Therapeutic advances in spinal muscular atrophy: a review of clinical, safety, and economic considerations
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.