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Background and Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020., Methods: This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected., Results: Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH ( p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH ( p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up., Discussion: This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned., Classification of Evidence: This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort., Competing Interests: F. Trucco reports participation to Scientific Advisory Boards for Roche UK and teaching initiatives for Biogen, Avexis, Roche, and BREAS. D. Ridout, I. Hughes, Z. Zolkipli-Cunningham, and M. Main report no disclosures. M. Scoto reports participation in Scientific Advisory Boards and teaching initiatives for Avexis, Biogen, and Roche. She is involved as an investigator in clinical trials from Avexis, Biogen, and Roche. In addition, she is the co-principal investigator of the SMA REACH UK clinical network, partially funded by Biogen and Roche. F. Muntoni reports participation in Scientific Advisory Boards and teaching initiatives for Biogen, Roche, and Novartis. He is member of the Rare Disease Scientific Advisory Board for Pfizer. He is involved as an investigator in clinical trials from Novartis, Biogen, and Roche. In addition, he is the principal investigator of the SMA REACH UK clinical network, partially funded by Biogen and Roche. E. Mercuri reports participation in Scientific Advisory Boards and teaching initiatives for Biogen, Roche, Scholar Rock, and Novartis. He is involved as an investigator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. In addition, he is the principal investigator of the Italian registry participating in iSMAc, partially funded by Biogen, Roche, and Novartis. R. Finkel reports participation in Medical and Scientific Advisory Boards on SMA topics with Novartis, Biogen, Ionis, Roche, Cure SMA, SMA Europe, SMA REACH UK, SMA Foundation, and MDA. Finkel participates as an investigator in SMA-related clinical trials sponsored or supported by Novartis, Biogen, Ionis, Roche, and Scholar Rock. Dr. D. De Vivo reports participation as a consultant in Medical and Scientific Advisory Boards and as an investigator with Novartis, Biogen, Ionis, Roche, PTC, Santhera, Scholar Rock, Sanofi, GliaPharm, Fulcrum Therapeutics, Sarepta, NS Pharma, SMA Foundation, Cure SMA, DoD, NIH, Glut1 Deficiency Foundation, and Hope for Children Research Foundation. B. Darras has served as an ad hoc Scientific Advisory Board member for Novartis, Biogen, Cytokinetics, Vertex, Genentech, Roche, and Sarepta; Steering Committee chair for Roche; and Data Safety Monitoring Board member for Amicus Inc. He has no financial interests in these companies. He has received research support from the NIH/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund and has received grants from Ionis Pharmaceuticals, Inc, for the ENDEAR, CHERISH, CS2/CS12 studies; from Biogen for CS11; and from Cytokinetics, Sarepta Pharmaceuticals, PTC Therapeutics, Fibrogen, and Summit. O. Mayer reports participation in Advisory Boards for Roche, Biogen, and PTC Therapeutics. He is participating in SMA REACH and iSMAC, partially funded by Biogen. C. Bruno reports participation in Scientific Advisory Boards on SMA topics with Novartis, Biogen, and Roche and participates as a principal investigator in SMA-related clinical trials sponsored by Novartis, Biogen, Ionis, and Roche. S. Messina reports participation in Scientific Advisory Boards and teaching initiatives for Novartis, Biogen, and Roche. She is involved as an investigator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. M. Pane reports participation in Scientific Advisory Boards and teaching initiatives for Novartis and Biogen. V.A. Sansone provides intellectual support in Advisory Boards and teaching activities for Biogen, Santhera, Sarepta, PTC, Dyne, Triplet, and Novartis. A. D'Amico reports participation in Scientific Advisory Board for Novartis, Roche, and Novartis and teaching initiatives for Biogen. She is also involved as an investigator in clinical trials from Novartis, Biogen, and Roche. In addition, she is an investigator of the Italian registry participating in iSMAc, partially funded by Biogen. E.S. Bertini reports participation in Scientific Advisory Boards for Novartis, Roche, Novartis, and PTC and teaching initiatives for Biogen. He is also involved as an investigator in clinical trials from Novartis, Biogen, Roche, and Novartis. In addition, he is an investigator of the Italian registry participating in iSMAc, partially funded by Biogen. C. Marini-Bettolo reports participation in Scientific Advisory Boards and teaching initiatives for Novartis, Biogen, and Roche. She is involved as an investigator in clinical trials from Novartis. In addition, she is principal investigator for the UK SMA patient registry funded by SMA UK. A. Childs reports participation in Advisory Boards for Novartis, Roche, Biogen, Santhera, and PTC Therapeutics. She is principal investigator for clinical trials supported by Sarepta, Santhera, and PTC Therapeutics. She is participating in SMA REACH and iSMAC, partially funded by Biogen. M. Ong reports participation in Advisory Boards or received consultation fees for Novartis, Roche, Biogen, and CSL Behring. She is participating in SMA REACH and iSMAC, partially funded by Biogen. Dr. A. Mayhew reports participation in Scientific Advisory Boards and teaching initiatives for Biogen and Roche. She is involved as an evaluator at site and acts as an independent consultant to train evaluators in clinical trials from Novartis, Biogen, and Roche. In addition, she is the principal investigator at Newcastle for the SMA REACH UK clinical network, partially funded by Biogen and by SMA UK. J. Montes reports participation as a consultant and on Scientific Advisory Boards for Biogen, Ionis, Roche, and Scholar Rock. G. Coratti reports consultant activities for Novartis, Biogen, Roche, Biologix, and Genesis Pharma. She is involved as a clinical evaluator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. R. De Sanctis reports consultant activities for Biogen and Roche. He is involved as a clinical evaluator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. L. Servais reports consultancy/board attendance/lectures for Novartis, Biogen, Roche, Scholar Rock, and BioHaven. A. Majumdar reports participation in Advisory Boards for Novartis, Roche, Biogen, Santhera, and PTC Therapeutics. He is principal investigator for clinical trials supported by Wave Therapeutics. He is participating in SMA REACH and iSMAC, partially funded by Biogen. D. Parasuraman reports participation in Advisory Boards for Roche, Biogen, Sarepta and has had support from PTC Therapeutics. He is principal investigator for clinical trials supported by Roche. He is participating in SMA REACH and iSMAC, partially funded by Biogen. V. Gowda reports participation in Advisory Boards or received consultation fees for Novartis, Roche, Biogen, PTC therapeutics, Wave Life Sciences, Pfizer, and Sarepta Therapeutics. She is participating in SMA REACH and iSMAC, partially funded by Biogen. FT, CB, EB, AD, EM, and MP are members of the ERN NMD (European Reference Networks). Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Competing Interests: Competing interests: VLG has received consultancy/speaker honoraria from Novartis, Roche, Biogen, PTC Therapeutics, Pfizer and Sarepta Therapeutics. EW has received consultancy/speaker honoraria from Pfizer, Biogen and Novartis. HJ has received consultancy/honoraria from Pfizer.

Spinal muscular atrophy (SMA) is a severe neurodegenerative condition due to recessive mutations in the SMN1 gene resulting in insufficiency of survival motor neuron (SMN) protein. Lack of SMN protein results in irreversible degeneration of lower motor neurons and consequential muscle atrophy and weakness. SMN2 , a SMN1 homologue, produces low levels of functional SMN protein with the potential to partially compensate SMN1 loss. Several compounds have been shown to successfully restore SMN protein production in motor neurons, either by enhancing SMN2 gene function or by direct replacement of the SMN1 gene. Clinical trials of these compounds have demonstrated the potential to substantially alter the natural history of SMA and have led to their implementation into clinical practice. To date, 3 novel drugs, nusinersen, onasemnogene aberparvovec and risdiplam, have received marketing authorisation for SMA treatment by several authorities including Food and Drug Administration and European Medicines Agency. While implementing these drugs into daily clinical practice, clinicians face a number of new challenges, including identifying the most advantageous treatment for any individual, optimisation of outcomes and management of a modified SMA phenotype. Considering that treatment initiation at the pre-symptomatic or paucisymptomatic stage appears to be associated with better outcomes, health services need to support early diagnosis for this now treatable condition. This review aims to give an overview of the current therapeutic landscape of SMA, to provide an understanding of current practice of SMA management and to help increase awareness of the imminent need for urgent early diagnosis at the pre-symptomatic stage., Competing Interests: Competing interests: VLG has received consultancy/speaker honoraria from Novartis, Roche, Biogen, PTC, Pfizer and Sarepta Therapeutics. EW has received consultancy/speaker honoraria from Pfizer, Biogen, Novartis., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe age and time at key stages in the Duchenne muscular dystrophy (DMD) prediagnosis pathway at selected centres to identify opportunities for service improvement., Design: A multicentre retrospective national audit., Setting: Nine tertiary neuromuscular centres across the UK and Ireland. A prior single-centre UK audit of 20 patients with no DMD family history provided benchmark criteria., Patients: Patients with a definitive diagnosis of DMD documented within 3 years prior to December 2018 (n=122)., Main Outcome Measures: Mean age (months) at four key stages in the DMD diagnostic pathway and mean time (months) of presentational and diagnostic delay, and time from first reported symptoms to definitive diagnosis. Type of symptoms was also recorded., Results: Overall, mean age at definitive diagnosis, age at first engagement with healthcare professional (HCP) and age at first reported symptoms were 53.9±29.7, 49.9±28.9 and 36.4±26.8 months, respectively. The presentational delay and time to diagnosis were 21.1 (±21.1) and 4.6 (±7.9) months, respectively. The mean time from first reported symptoms to definitive diagnosis was 24.2±20.9. The percentages of patients with motor and/or non-motor symptoms recorded were 88% (n=106/121) and 47% (n=57/121), respectively., Conclusions: Majority of data mirrored the benchmark audit. However, while the time to diagnosis was shorter, a presentational delay was observed. Failure to recognise early symptoms of DMD could be a contributing factor and represents an unmet need in the diagnosis pathway. Methods determining how to improve this need to be explored., Competing Interests: Competing interests: VLG has received grants from Biogen, PTC Therapeutics, Wave Life Sciences and Catabasis; MF has nothing to disclose; MP has received a grant from PTC Therapeutics; AMC has received fees from PTC Therapeutics in relation to contributions to advisory boards, invited lectures and a presentation; IH has nothing to declare; ST has received conference sponsorship; CGELDG has received grants from PTC Therapeutics; DOR has nothing to declare; DP has nothing to declare; TW has received honorariums for lectures and advisory boards from PTC therapeutics, Biogen, Genzyme Sanofi, Roche, Sarepta and Santhera; SS is an employee of OPEN VIE; ID is employed by PTC Therapeutics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We have investigated the ability of the novel muramyl dipeptide, GMDP, to act as an adjuvant for the induction of ovalbumin (OVA)-specific, CD8+ cytotoxic T lymphocyte (CTL) responses. C57Bl/6 mice were twice immunized s.c. with 50 micrograms OVA emulsified with a squalane, L121 pluronic containing Tween-80 vehicle either with (STP-GMDP) or without (STP) GMDP. Splenic precursor CD8+ CTL activity against E.G7-OVA, but not against EL-4 parental targets was detected in STP-GMDP immunized mice after 5 days of in vitro re-stimulation with irradiated E.G7-OVA cells, while mice immunized with OVA in STP alone or OVA alone failed to demonstrate CTL activity. OVA emulsified in a microfluidized STP vehicle formulation without GMDP also elicited the E.G7-OVA precursor CTL. The ability of GMDP to induce a class I-restricted, CD8+ CTL response to a soluble protein antigen may have implications for the development of useful vaccines against viral pathogens or tumours against which CTL responses are desirable.