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Background Due to the limited data from clinical trials and real-world settings in the realm of nusinersen, there is a need for further evidence. This study seeks to assess the impact of nusinersen, when combined with standard care, on bulbar function, respiratory function, and the necessity for respiratory support among pediatric patients with spinal muscular atrophy (SMA). Methods Prospective observational study, involving pediatric SMA patients (Types 1–3) undergoing nusinersen treatment at the Hospital Universitario Virgen del Rocío in Spain over at least 24 months. The cohort included 11 SMA type 1 patients, comprising 6 type 1b and 5 type 1c, 12 SMA type 2 patients, and 5 SMA type 3 patients. Results Twenty-eight pediatric patients were enrolled with the majority being male (n = 20). Patients with type 1 were diagnosed and received treatment significantly earlier than those with types 2 and 3 (p < 0.001). Additionally, there was a longer period between diagnosis and the start of treatment in types 2 and 3 (p = 0.002). Follow-up revealed statistically improved functional and respiratory outcomes associated with earlier initiation of nusinersen treatment at 6, 12, and 24 months in all phenotypes. The ability to swallow and feed correctly remained unchanged throughout the study, with SMA type 1c patients maintaining oral feeding in contrast to patients with SMA type 1b. Notably, no deaths were recorded. Conclusions This study provides important insights into the real-world clinical progress of pediatric SMA patients and their response to nusinersen treatment, highlighting the significance of early intervention for better functional and respiratory outcomes. [ABSTRACT FROM AUTHOR]

Background: Due to improved treatment options, more SMA patients reach childbearing age. Currently, limited data on pregnant SMA patients is available, especially in relation to disease-modifying therapies (DMT). This case report helps to elucidate new approaches for future guidelines in the management of pregnancy and SMA. Case Report: A 33-year-old wheelchair-bound patient with SMA type 3 (sitter) became pregnant following 36 months of Nusinersen treatment. The last dose was administered in the third gestational week. After pregnancy was confirmed, therapy was stopped immediately. A healthy child was born in the 34th gestational week by caesarean section. After a short nursing period, Nusinersen was restarted 6 weeks after the expected gestational date. At this time, the patient reported deteriorated motor functions, which stabilized at a lower level compared to pre-pregnancy in the 2-year follow-up, despite restarting Nusinersen treatment. Discussion: So far, only few cases of successful pregnancies of SMA patients on DMT have been reported. In natural history, the majority of patients experienced an increased deterioration of motor function while fetal outcome was not impaired. Our case shows that although Nusinersen treatment was applied in the third gestational week prior to proof of pregnancy, outcome was positive for mother and child. Future studies will have to determine whether ongoing treatment with Nusinersen during pregnancy should be recommended. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Nusinersen and risdiplam are U.S. Food and Drug Administration (FDA)‐approved treatments for spinal muscular atrophy (SMA). No head‐to‐head clinical trials to assess efficacy exist. Observational studies are needed to determine if transitioning to risdiplam is safe and efficacious.This retrospective study at Nationwide Children's Hospital included individuals with SMA treated with nusinersen who switched to risdiplam. Motor, pulmonary and bulbar function were assessed before and 2 years after nusinersen and risdiplam initiation.Forty‐four individuals were included: 11 with SMA type 1, 25 with SMA type 2 and 8 with SMA type 3. Motor function improved after initiation of nusinersen treatment with the most significant improvements seen in the first year. After transition to risdiplam, motor function remained largely stable. Need for noninvasive ventilation (NIV) overnight occurred in both groups. Cough peak flow significantly improved in the risdiplam group. Hospitalizations were the same in both groups. One individual in the nusinersen group gained the ability to take some food by mouth; two individuals in the risdiplam group achieved some oral feeding and two became exclusively orally fed.As expected, motor function was most improved in treatment naïve individuals in the first year after nusinersen initiation. Over half of our study population had posterior spinal fusion surgery (57%) which significantly impacted motor and respiratory outcomes, though slightly less so in the risdiplam group. Overall, our data demonstrates that transitioning from nusinersen to risdiplam is associated with a favorable safety profile and stable motor outcomes. [ABSTRACT FROM AUTHOR]

Onasemnogene abeparvovec (OA) is a novel gene replacement therapy for patients with spinal muscular atrophy (SMA). This study provides real-world respiratory data for pediatric SMA patients receiving OA who were assessed before and one year after treatment in a multicenter cohort study conducted from 2019 to 2021. Twenty-five OA-treated SMA patients (23 with type 1 and 2 with type 2; median age at treatment 6.1 months, with a range of 0.36–23 months) were included. Sixteen were treatment-naïve, and nine had received various prior treatments. Two patients died due to respiratory failure during the study period. Of the remaining 23 patients, four were put on non-invasive ventilation (NIV), bringing ventilated patients to a total of ten during the post-treatment year. Three patients required permanent NIV support, while 13 did not require any respiratory support. Ventilation time decreased from 14.3 to 11.1 hours per day, and respiratory hospitalizations decreased by 26% (from 0.76 to 0.57 per life year). Fifteen of the 23 patients maintained full oral nutrition at study closure compared to 20 of the 25 at study initiation. This real-world data analysis demonstrates that OA may improve respiratory outcomes in SMA patients. Importantly, compounding factors, such as age at treatment initiation, treatment combinations, and natural history, may influence the respiratory course, thus highlighting the need for standardized long-term management. What is Known: • Respiratory failure is a leading cause of mortality in untreated spinal muscular atrophy type 1 patients. • Onasemnogene abeparvovec (OA) improves neurological outcomes, but real-world respiratory data are limited. What is New: • Our real-world analysis suggests OA may improve respiratory outcomes. • Age at treatment and treatment combinations may also influence respiratory trajectory. [ABSTRACT FROM AUTHOR]

Objective: Spinal Muscular Atrophy linked to chromosome 5q (SMA) is an autosomal recessive neurodegenerative disease characterized by progressive proximal muscle atrophy and weakness. This study addresses the scarcity of research on novel disease-modifying therapies for SMA in Latin America by reporting a real-world experience in Southern Brazil. Methodology: This is a single-center historical cohort that included all patients diagnosed with spinal muscular atrophy at a Regional Reference Service for rare diseases. Results: Eighty-one patients were included, of whom 7 died during follow-up. Of the remaining 74 patients, 5.4 % were classified as pre-symptomatic, 24.3 % with SMA type 1, 28.4 % with type 2, 36.5 % with type 3, and 5.4 % with type 4. The mean follow-up time ranged from 1.8 years for pre-symptomatic cases to 8.7 years for SMA types 2 and 3. Approximately 42 % of these patients received specific disease-modifying therapy, of these, 96.8 % received Nusinersen, with 19.4 % transitioning to gene therapy using Onasemnogene Abeparvovec, and 6.4 % starting Risdiplam. Most patients with SMA type 1 were on disease-modifying treatment, whereas only slightly over a third of patients with type 2 and about 10 % of type 3 were receiving such treatments. Among treated patients, 80 % demonstrated improvement in motor performance during the follow-up, with a lesser therapeutic response being associated with late initiation of treatment and low motor function scores at baseline. Conclusion: This real-world study reinforces the effectiveness of disease-modifying therapies for SMA in Brazil within the context of low- and middle-income countries, which is greater the earlier and the better the patient's functional status. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction/Aims Methods Results Discussion The rising use of disease‐modifying therapy is progressively impacting the health‐related quality of life (HRQoL) of patients with spinal muscular atrophy (SMA) in their daily lives. This study aimed to evaluate the changes in HRQoL and independence in children with later‐onset SMA receiving longitudinal treatment with nusinersen.Forty‐nine pediatric patients with later‐onset SMA (symptom onset after 6 months of age) and their caregivers were enrolled. The HRQoL of patients evaluated by the proxy‐reported Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM) and the independence level determined by the SMA Independence Scale–Upper Limb Module (SMAIS–ULM) were assessed. Caregiver HRQoL was assessed using the Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM). Motor function was recorded using the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM), with subsequent analysis of the correlation between motor function, HRQoL, and independence scores.A significant difference was observed across all domains of the proxy‐reported PedsQL NMM and in the independence assessment over the 18‐month follow‐up period (p < 0.001). A positive correlation was identified between RULM and total PedsQL NMM scores (Pearson‐r = 0.539, p < 0.001), as well as SMAIS‐ULM scores (Spearman‐rho = 0.507, p < 0.001). Scores in all modules of the PedsQL FIM improved over time (p < 0.001).This study demonstrates the longitudinal effects of nusinersen treatment on multifaceted aspects of SMA patients, as captured by patient‐reported outcome measures (PROMs). The inclusion of PROMs should be considered as part of the SMA multidisciplinary assessment. [ABSTRACT FROM AUTHOR]

Objective: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by proximal muscle weakness and atrophy. The increasing availability of disease-modifying therapies has prompted the development of biomarkers to facilitate clinical assessments. We explored the association between disease severity and serum creatinine (Crn) levels in SMA patients undergoing up to two years of treatment with nusinersen. Methods: We measured serum Crn levels and assessed function performance using the Hammersmith Functional Motor Scale-Expanded (HFMSE), Medical Research Council Scale (MRC), 6-Minute Walk Test (6MWT), ulnar Compound Muscle Action Potential (CMAP), and forced vital capacity (FVC) in a cohort comprising 28 adolescent and adult patients with SMA. The association between Crn and disease severity was investigated through partial rank correlation analysis and linear mixed models while accounting for age, gender, and BMI. Linear models were employed to predict functional performance. Results: 28 SMA patients and 28 gender- and age-matched healthy controls (HCs) were included, resulting in a dataset of 185 visits. Compared to HCs, SMA patients exhibited significantly lower Crn values ​​(67.4 ± 14 vs. 23.7 ± 14.8 umol/L, p<0.0001). After adjusting for age, sex, and BMI, Crn showed positive correlations with the HFMSE (p<0.0001, r = 0.884), MRC (p<0.0001, r = 0.827), FVC (p = 0.002, r = 0.730), and ulnar CMAP (p<0.0001, r = 0.807). Patients with SMN2 copy number ≥ 4 had nearly twice as high Crn levels as those with SMN2 copy number < 4 (34.1 ± 3.75 vs. 17.2 ± 2.52 umol/L, p = 0.00145). Ambulant SMA patients had more than double the Crn levels compared to non-ambulant ones (32 ± 2.33 vs. 12.9 ± 2.38 umol/L, p<0.0001). Furthermore, Crn explained that up to 83.5% of the variance in functional performance measured by HFMSE, MRC, and 6MWT was significantly higher than that of traditional biomarkers. Conclusions: These findings suggest that Crn may be a potential biomarker for assessing disease severity in adolescents and adults with SMA, demonstrating its promise in clinical applications. [ABSTRACT FROM AUTHOR]

Purpose: Some patients with spinal muscular atrophy and scoliosis require CT guidance during injections of nusinersen. The radiation applied to the operator in such procedures becomes an important issue in terms of staff health and safety. The aim of the study was to assess the operator's radiation exposure during CT-guided nusinersen injections in patients with spinal muscular atrophy and scoliosis. Methods: Consecutive 40 CT-guided nusinersen injections were analyzed in terms of operator's radiation exposure measured in real time. Results: The median radiation dose measured under the physician's lead apron and patient dose in terms of DLP was 0.20 µSv and 31.90 mGy*cm respectively. The radiation doses were significantly higher (p = 0.047) in patients with spinal instrumentation. Conclusion: The results show that CT-guided nusinersen injection is a relatively safe procedure in terms of operator's radiation exposure. This can allow for interventional radiologists to perform more procedures without exceeding their annual dose limit. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease characterized by progressive muscle weakness and atrophy due to the absence of the survival motor neuron 1 (SMN1) gene. SMA is classified into types 0 through 4 based on the age of symptom onset and the severity of motor function decline. Recent advances in SMA treatment, including nusinersen, onasemnogene abeparvovec, and risdiplam, have significantly improved the prognosis of SMA patients. This study evaluated the safety and efficacy of nusinersen in pediatric patients with SMA types 1, 2, and 3 in a real-world clinical setting. Methods: This prospective observational single-center study assessed the treatment effects of nusinersen in 23 pediatric patients with genetically confirmed SMA over a 22-month observation period. All the participants received intrathecal loading doses of 12 mg of nusinersen on days 1, 14, 28, and 63, followed by maintenance doses every four months. Functional assessments were conducted using the CHOP-INTEND scale. Data were collected during routine patient visits, including clinical laboratory tests and vital sign parameters, and adverse events were recorded. The inclusion criteria were defined by the national reimbursement program for nusinersen treatment in Poland. Results: Initially, 37 patients ranging from 1 month old to 18 years old were included, but 23 were ultimately observed due to changes in treatment regimens or assessment scales. The patients showed significantly improved CHOP-INTEND scores over the 22-month period. At 6 months, the average increase was 4.2 points, continuing to 17.8 points at 22 months. By the end of the study, 100% of patients showed either stabilization or improvement, with significant clinical improvements observed in several patients. Nusinersen was generally well-tolerated, with post-lumbar puncture headache and lower back pain being the most common adverse events. Conclusions: Nusinersen treatment significantly enhances motor function in pediatric patients with SMA types 1, 2, and 3. This study demonstrates the importance of early and sustained treatment, with most patients showing the continuous improvement or stabilization of motor function. These findings support the use of nusinersen as an effective therapy for SMA; however, further research is needed to understand the long-term outcomes and optimize treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Persons with spinal muscular atrophy (pwSMA) report progressive muscle weakness but also reduced endurance when performing repetitive tasks in daily life, referred to as "performance fatigability" (PF). Data regarding the effects of the new disease‐modifying drugs on PF are scarce. Thus, our main objective was to examine PF in adult ambulatory pwSMA treated long‐term with nusinersen. Methods: Six‐minute walk test (6MWT) data from 14 adult pwSMA treated with nusinersen for up to 70 months were retrospectively analyzed to determine PF. Performance fatigability was defined as the percentage change in the distance covered between the last and first minute of the 6MWT. In addition, relationships between PF and other clinical features were assessed. Results: Performance fatigability was found in 12/14 pwSMA (85.7%) prior to treatment. The mean distance walked in the sixth minute (71.1 m) was shorter than the distance covered in the first minute (81.8 m), corresponding to a mean PF of 13.1% (95% confidence interval (CI): 6.5–19.6, p =.0007). During treatment with nusinersen, there was a mean reduction in PF of 5.6% (95% CI: −10.0 to −1.3, p =.0148). We found no relationship between PF and fatigue as measured by the Fatigue Severity Scale. Discussion: This study demonstrates the presence of PF as an independent component of motor impairment and as a potential therapeutic target in our cohort of adult ambulatory pwSMA. Furthermore, the observations in our cohort suggest that nusinersen may have a beneficial effect on PF. [ABSTRACT FROM AUTHOR]

Introduction/Aims: While prompt identification and treatment of infants with spinal muscular atrophy (SMA) can ameliorate outcomes, variability persists. This study assessed management and outcomes of early‐treated infants with SMA. Methods: We analyzed retrospective data at 12 centers on infants with SMA treated at age ≤6 weeks from August 2018 to December 2023. Results: Sixty‐six patients, 35 with two SMN2 copies and 31 with ≥3 SMN2 copies, were included. Twenty‐five (38%, 22 with two SMN2 copies), had SMA findings before initial treatment which was onasemnogene abeparvovec in 47 (71%) and nusinersen in 19 (29%). Thirty‐two received sequential or combination treatments, including 16 adding nusinersen or risdiplam due to SMA findings following onasemnogene abeparvovec. All sat independently. Compared to children with ≥3 SMN2 copies, those with two SMN2 copies were less likely to walk (23/34 [68%] vs. 31/31 [100%], p <.001) and less likely to walk on time (9/34 [26%] vs. 29/31 [94%], p <.001); one non‐ambulatory child was <18 months old and was excluded from this analysis. No patients required permanent ventilation or exclusively enteral nutrition; six required nocturnal non‐invasive ventilation and four utilized supplemental enteral nutrition, all with two SMN2 copies. Discussion: Early treatment of infants with SMA can improve outcomes as indicated by our cohort, all of whom sat independently and are without permanent ventilation. However, our study demonstrates ongoing disability in most children with two SMN2 copies despite early monotherapy and emphasizes the need for additional research, including earlier monotherapy, initial combination therapy, prenatal treatment, and non‐SMN modifying treatments. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a rare degenerative disorder with loss of motor neurons caused by mutations in the SMN1 gene. Nusinersen, an antisense oligonucleotide, was approved for SMA treatment to compensate the deficit of the encoded protein SMN by modulating the pre–mRNA splicing of SMN2, the centromeric homologous of SMN1, thus inducing the production of a greater amount of biologically active protein. Here, we reported a 10-month transcriptomics investigation in 10 adult SMA who received nusinersen to search for early genetic markers for clinical monitoring. By comparing their profiles with age-matched healthy controls (HC), we also analyzed the changes in miRNA/mRNAs expression and miRNA-target gene interactions possibly associated with SMA. A multidisciplinary approach of HT-NGS followed by bioinformatics/biostatistics analysis was applied. Within the study interval, those SMA patients who showed some clinical improvements were characterized by having the SMN2/SMN1 ratio slightly increased over the time, while in the stable ones the ratio decreased, suggesting that the estimation of SMN2/SMN1 expression may be an early indicator of nusinersen efficacy. On the other hand, the expression of 38/147 genes/genetic regions DE at T0 between SMA and HC like TRADD and JUND resulted “restored” at T10. We also confirmed the dysregulation of miR-146a(-5p), miR-324-5p and miR-423-5p in SMA subjects. Of interest, miR-146a-5p targeted SMN1, in line with experimental evidence showing the key role of astrocyte-produced miR-146a in SMA motor neuron loss. Molecular pathways such as NOTCH, NF-kappa B, and Toll-like receptor signalings seem to be involved in the SMA pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract Neuroinflammation is an emerging clinical feature in spinal muscular atrophy (SMA). Characterizing neuroinflammatory cytokines in cerebrospinal fluid (CSF) in SMA and their response to nusinersen is important for identifying new biomarkers and understanding the pathophysiology of SMA. We measured twenty-seven neuroinflammatory markers in CSF from twenty SMA children at different time points, and correlated the findings with motor function improvement. At baseline, MCP-1, IL-7 and IL-8 were significantly increased in SMA1 patients compared to SMA2, and were significantly correlated with disease severity. After six months of nusinersen treatment, CSF levels of eotaxin and MIP-1β were markedly reduced, while IL-2, IL-4 and VEGF-A were increased. The decreases in eotaxin and MIP-1β were associated with changes in motor scores in SMA1. We also detected a transient increase in MCP-1, MDC, MIP-1α, IL-12/IL-23p40 and IL-8 after the first or second injection of nusinersen, followed by a steady return to baseline levels within six months. Our study provides a detailed profile of neuroinflammatory markers in SMA CSF. Our data confirms the potential of MCP-1, eotaxin and MIP-1β as new neuroinflammatory biomarkers in SMA1 and indicates the presence of a subtle inflammatory response to nusinersen during the early phase of treatment.

Abstract Introduction Nusinersen clinical trials have limited data on adolescents and adults with 5q-associated spinal muscular atrophy (SMA). We conducted a systematic literature review (SLR) and meta-analysis to assess effectiveness of nusinersen in adolescents and adults with SMA in clinical practice. Methods Our search included papers published 12/23/2016 through 07/01/2022 with ≥ 5 individuals ≥ 13 years of age and with ≥ 6 months’ data on ≥ 1 selected motor function outcomes [Hammersmith Functional Motor Scale–Expanded (HFMSE), Revised Upper Limb Module (RULM), and Six-Minute Walk Test (6MWT)]. For meta-analysis, effect sizes were pooled using random-effects models. To understand treatment effects by disease severity, subgroup meta-analysis by SMA type and ambulatory status was conducted. Results Fourteen publications including 539 patients followed up to 24 months met inclusion criteria for the SLR. Patients were age 13–72 years and most (99%) had SMA Type II or III. Modest improvement or stability in motor function was consistently observed at the group level. Significant mean increases from baseline were observed in HFMSE [2.3 points (95% CI 1.3–3.3)] with 32.1% (21.7–44.6) of patients demonstrating a clinically meaningful increase (≥ 3 points) at 18 months. Significant increases in RULM were consistently found, with a mean increase of 1.1 points (0.7–1.4) and 38.3% (30.3–47.1) showing a clinically meaningful improvement (≥ 2 points) at 14 months. Among ambulatory patients, there was a significant increase in mean 6MWT distance of 25.0 m (8.9–41.2) with 50.9% (33.4–68.2) demonstrating a clinically meaningful improvement (≥ 30 m) at 14 months. The increases in HFMSE were greater for less severely affected patients, whereas more severely affected patients showed greater improvement in RULM. Conclusions Findings provide consolidated evidence that nusinersen is effective in improving or stabilizing motor function in many adolescents and adults with a broad spectrum of SMA.

Introduction/Purpose: Nusinersen, the first treatment approved for all spinal muscular atrophy (SMA) types, is administered intrathecally through lumbar puncture. We used ultrasound assistance or a landmark‐based technique to access the lumbar intrathecal space in adult SMA patients. This study aimed to evaluate the technical success and adverse events (AEs) in such patients using either technique over a long observation period. Methods: Fifty‐one adult patients received 507 consecutive interlaminar nusinersen administrations. Patients presented with both 'uncomplicated spines' or 'complicated spines'; two patients had previous back surgery. Technical success and AEs were recorded using either technique. A generalised linear mixed model was applied to evaluate predictors of technical success and complications. Results: An overall success rate of 99.6%, with only two procedures failing to reach the intrathecal space, and an overall optimal procedure rate of 90.3% have been reported. A total of 455 procedures (89.7%) were uneventfully performed. One (0.2%) case of severe AE (puncture of a bulky abdominal annexal cyst) was recorded. Twenty‐seven episodes (5.3%) of post‐dural puncture headache (PDPH) and 24 episodes (4.7%) of radicular or back pain, both successfully treated with medical therapy, have also been reported. Technical success was significantly associated with 'complicated spines' (P = 0.022) and the use of ultrasound assistance (P = 0.01), and the use of ultrasound was the only independent predictor of uncomplicated procedures (P = 0.007). Discussion: In adult patients with SMA both landmark‐based and ultrasound‐assisted techniques are safe and effective even in the long term. The use of assistance is associated with technical success and can predict uncomplicated procedures. Conclusion: Our results support the use of ultrasonography in order to improve the success and reduce the burden of nusinersen intrathecal administration. [ABSTRACT FROM AUTHOR]

Purpose: Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017–August 2025) in all patients in Japan who were administered nusinersen intrathecally in real-world clinical settings. We report the interim analysis results for safety and effectiveness. Methods: This interim analysis was conducted using data collected from 524 patients whose case report forms were obtained at least once by May 30, 2022. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness. Results: Of the 524 patients in the safety analysis set, 522 patients who were diagnosed with SMA were included in the effectiveness analysis (infantile-onset SMA [n = 153, 29.3%], later-onset SMA [n = 369, 70.7%]). The median duration of treatment was 785.0 (range 1–1549) days. AEs occurred in 35.9% of patients (49.0% in infantile-onset SMA and 30.6% in later-onset SMA). Nusinersen treatment significantly improved Hammersmith Infant Neurological Examination scores in patients with infantile-onset SMA and Hammersmith Functional Motor Scale-Expanded scores in patients with later-onset SMA for up to nearly 3 years. Based on CGI-I assessments, 98.5–100% of patients receiving nusinersen 'improved' or remain 'unchanged'. Conclusions: This interim analysis of the large-scale, all-case PMS in patients who were administered nusinersen in Japan supports the safety and effectiveness of nusinersen. The benefit–risk balance of nusinersen treatment remains favorable. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Nusinersen intrathecal administration can be challenging in spinal muscular atrophy (SMA) adults. We aimed to determine if the ultrasound (US)‐assistance reduces the number of needle attempts and needle redirections needed for intrathecal drug administration and its impact on the procedure time, the incidence of adverse events (AEs), and patient satisfaction in these patients. Methods: Fifty‐eight patients aged 18 years and older scheduled for intrathecal nusinersen injection were enrolled and randomized (1:1 ratio) into Group 1 (nusinersen infusion with US‐assisted technique) or Group 2 (nusinersen infusion with landmark‐based technique). The number of attempts, number of redirections, periprocedural time, AEs and patient satisfaction were reported. Continuous variables were compared with the Student t‐test or Wilcoxon rank sum test. Categorical variables were evaluated with the Chi‐square test or Fisher's exact test in case of expected frequencies <5. The p‐values <.05 were considered statistically significant. Results: There were no statistical differences in the number of attempts, AEs, or patient satisfaction between the two groups. The number of needle redirections was significantly lower in the ultrasound group versus landmark‐based group (p <.05) in both the overall group of patients and in the subgroup with difficult spines. The periprocedural time was about 40 seconds longer in US‐group versus landmark‐based group (p <.05). Discussion: In SMA adults, US assistance reduces the number of needle redirections needed for intrathecal drug administration. These results suggest that the US assistance may be advantageous for nusinersen therapy to reduce the therapeutic burden of intrathecal infusion. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Following the approval of risdiplam, there are more possibilities for disease‐modifying therapy (DMT) in children with spinal muscular atrophy (SMA). Non‐treatment‐naïve subjects with SMA involved in the JEWELFISH study, designed to evaluate the safety and tolerability of risdiplam, were required to undergo a washout period before receiving risdiplam. This study aims to investigate the safety of administering risdiplam in patients within 90 days of receiving treatment with nusinersen. Methods: Data were collected on SMA patients who had undergone treatment with nusinersen, and who then received risdiplam within 90 days of their last dose of nusinersen, including demographic characteristics, information on treatment with nusinersen and risdiplam, adverse events, and laboratory assessments in a follow‐up period of 90 days, presented as median (range). Results: A total of 15 children with SMA were reported, including 8 males and 7 females. The median number of doses of previous nusinersen treatment received was 8 (6–17) doses, and the median age at first risdiplam treatment was 4.3 (1.9–11.2) years. Specifically, 8 children received risdiplam 30 days or less after their most recent nusinersen treatment, 2 at 31–60 days after nusinersen, and 5 at 61–89 days post‐nusinersen. Adverse events of pyrexia, pneumonia, vomiting and rash were reported in 4 patients. Discussion: Our study showed good safety data on patients who received risdiplam following nusinersen within the washout period of 90 days. This supplements the JEWELFISH study in the era of DMT, providing additional guidance for clinicians, but additional data from other centers is needed. [ABSTRACT FROM AUTHOR]

New treatments for 5q spinal muscular atrophy (SMA) have led to changes in the disease phenotype. Questions about long-term efficacy, however, persist. We present the results from five-year follow-up of the first ten Norwegian patients with SMA type1 treated with nusinersen. – Ten patients referred to the expanded access program were included. Standardized assessments with Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), the Hammersmith Infant Neurological Examination (HINE-2), compound muscle action potential (CMAP) examination and cerebrospinal fluid analysis of neurofilament light chain (cNfL) were performed. Age at baseline ranged from three months to 11 years and eight months. Nine patients were alive and continued to receive treatment at 62 months of follow-up. CHOP INTEND scores increased significantly up to 38 months. Any further increase from 38 to 50 months was not statistically significant, and scores remained almost unchanged from 50 to 62 months. HINE-2 scores increased but the difference from baseline never reached statistical significance. The youngest patients showed the best motor outcome. The changes in CMAP scores were not statistically significant. cNfL values were significantly reduced after 18 months compared with baseline; the largest difference occurred between baseline and 6 months. There was a significant negative correlation between log cNfL and CHOP INTEND (p = 0.042). Bulbar and respiratory function did not improve during the observation period. Our findings support previously reported results on efficacy and safety of nusinersen. All patients have shown improvement in motor function. The need of respiratory and nutritional support did not improve. • There remains a need for information on long-term effects of nusinersen. The current study provides a five-year follow-up. • Motor improvement was seen in the initial three years. Older patients tended to deteriorate a little during the last period. • Improved motor function has resulted in a more proactive approach regarding respiratory nutritional and orthopedic management. • We found a negative correlation between log cNfL and CHOP INTEND suggesting that cNfL might be used as a biomarker. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA), identified over a century ago, is characterized by severe muscle wasting and early mortality. Despite its rarity, the high carrier frequency of the responsible genetic mutations and the variability in its manifestations make it a significant research focus. This prospective cross-sectional descriptive study evaluated health-related quality of life (HRQoL) across eight health domains in 43 Romanian SMA patients treated with nusinersen, using the SF-36 questionnaire to analyze influencing factors. The survey was conducted online with informed consent, and the data were analyzed using MedCalc software, employing both parametric and non-parametric statistical tests for accurate interpretation. The results revealed significant variations in HRQoL. Most patients were non-ambulatory (74.4%), reflecting SMA's impact on mobility. Urban residents reported better outcomes, particularly in physical functioning (p = 0.014), which may be attributed to improved access to healthcare services. Younger participants (under 14), represented by proxy responses, noted better general health (p = 0.0072) and emotional well-being (p = 0.0217) compared to older participants. These findings suggest that younger patients or their proxies perceive a better health status, highlighting the need for age-specific approaches in SMA management and the potential optimistic bias associated with proxy reporting on perceived health outcomes. [ABSTRACT FROM AUTHOR]

SMA is a neurodegenerative autosomal recessive disorder characterized by progressive degeneration of motor neurons of the spinal cord, leading to muscle weakness and early mortality. SMA can be divided into four types, extending from severe infantile-onset type I to milder forms that appear later in life, such as types II, III, and IV. The GCC countries have an unusually high prevalence of SMA, largely due to the high rate of consanguineous marriages, a situation that increases the risk of inheritance of autosomal recessive conditions. Genetic predisposition to SMA is due to mutations in the Survival Motor Neuron gene occurring in two almost identical copies, SMN1 and SMN2. The severity of this disease is correlated with the number of functional copies of these genes; however, SMN2 is also capable of playing a very critical compensatory role. The more the number of copies of SMN2 one has, the milder the forms of the disease. Molecular screening techniques such as genetic testing and carrier screening are very essential in this regard for early diagnosis and management of SMA. This orphan disease has several FDA- and EMA-approved treatment options for SMA, including Nusinersen, Onasemnogene abeparvovec, and Risdiplam. Results with these treatments are very promising and show improved motor function and survival in the affected patients. The present review outlines current developments in research and treatment of the disease, drawing attention to the high prevalence of the condition in GCC countries and also to the contribution that genetic screening, combined with the emerging therapies, can have in managing this devastating disorder. [ABSTRACT FROM AUTHOR]

Background and Purpose: The aim was to investigate whether neurofilament light chain (NfL) and profilin‐1 (PFN‐1) might qualify as surrogate disease and treatment‐response biomarkers by correlating their concentrations dynamic with clinical status in a cohort of 30 adult spinal muscular atrophy type 3 patients during nusinersen therapy up to 34 months. Methods: Neurofilament light chain was measured in cerebrospinal fluid at each drug administration with a commercial enzyme‐linked immunosorbent assay (ELISA); PFN‐1 concentrations were tested in serum sampled at the same time points with commercial ELISA assays. Functional motor scores were evaluated at baseline, at the end of the loading phase and at each maintenance dose and correlated to biomarker levels. The concurrent effect of age and clinical phenotype was studied. Results: Neurofilament light chain levels were included in the reference ranges at baseline; a significant increase was measured during loading phase until 1 month. PFN‐1 was higher at baseline than in controls and then decreased during therapy until reaching control levels. Age had an effect on NfL but not on PFN‐1. NfL was partially correlated to functional scores at baseline and at last time point, whilst no correlation was found for PFN‐1. Conclusion: Cerebrospinal fluid NfL levels did not qualify as an optimal surrogate treatment biomarker in adult spinal muscular atrophy patients with a long disease duration, whilst PFN‐1 might to a greater extent represent lower motor neuron pathological processes. The observed biomarker level variation during the first 2 months of nusinersen treatment might suggest a limited effect on axonal remodeling or rearrangement. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Severe spinal deformities and previous spinal orthopedic instrumentation may result in substantial technical challenges for nusinersen delivery through lumbar puncture in patients with spinal muscular atrophy (SMA). The aim of this paper was to review our experience with ultrasound‐guided cervical puncture as an alternative approach for the intrathecal administration of nusinersen. Methods: This was a retrospective medical record review of transverse interlaminar ultrasound‐guided C1‐C2 puncture for nusinersen delivery in SMA patients. The details of puncture, complications, and success rate of the procedure were summarized. Results: There were four patients who received a total of 13 cervical punctures for nusinersen delivery. All procedures were technically successful with no major complications. Full doses of nusinersen were delivered intrathecally. Discussion: Transverse interlaminar ultrasound‐guided C1‐C2 puncture is an alternative approach for administering nusinersen if lumbar puncture fails. The success of the technique requires a thorough preprocedural evaluation of cervical spine imaging, sound knowledge of the cervical sonoanatomy and careful manipulation of the needle. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Fatigue (subjective perception) and fatigability (objective motor performance worsening) are relevant aspects of disability in individuals with spinal muscular atrophy (SMA). The effect of nusinersen on fatigability in SMA patients has been investigated with conflicting results. We aimed to evaluate this in adult with SMA3. Methods: We conducted a multicenter retrospective cohort study, including adult ambulant patients with SMA3, data available on 6‐minute walk test (6MWT) and Hammersmith Functional Motor Scale—Expanded (HFMSE) at baseline and at least at 6 months of treatment with nusinersen. We investigated fatigability, estimated as 10% or higher decrease in walked distance between the first and sixth minute of the 6MWT, at baseline and over the 14‐month follow‐up. Results: Forty‐eight patients (56% females) were included. The 6MWT improved after 6, 10, and 14 months of treatment (p < 0.05). Of the 27 patients who completed the entire follow‐up, 37% improved (6MWT distance increase ≥30 m), 48.2% remained stable, and 14.8% worsened (6MWT distance decline ≥30 m). Fatigability was found at baseline in 26/38 (68%) patients and confirmed at subsequent time points (p < 0.05) without any significant change over the treatment period. There was no correlation between fatigability and SMN2 copy number, sex, age at disease onset, age at baseline, nor with 6MWT total distance and baseline HFMSE score. Discussion: Fatigability was detected at baseline in approximately 2/3 of SMA3 walker patients, without any correlation with clinical features, included motor performance. No effect on fatigability was observed during the 14‐month treatment period with nusinersen. [ABSTRACT FROM AUTHOR]

Introduction: Nusinersen clinical trials have limited data on adolescents and adults with 5q-associated spinal muscular atrophy (SMA). We conducted a systematic literature review (SLR) and meta-analysis to assess effectiveness of nusinersen in adolescents and adults with SMA in clinical practice. Methods: Our search included papers published 12/23/2016 through 07/01/2022 with ≥ 5 individuals ≥ 13 years of age and with ≥ 6 months' data on ≥ 1 selected motor function outcomes [Hammersmith Functional Motor Scale–Expanded (HFMSE), Revised Upper Limb Module (RULM), and Six-Minute Walk Test (6MWT)]. For meta-analysis, effect sizes were pooled using random-effects models. To understand treatment effects by disease severity, subgroup meta-analysis by SMA type and ambulatory status was conducted. Results: Fourteen publications including 539 patients followed up to 24 months met inclusion criteria for the SLR. Patients were age 13–72 years and most (99%) had SMA Type II or III. Modest improvement or stability in motor function was consistently observed at the group level. Significant mean increases from baseline were observed in HFMSE [2.3 points (95% CI 1.3–3.3)] with 32.1% (21.7–44.6) of patients demonstrating a clinically meaningful increase (≥ 3 points) at 18 months. Significant increases in RULM were consistently found, with a mean increase of 1.1 points (0.7–1.4) and 38.3% (30.3–47.1) showing a clinically meaningful improvement (≥ 2 points) at 14 months. Among ambulatory patients, there was a significant increase in mean 6MWT distance of 25.0 m (8.9–41.2) with 50.9% (33.4–68.2) demonstrating a clinically meaningful improvement (≥ 30 m) at 14 months. The increases in HFMSE were greater for less severely affected patients, whereas more severely affected patients showed greater improvement in RULM. Conclusions: Findings provide consolidated evidence that nusinersen is effective in improving or stabilizing motor function in many adolescents and adults with a broad spectrum of SMA. Plain Language Summary: Motor neurons are specialized cells in the brain and spinal cord that control the function of muscles. People with spinal muscular atrophy (SMA) do not make enough survival motor neuron (SMN) protein, which motor neurons need to function. As a result, people with SMA experience decreased muscle function that gets worse over time. Nusinersen is a drug that increases the amount of SMN protein made in the brain and spinal cord. However, most clinical trials of nusinersen have been in infants and children with SMA. Less is known about the effects of nusinersen in teenagers and adults with SMA who may have less severe but still progressive forms of the disease. In this manuscript, we first conducted a thorough review and analysis of research published by investigators who treated teenagers and adults with nusinersen for up to 24 months. We then used an additional analysis, called a meta-analysis, that allowed us to combine the information from several articles, so that we could better understand whether nusinersen helped these patients. We looked at 3 tests that investigators used to see how nusinersen affected patients' motor function. The Hammersmith Functional Motor Scale–Expanded (HFMSE) assesses upper and lower limb motor function; the Revised Upper Limb Module (RULM) evaluates upper limb function; and the Six-Minute Walk Test (6MWT) measures the maximum distance a person can walk in 6 minutes. Our study showed that nusinersen can improve motor function or prevent motor function from getting worse in many teenagers and adults with SMA. [ABSTRACT FROM AUTHOR]

Background: The introduction of newborn screening (NBS) for spinal muscular atrophy (SMA) has increased the early diagnosis of 5q-associated SMA in presymptomatic and symptomatic preterm infants. National and international recommendations for treating preterms and newborns < 38 weeks of gestational age are unavailable. Our retrospective multicentre study aimed to evaluate the postnatal clinical course of preterm infants with 5q-associated SMA diagnosed since the implementation of NBS in Germany in 2021 and to summarize the German experience regarding the decision-making process for available treatment regimens for preterm infants with ≤ 3 survival of motor neuron 2 (SMN2) copies. Results: Twelve preterm infants with 5q-associated SMA and a mean gestational age of 34.0 weeks (range: 26.1–36.8) and birth weight of 2022 g (range: 645–3370) were reported from 8/20 German SMA NBS follow-up centers using a pseudonymized questionnaire. Confirmatory diagnosis, including SMN2 copy number, was completed on average on postnatal day 13. All patients had a biallelic deletion of exon 7 or exons 7 and 8 of the survival of motor neuron 1 (SMN1) gene, with SMN2 copy numbers of two in 10 patients and three in two patients. The neonatal course was complicated by respiratory distress due to prematurity (n = 2), sepsis (n = 2), and jaundice (n = 2). At birth, 11 preterm infants (91.6%) were presymptomatic. However, the neurological status of one patient deteriorated at five weeks of age (postconceptional age of 41.8 weeks) prior to the start of treatment. Disease-modifying treatments were initiated in all patients at a mean postconceptional age of 38.8 weeks, with the majority receiving onasemnogene abeparvovec (83.3%, including 2 patients with prior risdiplam bridge therapy). Notably, consensus among participating experts from German neuromuscular centers resulted in 83.3% of patients receiving disease-modifying treatment at term. Conclusions: Premature infants with SMA require interdisciplinary care in close collaboration with the neuromuscular center. SMA NBS facilitates early initiation of disease-modifying therapy, ideally during the presymptomatic phase, which significantly influences the prognosis of the newborn. [ABSTRACT FROM AUTHOR]

Nusinersen is the first drug for precise targeted therapy of spinal muscular atrophy, a rare disease that occurs in one of 10,000 to 20,000 live births. Therefore, thorough and comprehensive reports on the safety of nusinersen in large, real-world populations are necessary. This study aimed to mine the adverse event (AE) signals related to nusinersen through the Food and Drug Administration Adverse Event Reporting System (FAERS) database. We extracted reports of AEs with nusinersen as the primary suspect from FAERS between December 2016 and March 2023. Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) were used for AE signal detection. We extracted a total of 4807 suspected AE cases with nusinersen as the primary suspect from the FAERS database. Among them, 106 positive signals were obtained using the ROR and BCPNN. The highest frequency reported systemic organ class was general disorders and administration site conditions. Common clinical AEs of nusinersen were detected in the FAERS database, such as pneumonia, vomiting, back pain, headache, pyrexia, and post–lumbar puncture syndrome. In addition, we identified potential unexpected serious AEs through disproportionality analysis, including sepsis, seizure, epilepsy, brain injury, cardiorespiratory arrest, and cardiac arrest. Analyzing large amounts of real-world data from the FAERS database, we identified potential new AEs of nusinersen by disproportionate analysis. It is advantageous for health care professionals and pharmacists to concentrate on effectively managing high-risk AEs of nusinersen, improve medication levels in clinical settings, and uphold patient medication safety. [ABSTRACT FROM AUTHOR]

Background: 5q spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease. Objective: We aimed to assess the effects of nusinersen on motor function and electrophysiological parameters in adolescent and adult patients with 5q SMA. Methods: Patients with genetically confirmed 5q SMA were eligible for inclusion, and clinical data were collected at baseline (V1), 63 days (V4), 180 days (V5), and 300 days (V6). The efficacy of nusinersen was monitored by encompassing clinical assessments, including the Revised Upper Limb Module (RULM), Hammersmith Functional Motor Scale Expanded (HFMSE), 6-Minute Walk Test (6MWT), and percent-predicted Forced Vital Capacity in sitting position (FVC%) and Compound Muscle Action Potential (CMAP) amplitude. The patients were divided into "sitter" and "walker" subgroups according to motor function status. Results: 54 patients were screened, divided into "sitter" (N = 22) and "walker" (N = 32), with the mean age at baseline of 27.03 years (range 13–53 years). The HFMSE in the walker subgroup increased significantly from baseline to V4 (mean change +2.32-point, P = 0.004), V5 (+3.09, P = 0.004) and V6 (+4.21, P = 0.005). The patients in both the sitter and walker subgroup had no significant changes in mean RULM between V1 and the following time points. Significant increases in CMAP amplitudes were observed in both upper and lower limbs after treatment. Also, patients with RULM ≥ 36 points showed significant CMAP improvements. Our analysis predicted that patients with CMAP amplitudes of trapezius ≥ 1.76 mV were more likely to achieve significant motor function improvements. Conclusions: Nusinersen effectively improves motor function and electrophysiological data in adolescent and adult patients with SMA. This is the first report on the CMAP amplitude changes in the trapezius after treatment in patients with SMA. The CMAP values effectively compensate for the ceiling effect observed in the RULM, suggesting that CMAP could serve as an additional biomarker for evaluating treatment efficacy. [ABSTRACT FROM AUTHOR]

Background. Spinal muscular atrophy (SMA) is an inherited disease with progressive muscle weakness and atrophy. Despite the new treatments developed recently, primary and secondary effects of muscle weakness in patients with SMA cause mortality and morbidity. The aim of this study is to identify common problems in the follow-up of patients after new treatment modalities and to examine the difficulties in management of these problems. Methods. The study included 16 patients diagnosed with SMA type 1 according to clinical findings and genetic results between 2017 and 2022. The patients were divided into two groups as living and deceased, and complications were examined and compared between the groups. Results. The patients comprised 8 (50%) females and 8 (50%) males with a median age at diagnosis of 3 months. The patients had a history of gastrointestinal problems, orthopedic problems, infection and sepsis, and especially respiratory distress. Death occurred in 8 (50%) patients during follow-up (median age 38 months). Mortality was higher in patients who needed tracheostomy and had gastroesophageal reflux. The survival rate was better in patients who received more nusinersen treatment and had a higher CHOP-INTEND score. Conclusions. Despite new-generation treatments for SMA type 1, morbidity and mortality rates remain very high. As the survival rate in SMA type 1 increases, the incidence of complications similar to those frequently seen in SMA type 2 and type 3 patients also increases. The follow-up and treatment of patients with SMA should be undertaken by a multidisciplinary team. [ABSTRACT FROM AUTHOR]

Objective: Spinal muscular atrophy (SMA) is a hereditary disorder with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide directed against SMN2 and has been shown in studies to improve the motor skills of patients. The aim of this study was to evaluate the efficacy of nusinersen treatment in patients with SMA type 2 and type 3 using the Hammersmith Functional Motor Scale Expanded (HFMSE) score. Method: The diagnosis and differentiation of SMA type 2 and type 3 were based on clinical findings and genetic tests. The HFMSE scores of all patients were evaluated in detail before nusinersen doses. Results: Evaluation was made of a total of 15 patients, 12 SMA type 2 and 3 SMA type 3, with a median age of 13 years. None of the patients had regression of acquired abilities after nusinersen treatment. The median HFMSE score of SMA type 2 patients before treatment was 9. After nine doses of nusinersen, the HFMSE score showed a significant increase from 9 to 30 points. Although none of the patients could walk, their motor skills improved significantly. The median HFMSE score of SMA type 3 patients before treatment was 60. After 3 doses of nusinersen treatment, HFMSE scores were found to be 63. Conclusion: Nusinersen is an effective and safe treatment for patients with late-onset SMA. It can be suggested that different motor scales should be applied and developed for SMA type 2 (sitter) and type 3 (walker) patients due to differences in the clinical characteristics of SMA types.

Abstract Background Lumbar puncture is challenging for patients with scoliosis. Previous ultrasound-assisted techniques for lumbar puncture used the angle of the probe as the needle trajectory; however, reproducing the angle is difficult and increases the number of needle manipulations. In response, we developed a technique that eliminated both the craniocaudal and lateromedial angulation of the needle trajectory to overall improve this technique. We assessed the feasibility and safety of this method in patients with scoliosis and identify factors related to difficult lumbar puncture. Methods Patients with spinal muscular atrophy and scoliosis who were referred to the anesthesia department for intrathecal nusinersen administrations were included. With a novel approach that utilized patient position and geometry, lumbar puncture was performed under ultrasound guidance. Success rates, performance times and adverse events were recorded. Clinical-demographic and spinal radiographic data pertaining to difficult procedures were analyzed. Results Success was achieved in all 260 (100%) lumbar punctures for 44 patients, with first pass and first attempt success rates of 70% (183/260) and 87% (226/260), respectively. Adverse events were infrequent and benign. Higher BMI, greater skin dural sac depth and smaller interlaminar size might be associated with greater difficulty in lumbar puncture. Conclusions The novel ultrasound-assisted horizontal and perpendicular interlaminar needle trajectory approach is an effective and safe method for lumbar puncture in patients with spinal deformities. This method can be reliably performed at the bedside and avoids other more typical and complex imaging such as computed tomography guided procedure.

Abstract This study aims to collect and analyze adverse event (AE) reports related to Nusinersen from the FAERS database. The study employed a combination of signal quantification techniques, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), to enhance the accuracy of signal detection and reduce the risk of false positives or negatives. Between the first quarter of 2017 and the third quarter of 2023, the FAERS database collected a total of 11,485,105 drug AE reports, of which 5772 were related to Nusinersen. Through signal mining analysis, 218 preferred term (PT) signals involving 27 system organ classes (SOCs) were identified. The study discovered AEs related to metabolism and nutrition disorders, psychiatric disorders, and cardiac disorders SOCs, which were not mentioned in the product information. Additionally, complications directly related to the intrathecal administration of Nusinersen, such as increased CSF pressure, positive CSF red blood cell count, and AEs related to the method of drug use, such as neuromuscular scoliosis and cerebrospinal fluid reservoir placement, were highlighted. Notably, AEs related to renal function abnormalities, such as abnormal Urine protein/creatinine ratio and protein urine presence, showed higher frequency and signal strength. The findings of this study emphasize the importance of comprehensive safety monitoring in the clinical application of Nusinersen. These results are significant for guiding future clinical practices, improving disease management strategies, and developing safer treatment protocols.

Abstract Background Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder that can be treated with intrathecal nusinersen, an antisense oligonucleotide. In addition to efficacy, safety is a determining factor in the success of any therapy. Here, we aim to assess the safety of nusinersen therapy in paediatric patients with SMA. Methods Laboratory data of paediatric patients with SMA who received nusinersen between October 2019 and May 2022 were retrospectively analysed. Results During the observation period, 46 infants and children aged 2.9 months to 13.6 years received a total of 213 nusinersen doses without safety concerns. Inflammatory markers were stable throughout the study. International normalized ratio was increased by 0.09 per injection. Urea levels were increased by 0.108 mmol/L, and cystatin C decreased by 0.029 mg/L per injection. There were no significant changes in platelet count, activated partial thrombin time, creatinine levels or liver enzyme levels during treatment. The cerebrospinal fluid (CSF) leukocyte count remained stable, and total protein increased by 24.038 mg/L per injection. Conclusion Our data showed that nusinersen therapy is generally safe in children with SMA. Laboratory monitoring did not identify any persistent or significantly abnormal findings. CSF protein should be monitored to gain more insights.

Abstract We analyzed the changes in various motor function scores over a four-year period in patients with non-ambulatory spinal muscular atrophy (SMA) during Nusinersen treatment. Patients underwent Hammersmith Infant Neurological Examination (HINE) or Hammersmith Functional Motor Scale Expanded (HFMSE) before treatment, and approximately every 4 months thereafter. Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) or Children’s Hospital of Philadelphia – Adult Test of Neuromuscular Disorders (CHOP ATEND), Revised Upper Limb Module (RULM), and Motor Function Measure (MFM) were performed based on baseline functional status. Narrative interviews were conducted to explore post-treatment physical improvement regarding activities of daily living (ADLs) and fatigue after ADLs. Based on HFMSE results, 9 patients achieved minimum clinically important differences. Average rates of change (slopes) with corresponding 95% confidence intervals for all assessment tools were in a positive direction. CHOP-INTEND showed the most prominent improvement in children and adolescents followed by HFMSE. Improvements in CHOP-ATEND were most noticeable in adults. Improvements were accompanied by changes in ADLs as observed in the narrative interviews. It is necessary to consider various functional aspects to determine the effectiveness of Nusinersen therapy. The objective assessment of the therapeutic effect of Nusinersen in non-ambulatory SMA requires consideration of functional aspects and the related ADLs.

Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy approved for the treatment of 5q spinal muscular atrophy in pediatric and adult patients. The objective of this clinical case series is to describe the efficacy and safety of nusinersen in treating spinal muscular atrophy in 20 pediatric and 18 adult patients across six treatment centers in Kuwait. Functional motor assessments (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module) were used to assess changes in motor function following nusinersen treatment. The safety assessment involved clinical monitoring of adverse events. The results demonstrate clinically meaningful or considerable improvement in motor performance for nearly all patients, lasting over 4 years in some cases. A total of 70% of patients in the pediatric cohort and 72% of patients in the adult cohort achieved a clinically meaningful improvement in motor function following nusinersen treatment. Additionally, nusinersen was well-tolerated in both cohorts. These findings add to the growing body of evidence relating to the clinical efficacy and safety of nusinersen.

ObjectiveTo provide a theoretical basis for different drug decision-making scenarios by conducting a comprehensive clinical evaluation of nusinersen.MethodsBased on the method of multi-criteria decision analysis, a comprehensive clinical evaluation index system of nusinersen was established. This system, including core criterion model and contextualized criterion model, covered multiple evaluation dimensions such as safety, effectiveness, economy, and social attributes. The evidence of nusinersen in various criteria was summarized and integrated through systematic reviews. Then, different stakeholders were assigned weights and scores in various criteria of the core criterion model. Finally, a holistic value of nusinersen was estimatedthrough standardizing and combining the results in contextualized criterion model.ResultsThe criteria, type of therapeutic benefit disease severity (0.08±0.02), unmet needs (0.08±0.01), quality of evidence (0.08±0.01), effectiveness (0.08±0.01) and safety (0.08±0.02) received the greatest weights after standardization. The higher mean scores for nusinersen versus placebo for the treatment of spinal muscular atrophy were disease severity (4.8±0.4), innovation of the drug (4.7±0.6), expert consensus or clinical practice guidelines (4.5±0.6), effectiveness (4.0±1.0) and quality of evidence (4.0±0.8).The holistic value of nusinersen was 0.41. The overall impact of the contextualized model on the evaluation of the drug was 0.26, indicating that it may overestimate the comprehensive value of nusinersen.ConclusionsThe method of multi-criteria decision analysis proves the positive role that nusinersen plays in spinal muscular atrophy treatment.

Clinical trials with treatments inhibiting myostatin pathways to increase muscle mass are currently ongoing in spinal muscular atrophy. Given evidence of potential myostatin pathway downregulation in Spinal Muscular Atrophy (SMA), restoring sufficient myostatin levels using disease-modifying treatments (DMTs) might arguably be necessary prior to considering myostatin inhibitors as an add-on treatment. This retrospective study assessed pre-treatment myostatin and follistatin levels' correlation with disease severity and explored their alteration by disease-modifying treatment in SMA. We retrospectively collected clinical characteristics, motor scores, and mysotatin and follistatin levels between 2018 and 2020 in 25 Belgian patients with SMA (SMA1 (n = 13), SMA2 (n = 6), SMA 3 (n = 6)) and treated by nusinersen. Data were collected prior to treatment and after 2, 6, 10, 18, and 30 months of treatment. Myostatin levels correlated with patients' age, weight, SMA type, and motor function before treatment initiation. After treatment, we observed correlations between myostatin levels and some motor function scores (i.e., MFM32, HFMSE, 6MWT), but no major effect of nusinersen on myostatin or follistatin levels over time. In conclusion, further research is needed to determine if DMTs can impact myostatin and follistatin levels in SMA, and how this could potentially influence patient selection for ongoing myostatin inhibitor trials. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a severe genetic disorder characterized by the loss of motor neurons, leading to progressive muscle weakness, loss of mobility, and respiratory complications. In its most severe forms, SMA can result in death within the first two years of life if untreated. The condition arises from mutations in the SMN1 (survival of motor neuron 1) gene, causing a deficiency in the survival motor neuron (SMN) protein. Humans possess a near-identical gene, SMN2, which modifies disease severity and is a primary target for therapies. Recent therapeutic advancements include antisense oligonucleotides (ASOs), small molecules targeting SMN2, and virus-mediated gene replacement therapy delivering a functional copy of SMN1. Additionally, recognizing SMA's broader phenotype involving multiple organs has led to the development of SMN-independent therapies. Evidence now indicates that SMA affects multiple organ systems, suggesting the need for SMN-independent treatments along with SMN-targeting therapies. No single therapy can cure SMA; thus, combination therapies may be essential for comprehensive treatment. This review addresses the SMA etiology, the role of SMN, and provides an overview of the rapidly evolving therapeutic landscape, highlighting current achievements and future directions. [ABSTRACT FROM AUTHOR]

• The majority of children treated with nusinersen show improvement in at least 1 item. • Most common score changes are changes from 0 to 1. • Sitters most likely improve in items that assess rolling. • Walkers most likely improve in items that assess half-kneeling. The Hammersmith Functional Motor Scale-Expanded (HFMSE) is a validated outcome measure for monitoring changes in functional strength in patients with spinal muscular atrophy (SMA). The objective of this study was to explore changes in HFMSE item-scores in children with SMA types 2 and 3a treated with nusinersen over a period of six to twenty months. We stratified patients according to motor ability (sitting and walking), and calculated numbers and percentages for each specific improvement (positive score change) or decrease (negative score change) for the total group and each subgroup and calculated frequency distributions of specific score changes. Ninety-one percent of the children showed improvement in at least 1 item, twenty-eight percent showed a score decrease in 1 or more items. In the first six to twenty months of nusinersen treatment motor function change was characterized by the acquisition of the ability to perform specific tasks with compensation strategies (score changes from 0 to 1). Children with the ability to sit were most likely to improve in items that assess rolling, whilst children with the ability to walk most likely improved in items that assess half-kneeling. The ability most frequently lost was hip flexion in supine position. [ABSTRACT FROM AUTHOR]

• New disease-modifying therapies benefit type II SMA patients. • Shift analysis reveals gains in activities across age groups. • Notable gains in activities, especially in children aged 2.5 to 13 years. • Treated patients show lower loss risk, higher gain likelihood. • Effectiveness linked to strength and function improvements. Several studies have shown the efficacy of new disease-modifying therapies in slowing down type II SMA progression using the Hammersmith Functional Motor Scale Expanded (HFMSE). This research aims to enhance understanding of activity changes across age groups post-nusinersen treatment using shift analysis, compared with untreated individuals. Retrospective data from the, international SMA consortium (iSMAc) dataset were analyzed, assessing individual item changes over 12 months. Shift analysis was used to determine the gain or loss of abilities, defining "gain" as a positive change between scores from 0 to either 1 or 2 and "loss" as a negative change from either 2 or 1 to 0. The cohort included 130 SMA II patients who underwent 12-month assessments from their first nusinersen dose, with age range between 0.6 and 49.6 years. One-third of the entire cohort experienced at least a loss in one activity, while 60% experienced a gain, particularly notable in children aged 2.5 to 5 years and 5 to 13 years. Overall, the study demonstrates a positive impact of nusinersen treatment on SMA II patients, showing a trend of increased activity gains and decreased probability of ability loss across different age groups. [ABSTRACT FROM AUTHOR]

Despite neweffective medications, patients with spinal muscular atrophy types 1-3 can continue to have inadequate cough flows to prevent episodes of acute respiratory failure. Ventilator unweanable intubated patients are thought to require tracheostomy tubes. As a result, potentially beneficial medications may be discontinued and patients die despite receiving these medications. Three cases are presented of medically treated, physically strengthening children, with spinal muscular atrophy type 1. All three subsequently died or underwent tracheotomy. However, there is no evidence of extubation attempts to noninvasive ventilatory support settings or optimal mechanical insufflation-exsufflation despite this option being described to be over 98% successful for extubating unweanable medically untreated children with spinal muscular atrophy 1. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients. Methods: Using a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results. Results: As of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4–5.4) and 4.1 (2.8–5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7–3.1) and 2.3 (1.2–3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5–5.3) and 4.3 (2.6–6.0) in HFMSE, and 2.1 (1.2–3.0) and 1.5 (0.0–3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae. Conclusions: These data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance. [ABSTRACT FROM AUTHOR]

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Spinal muscular atrophy (SMA) is a genetic disorder primarily caused by mutations in the SMN1 gene, leading to motor neuron degeneration and muscle atrophy, affecting multiple organ systems. Nusinersen treatment targets gene expression and is expected to enhance the motor function of voluntary muscles in the limbs and trunk. Motor skills can be assessed through specific scales like the Revised Upper Limb Module Scale (RULM) and Hammersmith Functional Motor Scale Expanded (HFMSE). This study aims to evaluate the influence of nusinersen on the motor skills of patients with SMA Type 2 and 3 using real-world data collected over 54 months. A prospective longitudinal study was conducted on 37 SMA patients treated with nusinersen, analyzing data with R statistical software. The outcomes revealed significant improvements in motor functions, particularly in SMA Type 3 patients with higher RULM and HFSME scores. Additionally, GEE analysis identified time, type, age, and exon deletions as essential predictors of motor score improvements. The extended observation period is both a major strength and a limitation of this research, as the dropout rates could present challenges in interpretation. Variability in responses, influenced by genetic background, SMA type, and onset age, highlights the need for personalized treatment approaches. [ABSTRACT FROM AUTHOR]