Aug 2026· Journal of International Child Neurology Association· 0 citations· 45 references
TL;DR
An overview of the history of SMA is provided, highlighting its evolving classification and the genetic basis underlying its clinical variability, and the development and clinical trial data of the three Food and Drug Administration- and European Medicines Agency-approved therapies: nusinersen, onasemnogene abeparvovec, and risdiplam are outlined.
Abstract
In recent years, pediatric neurology has witnessed significant advances in the development of disease-modifying therapies, with spinal muscular atrophy (SMA) emerging as one of the most impactful conditions in this field. This article provides a comprehensive overview of the history of SMA, highlighting its evolving classification and the genetic basis underlying its clinical variability. Moreover, it outlines the development and clinical trial data of the three Food and Drug Administration- and European Medicines Agency-approved therapies: nusinersen, onasemnogene abeparvovec, and risdiplam. These treatments have shifted SMA from a fatal diagnosis to a treatable condition, especially when initiated presymptomatically. Finally, the article discusses future directions, including combination therapies, novel pharmacological targets, biomarker development, and the need for ethical and equitable access to treatment worldwide. With ongoing research, SMA continues to serve as a paradigm for progress in neuromuscular medicine and the potential of personalized, gene-targeted therapies.
Recently instituted world-wide newborn screening programs for spinal muscular atrophy (SMA) permit identification of at-risk individuals prior to clinical presentation of the disease. Early intervention with one or more of the available disease-modifying therapies has dramatically changed the clinical course for individuals affected by SMA. These therapies that yield such impressive results in pediatric SMA populations frequently provide more muted responses in adolescent and adult individuals with SMA. Many treated individuals experience plateau effects and pursue combination treatments to hopefully boost functional outcomes. In addition, individuals with SMA are also now living longer and experience altered disease phenotypes and challenges, such as severe and progressive scoliosis, bulbar issues and neurocognitive issues. Thus, although recent years are marked by significant advances in our understanding of disease pathogenesis and in the development and implementation of therapies to treat SMA, there are still ongoing challenges and unmet needs that will require new and innovate solutions to more fully address the needs of individuals with SMA. In this review, we provide an overview of SMA disease, including a discussion of the many diverse primary defects that have been documented in many different tissues of individuals with SMA and models of the disease, and provide an overview of the therapeutics currently available and in development to treat SMA.
Charlotte A. René, Robin J. Parks· Therapeutic Advances in Neur...· 0 citations
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by insufficient levels of survival motor neuron (SMN) protein due to mutations in the
SMN1
gene, leading to progressive degeneration of lower motor neurons in the spinal cord. In this comprehensive narrative review, we extensively summarise the clinical efficacy and real-world effectiveness of approved disease-modifying therapies, including nusinersen, onasemnogene abeparvovec, and risdiplam, underscoring significant improvements in survival, motor milestones, and quality of life, particularly with early treatment initiation. Safety profiles and post-marketing surveillance data are examined, revealing manageable adverse events aligned with clinical trial findings. Economic evaluations are also discussed, illustrating the high costs associated with SMA therapies and the challenges in cost-effectiveness under conventional thresholds, while noting the potential advantages of some treatments in specific contexts. In the review, we explore the promising pipeline of investigational therapies targeting both SMN-dependent and independent mechanisms such as muscle enhancers and neuromuscular junction modifiers, reflecting evolving multidimensional treatment strategies. Future directions emphasise early diagnosis through newborn screening, optimised treatment regimens, combination therapies, biomarker-guided personalised approaches, and comprehensive multidisciplinary care. Lessons from SMA provide a valuable framework for rare-disease management, highlighting the importance of mechanistic insights, early intervention, collaborative research, patient advocacy, and innovative health technology assessment to improve access and outcomes. Our aim is for the review to guide clinical practice, research priorities, and health policy by synthesising contemporary advances and challenges in SMA treatment and care.
Andrej Belančić, Elvira Meni Maria Gkrinia, Yun-Wah Lam et al.· Frontiers in Pharmacology· 0 citations
Spinal Muscular Atrophy (SMA) is a rare and debilitating neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord, leading to muscle weakness, respiratory failure, and premature mortality. The pathogenesis of SMA is highly complex and the investigation of downstream pathways and specific cellular mechanisms is still ongoing. In recent years, three FDA-approved disease-modifying therapies, nusinersen, risdiplam, and onasemnogene abeparvovec, have improved the quality of life for patients with SMA and have eased the management of associated symptoms. However, unmet needs remain as comorbidities become increasingly apparent in the era of disease-modifying therapies. Despite the remarkable progress achieved over the past decade, continued research is essential to further improve the quality of life, clinical outcomes, and standard of care for individuals living with SMA.
Madison M. Sexton, Emma W. Crow, Cong-Yue Peng· Frontiers in Molecular Medic...· 0 citations
Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disorder characterized by progressive degeneration of lower motor neurons, leading to muscle weakness and atrophy predominantly manifesting in childhood. The disease is caused by homozygous deletion or loss-of-function mutations in the survival motor neuron 1 (SMN1) gene, with the nearly identical SMN2 gene acting as a critical modifier of disease severity. Since the initial clinical descriptions in 1891 and the identification of the causative gene in 1995, the field has witnessed transformative therapeutic progress. The FDA approval of nusinersen, an antisense oligonucleotide targeting SMN2 splicing, in 2016 marked the first disease-modifying therapy, followed by the gene replacement therapy onasemnogene abeparvovec in 2019 and the orally administered small-molecule splicing modifier risdiplam in 2020. These SMN-targeted therapies have substantially improved survival and motor outcomes, particularly when administered presymptomatically as enabled by increasingly widespread newborn screening programs. However, a significant proportion of patients, especially those with later-onset disease and adults, show limited responses, and existing therapies cannot reverse established neurodegeneration or muscle pathology. In this review, we trace the history of SMA research and therapy development, critically compare the three approved treatments, and discuss key unresolved challenges including treatment-switching criteria, management of late-diagnosed patients, and the emerging role of biomarkers such as neurofilament light chain and compound muscle action potential. We further explore non-SMN therapeutic strategies targeting PTEN, plastin 3, neurocalcin delta, myostatin, and neuroinflammation, and examine the rationale for combination approaches that integrate SMN restoration with muscle- and neuro-protective agents. Finally, we address future directions encompassing precision medicine, next-generation gene editing, and biomarker-driven trial design. While SMA has been transformed from a fatal childhood disorder to a treatable condition, a definitive cure for all patients remains the goal of ongoing and future research.
Jiayi Liu, Yang Liu, An-Nie Yuan et al.· Frontiers in Human Neuroscie...· 0 citations
Genomics is rapidly becoming an essential component of day-to-day pediatric neurology practice rather than a niche research discipline, and preparing the workforce through initiatives such as the Child Neurology Society Genetics Curriculum and partnering with patient advocacy organizations will be critical to ensuring equitable implementation of genomic medicine and precision therapeutics.
Kuntal Sen, Andrea L. Gropman, Cansu Ensert Cihan et al.· Current opinion in pediatric...· 0 citations
Charcot-Marie-Tooth disease (CMT) comprises a genetically and clinically heterogeneous group of inherited peripheral neuropathies and remains a major indication for gene-based diagnostic evaluations in neuromuscular practice. Although supportive management has traditionally been applied across most subtypes, there has recently been a notable expansion of disease-modifying approaches due to advances in molecular diagnostics and accumulating preclinical and early clinical evidence. Improved genetic classification, including the recognition of metabolically defined and potentially treatable subtypes, has increased diagnostic precision and the development of subtype-specific therapeutics, with an increasing emphasis on mechanism-based stratification. This review summarizes recent progress in inherited neuropathies from a clinical perspective. We describe ongoing developments in clinical interventions, including combination pharmacotherapy for Charcot-Marie-Tooth disease type 1A (CMT1A), pathway-targeted therapy for CMT associated with sorbitol dehydrogenase deficiency and related metabolic neuropathies, and early biological and gene-based approaches that are being applied in selected subtypes. We also review the evolving preclinical approaches aimed at normalizing the peripheral myelin protein 22 dosage in CMT1A and gene-replacement and other precision therapies for loss-of-function and dominant-negative conditions. Because many subtypes of CMT progress slowly and conventional clinical scales have low sensitivity, we further discuss recent advances in the approaches used in clinical trials, including the refinement of clinical outcome assessments and the identification of candidate biomarkers such as the magnetic resonance imaging-based muscle fat fraction and the circulating level of neurofilament light chain. Collectively these developments are making subtype-specific therapeutic approaches increasingly feasible, although continued progress will depend on aligning disease biology, therapeutic approaches, and outcome measurements.
Jin-Mo Park· Annals of Clinical Neurophys...· 0 citations
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