swallowing pills (68.1%); food sticks to my throat (66.0%); and swallowing solids (61.7%). The two PROs were moderately associated (rs = 0.66).Weaker individuals with SMA experience bulbar problems including difficulties with voice and swallowing. Further refinement and assessment of functional bulbar scales will help determine their relevance and responsiveness to changes in SMA. Additional study is needed to quantify bulbar changes caused by SMA and their response to disease-modifying treatments.

    View details for DOI 10.3233/JND-221573

    View details for PubMedID 36776075

  • Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA). Journal of neurology Oskoui, M., Day, J. W., Deconinck, N., Mazzone, E. S., Nascimento, A., Saito, K., Vuillerot, C., Baranello, G., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Papp, G., Gorni, K., Kletzl, H., Martin, C., McIver, T., Scalco, R. S., Staunton, H., Yeung, W. Y., Fontoura, P., Mercuri, E., SUNFISH Working Group 2023

    Abstract

    Risdiplam is an oral, survival of motor neuron2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of≥3) from baseline in MFM32 total score; 58% showed stabilization (a change of≥0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24months was consistent with that observed after 12months. Risdiplam over 24months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment.

    View details for DOI 10.1007/s00415-023-11560-1

    View details for PubMedID 36735057