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The nutritional implications of spinal muscular atrophy (SMA) are profound. Disease modifying therapies (DMT) have improved clinical outcomes. This review describes the impact of DMT on nutrition outcomes. A systematic search strategy was applied across seven databases until May 2023. Eligible studies measured nutrition outcomes in individuals with SMA on DMT (nusinersen, risdiplam or onasemnogene abeparvovec [OA]) compared to untreated comparators. Nutrition outcomes included anthropometry, feeding route, swallowing dysfunction, dietary intake, dietetic intervention, nutritional biochemistry, metabolism, gastrointestinal issues and energy expenditure. Articles retrieved were screened in duplicate, data were extracted and appraised systematically. Sixty three articles from 54 studies were included; 41% (n = 22) investigated nusinersen in pediatric participants with SMA type 1. Anthropometry (n = 18), feeding route (n = 39), and swallowing dysfunction (n = 18) were the most commonly reported outcomes. In combined pediatric and adult cohorts, BMI z-score remained stable post nusinersen therapy. The proportion of children with SMA requiring enteral nutrition was stable post nusinersen therapy. Ability to thrive at age 1.5 years was higher in children treated in early infancy with OA compared to historical controls. Significant heterogeneity existed across study population characteristics and outcome measures. Nusinersen may prevent deterioration in some nutrition outcomes; and OA in early infancy may be associated with improved nutrition outcomes. Timing of DMT initiation is an important consideration for future nutrition research. Studies investigating nutrition as a primary outcome of DMT, using consistent outcome measures are required for nutritional management strategies for this cohort to be appropriately tailored., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by skeletal muscle weakness and atrophy. Patients with SMA types 1 and 2 develop severe disabilities conferring substantial patient and caregiver burden. Caregiver treatment characteristic preferences are useful for informing treatment choices and improving adherence. We aimed to identify drivers of SMA treatment preference from the perspective of caregivers of patients with SMA types 1 or 2 in the United States. We quantified the relative importance of different treatment characteristics and compared preferences for hypothetical treatment scenarios. Treatment attributes and attribute levels elicited were based on a literature search and interviews with caregivers and health care professionals. The most important treatment characteristics from the perspective of health care professionals and caregivers were identified and used in a survey to quantify relative importance for caregivers. Caregivers completed surveys regarding their preferences using swing weighting methodology. These results were used to estimate the relative value of four hypothetical SMA treatment scenarios exploring different modes of treatment administration. The swing weighting survey, completed by 20 caregivers, demonstrated that the attributes driving treatment preference were reduction in permanent ventilation needs and risk of severe adverse events, followed by treatment access (including cost coverage and availability), increased ability to sit without support, and less treatment administration burden. The hypothetical SMA treatment scenarios with the highest relative value offered an easier mode of administration, lowest risk of severe adverse events, less need of permanent ventilation, and highest ability of patients to feed and sit without support. Our findings suggest that caregivers prefer a treatment with reduced clinical burden and risk in which the cost is covered and treatment is available in the short term. These results can provide important contextual information for decision-makers and help promote patient-centered care for patients with SMA., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Anish Patel, Walter Toro, Sandra P. Reyna, and Omar Dabbous are employees of Novartis Gene Therapies, Inc., and own stock and options. Siobhan Bourke, Yemi Oluboyede, Sylvaine Barbier, and Natalyia Bogoeva are employees of Putnam Associates and were contracted by Novartis Gene Therapies, Inc., as part of this research and analysis. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Patel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The 5q Spinal Muscular Atrophy (SMA) is a hereditary autosomal recessive disease caused by defects in the survival motor neuron ( SMN1 ) gene encoding survival motor neuron (SMN) protein. Currently, it is the leading cause of infantile mortality worldwide. SMA is a progressive neurodegenerative disease with "continuum of clinical severity", which can be modulated by genetic and epigenetic factors known as disease modifiers (DMs). Individuals (even siblings) with the same defects in SMN1 gene might have strikingly different types of SMA, supposedly due to the impact of DMs. There are several therapeutic options for SMA, all of them focusing on the restoration of the SMN protein levels to normal. Determining DMs and the pathways in which they are involved might aid in enhancing existing curative approaches. Furthermore, DMs might become novel therapeutic targets or prognostic biomarkers of the disease. This narrative review provides a brief overview of the genetics and pathobiology of SMA, and its bona fide modifiers. We describe novel, emerging DMs, approaches and tools used to identify them, as well as their potential mechanisms of action and impact on disease severity. We also propose several disease-modifying molecular mechanisms which could provide a partial explanation of the staggering variability of SMA phenotypes.

Background: Spinal muscular atrophy is a rare neurodegenerative disorder in children which leads untreated to muscle wasting, respiratory impairments, and a shortened life expectancy. Parents as primary caregivers are often physically and psychologically burdened. In recent years, new and promising treatment options have been approved, but it remains unclear if they have an impact on the psychosocial situation of affected families., Objectives: The aim of this study was to explore the views and experiences of parents as informal caregivers of children with SMA in the course of the disease against the background of new treatment options (Spinraza® or Zolgensma®)., Methods: We conducted qualitative interviews with 27 parents of children with SMA treated with Spinraza® and Zolgensma® from April to September 2020. The analysis was done using thematic analysis and reported according to the COREQ criteria., Results: The data analysis resulted in three main themes: a) caregiver burden and negative consequences for families, b) resources and protective aspects, c) psychosocial care needs. The results are discussed against the background of new treatment options and previous models of supportive care needs. Parental caregivers of affected children face multiple burdens in different stages of the child's disease progression., Conclusion: Although new treatment options for SMA showed observable effects for most parents, the main caregiver burden and reported symptoms were attributable to the overburdening care tasks. To unburden families, more screening for unmet needs, family-centered help services, professional caregivers, childcare, and sufficient financial support are needed., (© 2024. The Author(s).)

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Gene editing technology repairs the conversion of the 6th base T to C in exon 7 of the paralogous SMN2 gene, compensating for the SMN protein expression and promoting the survival and function of motor neurons. However, low editing efficiency and unintended off-target effects limit the application of this technology. Here, we optimized a TaC9-adenine base editor (ABE) system by combining Cas9 nickase with the transcription activator-like effector (TALE)-adenosine deaminase fusion protein to effectively and precisely edit SMN2 without detectable Cas9 dependent off-target effects in human cell lines. We also generated human SMA-induced pluripotent stem cells (SMA-iPSCs) through the mutation of the splice acceptor or deletion of the exon 7 of SMN1. TaC9-R10 induced 45% SMN2 T6 > C conversion in the SMA-iPSCs. The SMN2 T6 > C splice-corrected SMA-iPSCs were directionally differentiated into motor neurons, exhibiting SMN protein recovery and antiapoptosis ability. Therefore, the TaC9-ABE system with dual guides from the combination of Cas9 with TALE could be a potential therapeutic strategy for SMA with high efficacy and safety., (© 2024 Wiley Periodicals LLC.)

Introduction/aims: Spinal muscular atrophy (SMA) manifests with progressive motor neuron degeneration, leading to muscle weakness. Onasemnogene abeparvovec is a US Food and Drug Administration-approved gene replacement therapy for SMA. This study aimed to present short-term data of children in the United Arab Emirates (UAE) treated with onasemnogene abeparvovec, particularly in the context of children requiring invasive ventilatory support via tracheostomy., Methods: A retrospective analysis was performed on 60 children who received onasemnogene abeparvovec. All these children received corticosteroids. They were followed up for up to 3 months. Motor function assessments were performed before and after the gene therapy. Comprehensive clinical evaluations, including pulmonary functions, were performed at baseline and the 3-month mark., Results: Forty-three percent were male, and the mean age at the time of infusion was 29.6 months (SD ± 17.2). The mean weight was 10.1 kg (SD 2.6). All children demonstrated marked improvements in motor function within 3 months of gene therapy administration. No adverse effects attributable to corticosteroid therapy were observed. Positive clinical outcomes, including increased ventilator-free intervals, reduced antibiotic dependency, and fewer hospital admissions, were reported among children with invasive ventilation via tracheostomy., Discussion: This study demonstrates the favorable tolerability and promising responses to onasemnogene abeparvovec in invasively ventilated pediatric patients. Early improvements in motor function, as observed within 3 months post-treatment, suggest its potential as a viable therapeutic option for this vulnerable patient population., (© 2024 Wiley Periodicals LLC.)

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease characterized by progressive weakness and atrophy of skeletal muscles. With homozygous survival motor neuron 1 (SMN1) gene mutation, all SMA patients have at least one copy of the SMN2 gene, which provides an opportunity for drug targeting to enhance SMN expression. Current three disease modifying drugs, including nusinersen, onasemnogene abeparvovec, and risdiplam, have demonstrated impressive effectiveness in SMA treatment. Nusinersen is an antisense oligonucleotide targeting SMN2 pre-messenger RNA (mRNA) to modify alternative splicing and is effective in SMA children and adults, administrating via intermittent intrathecal injection. Onasemnogene abeparvovec is an adeno-associated viral vector carrying human SMN1 gene, featuring intravenous injection once in a lifetime for SMA patients less than 2 years of the age. Risdiplam is a small molecule also targeting SMN2 pre-mRNA and is effective in SMA children and adults with administration via oral intake once per day. Patients with SMA should receive these disease modifying therapies as soon as possible to not only stabilize disease progression, but potentially obtain neurological improvement. The development in these therapies has benefited patients with SMA and will potentially provide insight in future drug discovery for other neurodegenerative diseases. Keywords: Adeno-associated viral vector, antisense oligonucleotide, disease modifying therapy, gene therapy, motor neuron disease, spinal muscular atrophy.

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., (© 2024. The Author(s).)

Spinal Muscular Atrophy (SMA) emerges as a prominent genetic neuromuscular disorder primarily caused by variants in the survival motor neuron (SMN) gene. However, it is noteworthy that alternative variants impacting DYNC1H1 have also been linked to a subtype known as spinal muscular atrophy lower extremity predominant (SMA-LED). This observation underscores the complexity of SMA and highlights the necessity for tailored, gene-specific management strategies. Our study elucidates how similar approaches to managing SMA can yield distinct outcomes, emphasizing the imperative for personalized gene-based interventions in effectively addressing these conditions. Two patients were referred for further management due to clinical suspicion of type-3 SMA. The definitive diagnosis was confirmed through the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) technique, as well as whole-exome sequencing (WES). The analysis revealed deletions in exon-7 and 8 of SMN1 in the first patient and a likely pathogenic mutation (NM&#95;001376.5(DYNC1H1):c.1867 T > C (NP&#95;001367.2: p.Phe623Leu)) in DYNC1H1 in the second patient. Both patients presented with lower limb muscle weakness. However, while the first patient exhibited a gradual increase in severity over the years, the second patient displayed no progressive symptoms. The management was adjusted accordingly based on the genetic findings. Our observation underscores the complexity of SMA and highlights the necessity for tailored, gene-specific management strategies. Our study elucidates how similar approaches to managing SMA can yield distinct outcomes, emphasizing the imperative for personalized gene-based interventions in effectively addressing these conditions., (© 2024. Fondazione Società Italiana di Neurologia.)

Objective: To elucidate the clinical characteristics and standard of care (SoC) of spinal muscular atrophy (SMA) patients in Thailand, focusing on primary endpoints: age at death and a composite of death or tracheostomy need., Design: Retrospective observational study., Setting: Seven tertiary centres across Thailand., Patients: Records of 110 patients with genetically confirmed SMA, spanning 2012-2021., Interventions: Historical data review; no active interventions., Main Outcome Measures: Age at death and a composite measure of death or tracheostomy necessity., Results: The cohort included 1 SMA0, 50 SMA1, 40 SMA2 and 19 SMA3 cases. Median ages at the onset and diagnosis of SMA1 were 3 and 6.2 months. Of SMA1 patients, 63% required ventilators, and eight received dimethyltryptamines (DMTs) at a median of 15 months (range 6.4-24.5 months). The median time from onset to DMT was 11 months (range 4.2-20.5 months). Among SMA1 patients, 73% died by the study's end. SMA2 and SMA3 patients' median onset ages were 11 and 24 months, respectively, with diagnosis at 24.8 and 68.7 months. Half of all types received physical therapy., Conclusions: Significant delays in diagnosis and SoC access, including DMTs, were observed, underscoring urgent needs for improved diagnostic and care strategies to enhance SMA patient outcomes in Thailand., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that leads to multiple organ dysfunction. The advent of disease-modifying treatments makes the early diagnosis of SMA critical. Health information literacy is vital for obtaining, understanding, screening, and using health information. Considering the importance of early diagnosis and the challenges in obtaining accurate information on patients with SMA, this cross-sectional study assessed health information literacy among children with SMA and their caregivers in China., Methods: Interviews with the caregivers of 10 patients with SMA were conducted by neurologists specializing in SMA. A questionnaire for evaluating the level of health information literacy was further developed among 145 children with SMA aged 10.0-120.0 months, with the average age of 81.9 months, and their caregivers. Parameters, such as the age at the onset of the first symptom and time from recognition of the first symptom to diagnosis, were examined. Health information literacy was measured using four dimensions: cognition, search, evaluation, and application., Results: The average time from the first symptom to first medical consultation was 4.8 months, and that from the first symptom to diagnosis was 10.8 months. There is a significant delay from the onset of the initial symptoms to a definitive diagnosis. Thirty-five (24%) patients had poor while 26 (18%) had high health information literacy. The overall score for health information literacy was 69; the scores for health information cognition and application were 90 and 84, respectively. The scores for evaluation (61) and search (57) were low. Medical personnel were considered the most professional and credible sources of information. Additionally, search engines and patient organizations were the other two most important sources of health literacy., Conclusion: Patients with SMA and their caregivers had low levels of health information literacy. SMA information visibility and standardization need to be improved. Medical personnel with experience in the diagnosis and treatment of SMA and media should aim to share knowledge and increase the quality of life of those with SMA., (© 2024. The Author(s).)

Spinal muscular atrophy (SMA) is one of the most frequent causes of death in childhood. The disease's molecular basis is deletion or mutations in the SMN1 gene, which produces reduced survival motor neuron protein (SMN) levels. As a result, there is spinal motor neuron degeneration and a large increase in muscle atrophy, in which the ubiquitin-proteasome system (UPS) plays a significant role. In humans, a paralogue of SMN1 , SMN2 encodes the truncated protein SMNΔ7. Structural differences between SMN and SMNΔ7 affect the interaction of the proteins with UPS and decrease the stability of the truncated protein. SMN loss affects the general ubiquitination process by lowering the levels of UBA1, one of the main enzymes in the ubiquitination process. We discuss how SMN loss affects both SMN stability and the general ubiquitination process, and how the proteins involved in ubiquitination could be used as future targets for SMA treatment.

Spinal muscular atrophy is a rare and progressive neuromuscular disease that, without treatment, leads to progressive weakness and often death. A plethora of studies have led to the approval of three high-cost and effective treatments since 2016. These treatments, nusinersen, onasemnogene abeparvovec, and risdiplam, have not been directly compared and have varying challenges in administration. In this review, we discuss the evidence supporting the use of these medications, the process of treatment selection, monitoring after treatment, the limited data comparing treatments, as well as future directions for investigation and therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre-symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination-resistant variant of survival motor neuron (SMN), SMN K186R , has improved therapeutic effects for SMA compared with wild-type SMN (SMN WT )., Methods: A severe SMA mouse model, SMA type 1.5 (Smn -/- ; SMN2 +/+ ; SMN∆7 +/- ) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMN WT and AAV9-SMN K186R . All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle., Results: AAV9-SMN K186R -treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMN WT -treated mice. Lifespan increased by more than 10-fold in AAV9-SMN K186R -treated mice (144.8 ± 26.11 days) as compared with AAV9-SMN WT -treated mice (26.8 ± 1.41 days). AAV9-SMN K186R -treated mice showed an ascending weight pattern, unlike AAV9-SMN WT -treated mice, which only gained weight until P20 up to 5 g on average. Several motor function tests showed the improved therapeutic efficacy of SMN K186R . In the negative geotaxis test, AAV9-SMN K186R -treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMN WT -treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMN K186R -treated mice, unlike AAV9-SMN WT -treated mice that showed clasping phenotype for more than 20 out of 30 s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMN K186R -treated mice compared with AAV9-SMN WT -treated mice without prominent neurotoxicity. AAV9-SMN K186R had fewer liver defects compared with AAV9-SMN WT , as judged by increased proliferation of hepatocytes (P < 0.0001) and insulin-like growth factor-1 production (P < 0.0001). Especially, low-dose AAV9-SMN K186R (nine-fold) also reduced clasping time compared with SMN WT ., Conclusions: SMN K186R will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low-dose treatment of SMA patients with AAV9-SMN K186R can reduce the adverse events of Zolgensma. Collectively, SMN K186R has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

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.

Defect in the SMN1 gene causes spinal muscular atrophy (SMA), which shows loss of motor neurons, muscle weakness and atrophy. While current treatment strategies, including small molecules or viral vectors, have shown promise in improving motor function and survival, achieving a definitive and long-term correction of SMA's endogenous mutations and phenotypes remains highly challenging. We have previously developed a CRISPR-Cas9 based homology-independent targeted integration (HITI) strategy, enabling unidirectional DNA knock-in in both dividing and non-dividing cells in vivo. In this study, we demonstrated its utility by correcting an SMA mutation in mice. When combined with Smn1 cDNA supplementation, it exhibited long-term therapeutic benefits in SMA mice. Our observations may provide new avenues for the long-term and efficient treatment of inherited diseases., (© 2024. The Author(s).)

Background: SMA is a hereditary neuromuscular disease that causes progressive muscle weakness and atrophy. Several studies have shown that the burden of SMA is very high at many levels. Functional assessment tools currently used do not completely address the impact of the disease in patients' life. The objective of this qualitative study was to identify aspects of SMA that are relevant to patients and to design items useful for assessment purposes., Results: Five focus group sessions were run during an annual SMA families meeting in Madrid, Spain. Focus groups were composed by parents of SMA type I children, sitter children type II-III, parents of sitter children type II-III, adult patients, and parents of walker children. Two trained facilitators conducted the focus groups using a semi-structured guideline to cover previously agreed topics based on the input of a Scientific and Patient Advisory Committee. The guideline was adapted for the different groups. According to what was communicated by participants, SMA entails a high burden of disease for both patients and their parents. Burden was perceived in physical, psychological, and social areas. Patient's physical domain was the most relevant for participants, especially for parents of non-ambulant children, followed by limitations of motor scales to capture all changes, parents psychological burden, treatment expectations and patient's psychological burden. Ten domains were the main areas identified as impacted by the disease: mobility and independence, fatigue and fatigability, infections and hospital consultations, scoliosis and contractures, vulnerability, pain, feeding, time spent in care, breathing, and sleep and rest., Conclusions: This study confirms the necessity of evaluating other aspects of the disease that are not assessed in the functional motor scale. Measures of other aspects of the disease, such as pain, fatigue, feeding, should be also considered. A patient-reported outcomes instrument measuring such aspects in a valid and reliable way would be very useful. This study generated a list of new items relevant to be systematically measured in the assessment of the impact of SMA on the patients' everyday life., (© 2024. The Author(s).)

Spinal muscular atrophy is no longer a leading cause of inherited infant death in the United States. Since 2016, three genetic therapies have been approved for the treatment of spinal muscular atrophy. Each therapy has been well studied with robust data for both safety and efficacy. However, there are no head-to-head comparator studies to inform clinical decision making. Thus, treatment selection, timing, and combination therapy is largely up to clinician preference and insurance policies. As the natural history of spinal muscular atrophy continues to change, more data is needed to assist in evidence-based and cost-effective clinical decision making., Competing Interests: Declaration of competing interest MAW has received clinical trial support from and served as an advisory board member for Novartis Gene Therapies., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness, ventilatory failure, and reduced survival. Onasemnogene abeparvovec is the first gene replacement therapy (GT) approved to treat this condition. An observational retrospective study was conducted to assess adverse events and efficacy of GT in SMA patients. Forty-one patients with SMA (58.5% females and 80.1% SMA type 1) were included. The mean age at GT dosing was 18 (±6.4) months. Thirty-six patients (87.8%) were under previous treatment with nusinersen, and 10 (24.4%) continued nusinersen after GT. Mean CHOP-INTEND increased 13 points after 6 months and this finding did not differ between groups according to nusinersen maintenance after GT (p = 0.949). Among SMA type 1 patients, 14 (46.6%) reached the ability to sit alone. Liver transaminases elevation at least two times higher than the upper limit of normal value occurred in 29 (70.7%) patients. Thrombocytopenia occurred in 13 (31.7%) patients, and one presented thrombotic microangiopathy. Older age (>2 years) was associated with more prolonged use of corticosteroids (p = 0.021). GT is effective in SMA patients, combined nusinersen after GT did not appear to add gain in motor function and older age is associated with prolonged corticosteroid use., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: This study aims to systematically collect data on cost-effectiveness analyses that assess technologies to treat type I and II spinal muscular atrophy and evaluate their recommendations., Methods: A structured electronic search was conducted in 4 databases. Additionally, a complementary manual search was conducted. Complete economic studies that evaluated nusinersen, risdiplam, onasemnogene abeparvovec (OA), and the best support therapy (BST) from the health system's perspective were selected. The incremental cost-effectiveness ratios were compared with various thresholds for the analysis. The review was registered a priori in PROSPERO (CRD42022365391)., Results: Twenty studies were included in the analyses. They were all published between 2017 and 2022 and represent the recommendations in 8 countries. Most studies adopted 5, 6, or 10-state Markov models. Some authors took part in multiple studies. Four technologies were evaluated: BST (N = 14), nusinersen (N = 19), risdiplam (N = 5), and OA (N = 9). OA, risdiplam, and nusinersen were considered inefficient compared with the BST. Risdiplam and OA were generally regarded as cost-effective when compared with nusinersen. Because nusinersen is not a cost-effective drug, no recommendation can be derived from this result. Risdiplam and OA were compared in 2 studies that presented opposite results., Conclusions: Nusinersen, risdiplam, and OA are being adopted worldwide as a treatment for spinal muscular atrophy. Despite that, the pharmacoeconomic analyses show that the technologies are not cost-effective compared with the BST. The lack of controlled studies for risdiplam and OA hamper any conclusions about their face-to-face comparison., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: Gene replacement therapy (onasemnogene abeparvovec) is associated with an improvement of the prognosis of children with spinal muscular atrophy, but information on long-term respiratory outcome is scarce. The aim of this study was to report the polysomnography findings and respiratory muscle function of infants with treatment-naive spinal muscular atrophy type 1 and 2 up to 24 months after onasemnogene abeparvovec monotherapy., Methods: A clinical and motor evaluation, respiratory muscle function testing, and polysomnography were performed repeatedly., Results: Fifteen spinal muscular atrophy patients (1 presymptomatic, 7 type 1b, 6 type 1c, and 1 type 2) were included at a median age of 8.6 months (range 3.8-12.6) and followed for 24 months. The thoracic over head circumference ratio was close to normal at baseline (median 1.00 (range 0.90-1.05)) and increased significantly over time. All polysomnography and nocturnal gas exchange parameters were within normal ranges at baseline (median apnea-hypopnea index 2.5 events/hour (range 0.4-5.3)) and follow-up. The inspiratory muscle strength was normal at baseline but tended to slightly decrease over time and the expiratory muscle strength was low at any time especially for patients with recurrent respiratory infections (median (range) at baseline in cmH 2 O: crying esophageal pressure 54 (30-110), crying transdiaphragmatic pressure 65 (35-107), gastric pressure during maximal cough 26 (10-130), esophageal pressure during maximal cough 61 (38-150)). Only 3 patients required noninvasive ventilation., Conclusion: A continuous respiratory monitoring of spinal muscular atrophy patients during the first years of life following onasemnogene abeparvovec monotherapy seems recommended despite the normality of polysomnography parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study presents the findings of a newborn screening (NBS) pilot project for 5q-spinal muscular atrophy (5q-SMA) in multiple regions across Russia for during the year 2022. The aim was to assess the feasibility and reproducibility of NBS for SMA5q in diverse populations and estimate the real prevalence of 5q-SMA in Russia as well as the distribution of patients with different number of SMN2 copies., Methods: The pilot project of NBS here was based on data, involving the analysis of 202,908 newborns. SMA screening assay was performed using a commercially available real-time polymerase chain reaction kit, the Eonis SCID-SMA., Results: In one year, 202,908 newborns were screened, identifying 26 infants with homozygous deletion of SMN1 exon 7, yielding an estimated 5q-SMA incidence of 1:7804 newborns. It was found that 38.46% had two SMN2 copies, 42.31% had three copies, 15.38% had four copies, and 3.85% had five copies of SMN2. Immediate treatment was proposed for patients with two or three SMN2 copies. Infants with four or more SMN2 copies warranted further investigation on management and treatment. Short-term monitoring after gene therapy showed motor function improvements. Delays in treatment initiation were observed, including the testing for adeno-associated virus 9 antibodies and nonmedical factors., Conclusions: The study emphasizes the need for a standardized algorithm for early diagnosis and management through NBS to benefit affected families. Overall, the NBS program for 5q-SMA in Russia demonstrated the potential to improve outcomes and transform SMA from a devastating disease to a chronic condition with evolving medical requirements., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrey V. Marakhonov reports equipment, drugs, or supplies was provided by Novartis Pharma LLC. Andrey V. Marakhonov reports equipment, drugs, or supplies was provided by Skopinfarm LLC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Spinal muscular atrophy (SMA) is a rare neurodegenerative neuromuscular disorder with a wide phenotypic spectrum of severity. SMA was previously life limiting for patients with the most severe phenotype and resulted in progressive disability for those with less severe phenotypes. This has changed dramatically in the past few years with the approvals of three disease-modifying treatments. We review the evidence supporting the use of currently approved SMA treatments (nusinersen, onasemnogene abeparvovec, and risdiplam), focusing on mechanisms of action, side effect profiles, published clinical trial data, health economics, and pending questions. Whilst there is robust data from clinical trials of efficacy and side effect profile for individual drugs in select SMA populations, there are no comparative head-to-head clinical trials. This presents a challenge for clinicians who need to make recommendations on the best treatment option for an individual patient and we hope to provide a pragmatic approach for clinicians across each SMA profile based on current evidence., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Spinal muscular atrophy (SMA) is one of the most common genetic diseases and was, until recently, a leading genetic cause of infant mortality. Three disease-modifying treatments have dramatically changed the disease trajectories and outcome for severely affected infants (SMA type 1), especially when initiated in the presymptomatic phase. One of these treatments is the adeno-associated viral vector 9 (AAV9) based gene therapy onasemnogene abeparvovec (Zolgensma®), which is delivered systemically and has been approved by the European Medicine Agency for SMA patients with up to three copies of the SMN2 gene or with the clinical presentation of SMA type 1. While this broad indication provides flexibility in patient selection, it also raises concerns about the risk-benefit ratio for patients with limited or no evidence supporting treatment. In 2020, we convened a European neuromuscular expert working group to support the rational use of onasemnogene abeparvovec, employing a modified Delphi methodology. After three years, we have assembled a similar yet larger group of European experts who assessed the emerging evidence of onasemnogene abeparvovec's role in treating older and heavier SMA patients, integrating insights from recent clinical trials and real-world evidence. This effort resulted in 12 consensus statements, with strong consensus achieved on 9 and consensus on the remaining 3, reflecting the evolving role of onasemnogene abeparvovec in treating SMA., Competing Interests: Declaration of competing interest JK has received honoraria for participating in advisory boards and/or symposia by Biogen, Novartis, Roche, and Scholar Rock. His institution receives funding for clinical research from Biohaven, Biogen, Novartis, Roche, and Scholar Rock. GB has received honoraria for participating in advisory boards and/or symposia by Biogen, Novartis, PTC, Pfizer, Roche, and Santhera, and research support from PTC. NB's institution has received funding from Biogen for equipment for the physiotherapy department and for a cough assist machine for patients. LDW has received speaker and consulting fees from Novartis Gene Therapies, Biogen, and Roche, has worked as a principal investigator of SMA studies sponsored by Novartis Gene Therapies, Roche, Scholar Rock, and Biohaven, and has received research grants from Novartis Gene Therapies, Roche, and Biogen. AFV has received honoraria for participating in advisory boards and/or symposia by Biogen, Novartis, and Roche. Her institution has received funding for a SMA registry from Biogen and for a pilot project of newborn screening for SMA from Novartis, Biogen, and Roche. JH has received honoraria for participating to advisory boards and/or symposia by Biogen, Novartis, and Roche. Her institution receives funding for clinical research from Biogen and Roche. TM has received honoraria for participating in meetings, formations and advisory boards from Biogen, Novartis, Roche, PTC, Astellas Gene Therapies, and Pfizer. AK has received honoraria for participating in advisory boards and/or symposia by Biogen, Novartis, Roche. She serves as clinical lead of the Swiss-Reg NMD, that receives funding for clinical research from Biogen, Novartis, and Roche. AKP has received honoraria for advisory boards and for speaking at educational events from Biogen, Novartis, PTC, and Roche; support for congress participation from Biogen, Roche, and Novartis; institutional grant support from Biogen, and support from Roche as principal investigator for SMA studies. EM has received honoraria for participating to advisory boards and/or symposia by Biogen, Novartis, Roche, and Scholar Rock. His institution receives funding for clinical research from Biogen, Novartis, Roche, and Scholar Rock. SQR has received honoraria for participating in advisory boards and giving lectures, as well as travel expenses from Novartis, Biogen, and Roche. TS has received honoraria for lectures or consultancy from Biogen, Novartis, PTC Therapeutics, Sarepta Therapeutics, Roche, Hansa Biopharma, and Sanofi Genzyme. EFT has received support to conduct clinical trials and research on SMA from Biogen and Roche, and has served as consultant to Novartis, Biogen, Biologix, Cytokinetics, Argenx, and Roche. WLP is member of the scientific advisory board of SMA Europe, his employer has received a fee-for-service for scientific advisory boards and participation in educational activities by Novartis, Biogen, and Roche. He was principal investigator for SMA trials sponsored by Novartis, Biogen, and Roche. SW has served as unpaid member on advisory boards for Biogen, Roche, and Novartis. DZ has received honoraria for participating in advisory boards and giving lectures, as well as travel and research grants from Novartis, Biogen, and Roche. AZ has received honoraria for participating in advisory boards and/or symposia by Biogen, Novartis, and Roche. His institution receives funding for clinical research from Biogen. FM has received honoraria for participating in advisory boards and/or symposia by Biogen, Novartis, and Roche. His institution receives funding for clinical trials and the UK SMA REACH registry from Biogen, Novartis, and Roche. LS has received honoraria for participating in advisory boards and/or symposia by Biogen, Novartis, Roche, Scholar Rock, Zentech, Illumina, and BioHaven. His institution receives funding for clinical research and educative events from Biogen, Novartis, Scholar Rock, BioHaven, Zentech, and Roche., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Spinal muscular atrophy (SMA) is a neuromuscular disease, causing progressive muscle weakness due to loss of lower motoneurons. Since 2017, three therapies, two modifying gene transcription and one adding the defective gene, have been approved with comparable efficacy on motor outcome. Data on cognitive outcomes of treated SMA type 1 patients is limited. The aim of this study was to evaluate cognitive function in symptomatic and presymptomatic SMA type 1 patients with two or three SMN2 copies who received SMN-modifying or gene-addition therapy in the first year of life., Methods: Cognitive testing was performed in 20 patients, including 19 symptomatic SMA type 1 patients with up to three SMN2 copies and 1 pre-symptomatically treated patient. Children were tested using Bayley Scales of Infant Development (BSID-III) at the age of 2 or 3 years or the Wechsler Preschool and Primary Scale of Intelligence (WPSII-IV) at the of age of 5 years., Results: 11/20 patients showed subnormal cognitive development. Boys had significantly lower cognitive scores. Patients requiring assisted ventilation or feeding support were more likely to have cognitive deficits. Achieving more motor milestones was associated with a better cognitive outcome., Conclusion: Treated patients with SMA type 1 have heterogeneous cognitive function with 55 % of patients showing deficits. Risk factors for cognitive impairment in our cohort were male gender and need for assisted ventilation or feeding support. Therefore, cognitive assessment should be included in the standard of care to allow early identification of deficits and potential therapeutic interventions., Competing Interests: Declaration of competing interest JJ, AZ and AH received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, Roche, PTC, Pfizer and Sarepta Therapeutics. DW received compensation for advisory boards and speaker honoraria from Roche. JDe received speaker honoraria from Biogen and Roche. CW received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, BiogenRS and Roche.MvH received compensation for advisory boards and speaker honoraria from Pfizer, Roche and Novartis. PS, AP, MA, PW, CS, UE, JS, BC, IL, RS, LR have nothing to declare., (© 2024 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

In recent years, significant progress has been made in 5q Spinal Muscular Atrophy therapeutics, emphasizing the importance of early diagnosis and intervention for better clinical outcomes. Characterized by spinal cord motor neuron degeneration, 5q-SMA leads to muscle weakness, swallowing difficulties, respiratory insufficiency, and skeletal deformities. Recognizing the pre-symptomatic phases supported by screening and confirmatory genetic tests is crucial for early diagnosis. This work addresses key considerations in implementing 5q-SMA screening within the Brazilian National Newborn Screening Program and explores Brazil's unique challenges and opportunities, including genetic tests, time-to-patient referral to specialized centers, program follow-up, and treatment algorithms. We aim to guide healthcare professionals and policymakers, facilitating global discussions, including Latin American countries, and knowledge-sharing on this critical subject to improve the care for newborns identified with 5q SMA.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 ( SMN1 ) gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept at binding to target RNA to prevent translation or promote alternative splicing. Nusinersen is an FDA-approved ASO for the treatment of SMA. It effectively promotes alternative splicing in pre-mRNA transcribed from the SMN2 gene, an analog of the SMN1 gene, to produce a greater amount of full-length SMN protein, to compensate for the loss of functional protein translated from SMN1 . Despite its efficacy in ameliorating SMA symptoms, the cellular uptake of these ASOs is suboptimal, and their inability to penetrate the CNS necessitates invasive lumbar punctures. Cell-penetrating peptides (CPPs), which can be conjugated to ASOs, represent a promising approach to improve the efficiency of these treatments for SMA and have the potential to transverse the blood-brain barrier to circumvent the need for intrusive intrathecal injections and their associated adverse effects. This review provides a comprehensive analysis of ASO therapies, their application for the treatment of SMA, and the encouraging potential of CPPs as delivery systems to improve ASO uptake and overall efficiency.

Purpose of Review: Genetic therapies made a significant impact to the clinical course of patients with spinal muscular atrophy and Duchenne muscular dystrophy. Clinicians and therapists who care for these patients want to know the changes in respiratory sequelae and implications for clinical care for treated patients., Recent Findings: Different genetic therapy approaches have been developed to replace the deficient protein product in spinal muscular atrophy and Duchenne muscular dystrophy. The natural history of these conditions needed to be understood in order to design clinical trials. Respiratory parameters were not the primary outcome measures for the clinical trials. The impact of these therapies is described in subsequent clinical trial reports or real-world data., Summary: Genetic therapies are able to stabilize or improve the respiratory sequelae in patients with spinal muscular atrophy and Duchenne muscular dystrophy. Standardized reporting of these outcomes is needed to help inform the future revisions of clinical standards of care and practice guidelines., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

5q-spinal muscular atrophy (SMA) is a neuromuscular disorder (NMD) that has become one of the first 5% treatable rare diseases. The efficacy of new SMA therapies is creating a dynamic SMA patient landscape, where disease progression and scoliosis development play a central role, however, remain difficult to anticipate. New approaches to anticipate disease progression and associated sequelae will be needed to continuously provide these patients the best standard of care. Here we developed an interpretable machine learning (ML) model that can function as an assistive tool in the anticipation of SMA-associated scoliosis based on disease progression markers. We collected longitudinal data from 86 genetically confirmed SMA patients. We selected six features routinely assessed over time to train a random forest classifier. The model achieved a mean accuracy of 0.77 (SD 0.2) and an average ROC AUC of 0.85 (SD 0.17). For class 1 'scoliosis' the average precision was 0.84 (SD 0.11), recall 0.89 (SD 0.22), F1-score of 0.85 (SD 0.17), respectively. Our trained model could predict scoliosis using selected disease progression markers and was consistent with the radiological measurements. During post validation, the model could predict scoliosis in patients who were unseen during training. We also demonstrate that rare disease data sets can be wrangled to build predictive ML models. Interpretable ML models can function as assistive tools in a changing disease landscape and have the potential to democratize expertise that is otherwise clustered at specialized centers., (© 2024. The Author(s).)

Background: Spinal muscular atrophy is a progressive neuromuscular disorder and among the most frequent genetic causes of infant mortality. While recent advancements in gene therapy provide the potential to ameliorate the disease severity, there is currently no modality in clinical use to visualize dynamic pathophysiological changes in disease progression and regression after therapy., Methods: In this prospective diagnostic clinical study, ten pediatric patients with spinal muscular atrophy and ten age- and sex-matched controls have been examined with three-dimensional optoacoustic imaging and clinical standard examinations to compare the spectral profile of muscle tissue and correlate it with motor function (ClinicalTrials.gov: NCT04115475)., Findings: We observed a reduced optoacoustic signal in muscle tissue of pediatric patients with spinal muscular atrophy. The reduction in signal intensity correlated with disease severity as assessed by grayscale ultrasound and standard motor function tests. In a cohort of patients who received disease-modifying therapy prior to the study, the optoacoustic signal intensity was similar to healthy controls., Conclusions: This translational study provides early evidence that three-dimensional optoacoustic imaging could have clinical implications in monitoring disease activity in spinal muscular atrophy. By visualizing and quantifying molecular changes in muscle tissue, disease progression and effects of gene therapy can be assessed in real time., Funding: The project was funded by ELAN Fonds (P055) at the University Hospital of the Friedrich-Alexander-Universität (FAU) Erlangen-Nurnberg to A.P.R., Competing Interests: Declaration of interests M.J.W., F.K., and A.P.R. are shared patent holders with iThera Medical GmbH (Munich, Germany) on the OAI system/software described in the study. F.K. and U.R. are members of the clinical advisory board of iThera Medical GmbH (Munich, Germany)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Mandatory newborn screening (NBS) for spinal muscular atrophy (SMA) was implemented for the first time in Italy at the end of 2021, allowing the identification and treatment of patients at an asymptomatic stage., Methods: DNA samples extracted from dried blood spot (DBS) from newborns in Apulia region were analysed for SMA screening by using a real-time PCR-based assay. Infants harbouring homozygous deletion of SMN1 exon 7 confirmed by diagnostic molecular tests underwent clinical and neurophysiological assessment and received a timely treatment., Results: Over the first 20 months since regional NBS introduction, four out of 42,492 (0.009%) screened children were found to carry a homozygous deletion in the exon 7 of SMN1 gene, with an annual incidence of 1:10,623. No false negatives were present. Median age at diagnosis was 7 days and median age at treatment was 20.5 days. Three of them had two copies of SMN2 and received gene therapy, while the one with three SMN2 copies was treated with nusinersen. All but one were asymptomatic at birth, showed no clinical signs of disease after a maximum follow-up of 16 months and reached motor milestones appropriate with their age. The minimum interval between diagnosis and the treatment initiation was 9 days., Interpretation: The timely administration of disease-modifying therapies prevented presymptomatic subjects to develop disease symptoms. Mandatory NBS for SMA should be implemented on a national scale., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. With the emergence of disease-modifying therapies, the prognosis of SMA has significantly improved, drawing increased attention to the importance of home rehabilitation and nursing management. Long-term, standardized home rehabilitation and nursing can delay the progression of SMA, enhance the psychological well-being, and improve the quality of life of both patients and caregivers. This article provides an overview of the goals of home rehabilitation, basic functional training methods, respiratory management, and nutritional management for SMA patients, as well as psychological health issues, emphasizing the significance of obtaining appropriate home rehabilitation and support during the care process.

Background: Spinal Muscular Atrophy (SMA) is an autosomal-recessive neuromuscular disease affecting children. It is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene resulting in lower motor neuron (MN) degeneration followed by motor impairment, progressive skeletal muscle paralysis and respiratory failure. In addition to the already existing therapies, a possible combinatorial strategy could be represented by the use of adipose-derived mesenchymal stem cells (ASCs) that can be obtained easily and in large amounts from adipose tissue. Their efficacy seems to be correlated to their paracrine activity and the production of soluble factors released through extracellular vesicles (EVs). EVs are important mediators of intercellular communication with a diameter between 30 and 100 nm. Their use in other neurodegenerative disorders showed a neuroprotective effect thanks to the release of their content, especially proteins, miRNAs and mRNAs., Methods: In this study, we evaluated the effect of EVs isolated from ASCs (ASC-EVs) in the SMNΔ7 mice, a severe SMA model. With this purpose, we performed two administrations of ASC-EVs (0.5 µg) in SMA pups via intracerebroventricular injections at post-natal day 3 (P3) and P6. We then assessed the treatment efficacy by behavioural test from P2 to P10 and histological analyses at P10., Results: The results showed positive effects of ASC-EVs on the disease progression, with improved motor performance and a significant delay in spinal MN degeneration of treated animals. ASC-EVs could also reduce the apoptotic activation (cleaved Caspase-3) and modulate the neuroinflammation with an observed decreased glial activation in lumbar spinal cord, while at peripheral level ASC-EVs could only partially limit the muscular atrophy and fiber denervation., Conclusions: Our results could encourage the use of ASC-EVs as a therapeutic combinatorial treatment for SMA, bypassing the controversial use of stem cells., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Physiological regulation of transgene expression is a major challenge in gene therapy. Onasemnogene abeparvovec (Zolgensma ® ) is an approved adeno-associated virus (AAV) vector gene therapy for infants with spinal muscular atrophy (SMA), however, adverse events have been observed in both animals and patients following treatment. The construct contains a native human survival motor neuron 1 (hSMN1) transgene driven by a strong, cytomegalovirus enhancer/chicken β-actin (CMVen/CB) promoter providing high, ubiquitous tissue expression of SMN. We developed a second-generation AAV9 gene therapy expressing a codon-optimized hSMN1 transgene driven by a promoter derived from the native hSMN1 gene. This vector restored SMN expression close to physiological levels in the central nervous system and major systemic organs of a severe SMA mouse model. In a head-to-head comparison between the second-generation vector and a benchmark vector, identical in design to onasemnogene abeparvovec, the 2nd-generation vector showed better safety and improved efficacy in SMA mouse model., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: This single-arm prospective cohort study aimed to evaluate the feasibility and utility of in-home body weight support harness system (BWSS) use in children treated for spinal muscular atrophy (SMA)., Methods: Individuals with 2 or 3 copies of SMN2 who received pharmacotherapeutic treatment, had head control, and weight <50lbs were enrolled. Families were provided a BWSS and documented use. Motor outcome assessments were completed at baseline, month 3 and month 6. Families provided feedback in an end of study survey., Results: All 32 participants (2.9 (SD 1.9) yrs), improved or remained stable on all outcomes. Average reported frequency of use was 4.1(2.3) hrs/week. Controlling for other covariates, frequency of use explained over 70% of the variability in change scores. Family feedback was overwhelmingly positive., Conclusion: Use of in-home BWSS is a safe, feasible and useful option to increase exercise dosage after treatment in SMA and may help optimize motor abilities., Trial Registration: Study registered with: Clinicaltrials.gov Clinicaltrials.gov identifier: NCT05715749., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Iammarino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The aims of the study are to present noninvasive respiratory management outcomes using continuous noninvasive ventilatory support and mechanical in-exsufflation from infancy for spinal muscular atrophy type 1 and to consider bearing on new medical therapies., Design: Noninvasive ventilatory support was begun for consecutively referred symptomatic infants with spinal muscular atrophy type 1 from 1 to 10 mos of age. Intercurrent episodes of respiratory failure were managed by intubation then extubation to continuous noninvasive ventilatory support and mechanical in-exsufflation despite failing ventilator weaning and extubation attempts. Intubations, tracheotomies, and survival were monitored., Results: Of 153 patients with spinal muscular atrophy 1 consecutively referred since 1995, 37 became continuous noninvasive ventilatory support dependent, almost half before 10 yrs of age. Of the 37, 18 required continuous noninvasive ventilatory support for a mean 18.6 ± 3.3 yrs to a mean 25.3 (range, 18-30) yrs of age, dependent from as young as 4 mos of age with 0 to 40 ml of vital capacity. One of the 18 died from COVID-19 acute respiratory distress syndrome at age 24 after 23 yrs of continuous noninvasive ventilatory support. Extubation success rate of 85% per attempt (150/176) resulted in only one undergoing tracheotomy., Conclusions: Medical treatments begun during the first 6 wks of age convert spinal muscular atrophy 1 into spinal muscular atrophy 2 or 3 but cough flows remain inadequate to avoid many pneumonias that, once resolved by a treatment paradigm of extubation to continuous noninvasive ventilatory support and mechanical in-exsufflation, eliminates need to resort to tracheotomies., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Newborn screening (NBS) identifies infants with severe, early-onset diseases, enabling early diagnosis and treatment. In Canada, decisions regarding disease inclusion in NBS programs occur at the provincial level, which leads to variability in patient care. We aimed to determine whether important differences exist in NBS programs across provinces and territories. Given that spinal muscular atrophy (SMA) is the most recent disease added to NBS programs, we hypothesized that its inclusion would show interprovincial variability and be more likely in provinces already screening for a greater number of diseases., Methods: We conducted a cross-sectional survey of all NBS labs in Canada to understand: 1) what conditions were included in their program; 2) what genetic-based testing was performed and; 3) if SMA was included., Results: All NBS programs ( N = 8) responded to this survey by June 2022. There was a 2.5-fold difference in the number of conditions screened ( N = 14 vs N = 36) and a 9-fold difference in the number of conditions screened by gene-based testing. Only nine conditions were common to all provincial NBS programs. NBS for SMA was performed in four provinces at the time of our survey, with BC recently becoming the fifth province to add SMA to their NBS on October 1, 2022. Currently, 72% of Canadian newborns are screened for SMA at birth., Conclusion: Although healthcare in Canada is universal, its decentralization gives rise to regional differences in NBS programs which creates inequity in the treatment, care, and potential outcomes of affected children across provincial jurisdictions.

The underlying cause of Spinal Muscular Atrophy (SMA) is in the reduction of survival motor neuron (SMN) protein levels due to mutations in the SMN1 gene. The specific effects of SMN protein loss and the resulting pathological alterations are not fully understood. Given the crucial roles of the SMN protein in snRNP biogenesis and its interactions with ribosomes and translation-related proteins and mRNAs, a decrease in SMN levels below a specific threshold in SMA is expected to affect translational control of gene expression. This review covers both direct and indirect SMN interactions across various translation-related cellular compartments and processes, spanning from ribosome biogenesis to local translation and beyond. Additionally, it aims to outline deficiencies and alterations in translation observed in SMA models and patients, while also discussing the implications of the relationship between SMN protein and the translation machinery within the context of current and future therapies., (© 2024 The Author(s).)

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is caused by the loss of the SMN1 gene and low SMN protein levels. Current SMA therapies work by increasing SMN protein in the body. Although SMA is regarded as a motor neuron disorder, growing evidence shows that several peripheral organs contribute to SMA pathology. A gene therapy treatment, onasemnogene abeparvovec, is being explored in clinical trials via both systemic and central nervous system (CNS) specific delivery, but the ideal route of delivery as well as the long-term effectiveness is unclear. To investigate the impact of gene therapy long term, we assessed SMA mice at 6 months after treatment of either intravenous (IV) or intracerebroventricular (ICV) delivery of scAAV9-cba-SMN. Interestingly, we observed that SMN protein levels were restored in the peripheral tissues but not in the spinal cord at 6 months of age. However, ICV injections provided better motor neuron and motor function protection than IV injection, while IV-injected mice demonstrated better protection of neuromuscular junctions and muscle fiber size. Surprisingly, both delivery routes resulted in an equal rescue on survival, weight, and liver and pancreatic defects. These results demonstrate that continued peripheral AAV9-SMN gene therapy is beneficial for disease improvement even in the absence of SMN restoration in the spinal cord., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by degeneration of lower motor neurons (LMNs), causing muscle weakness, atrophy, and paralysis. SMA is caused by mutations in the Survival Motor Neuron 1 ( SMN1 ) gene and can be classified into four subgroups, depending on its severity. Even though the genetic component of SMA is well known, the precise mechanisms underlying its pathophysiology remain elusive. Thus far, there are three FDA-approved drugs for treating SMA. While these treatments have shown promising results, their costs are extremely high and unaffordable for most patients. Thus, more efforts are needed in order to identify novel therapeutic targets. In this context, zebrafish ( Danio rerio ) stands out as an ideal animal model for investigating neurodegenerative diseases like SMA. Its well-defined motor neuron circuits and straightforward neuromuscular structure offer distinct advantages. The zebrafish's suitability arises from its low-cost genetic manipulation and optical transparency exhibited during larval stages, which facilitates in vivo microscopy. This review explores advancements in SMA research over the past two decades, beginning with the creation of the first zebrafish model. Our review focuses on the findings using different SMA zebrafish models generated to date, including potential therapeutic targets such as U snRNPs, Etv5b, PLS3, CORO1C, Pgrn, Cpg15, Uba1, Necdin, and Pgk1, among others. Lastly, we conclude our review by emphasizing the future perspectives in the field, namely exploiting zebrafish capacity for high-throughput screening. Zebrafish, with its unique attributes, proves to be an ideal model for studying motor neuron diseases and unraveling the complexity of neuromuscular defects.

Competing Interests: MAF and DSK have received honoraria for scientific advisory boards and presentations at educational meetings from Novartis Gene Therapies, Biogen, and Roche. MAF is the recipient of a National Health and Medical Research Council of Australia Investigator (grant APP1194940).

Spinal muscular atrophy (SMA) is caused by mutations in SMN1. SMN2 is a paralogous gene with a C•G-to-T•A transition in exon 7, which causes this exon to be skipped in most SMN2 transcripts, and results in low levels of the protein survival motor neuron (SMN). Here we show, in fibroblasts derived from patients with SMA and in a mouse model of SMA that, irrespective of the mutations in SMN1, adenosine base editors can be optimized to target the SMN2 exon-7 mutation or nearby regulatory elements to restore the normal expression of SMN. After optimizing and testing more than 100 guide RNAs and base editors, and leveraging Cas9 variants with high editing fidelity that are tolerant of different protospacer-adjacent motifs, we achieved the reversion of the exon-7 mutation via an A•T-to-G•C edit in up to 99% of fibroblasts, with concomitant increases in the levels of the SMN2 exon-7 transcript and of SMN. Targeting the SMN2 exon-7 mutation via base editing or other CRISPR-based methods may provide long-lasting outcomes to patients with SMA., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)