A systematic review of advances in the knowledge and therapeutics of spinal myotropic atrophy from three-dimensional stem cell derived spinal organoid model

IntroductionSpinal Muscular Atrophy (SMA) is a fatal neurodegenerative disorder with limited therapies and incomplete mechanistic understanding. Emerging 3D spinal cord organoids derived from human pluripotent stem cells offer physiologically relevant models, enabling improved disease modeling and therapeutic exploration. This review highlights their potential in addressing critical gaps in SMA research.MethodsThis review systematically evaluates 3D spinal cord organoid studies modeling SMA, using strict PICO-based criteria, comprehensive database searches, and SYRCLE bias assessment to extract mechanistic, therapeutic, and methodological insights.ResultWe included 9 studies using 3D spinal organoids derived from human iPSCs to model SMA. Organoids effectively recapitulated motor neuron degeneration, developmental defects, and glial contributions. They enabled therapeutic testing (e.g., risdiplam, antisense oligonucleotides), but faced limitations in maturity, reproducibility, and cellular diversity. Despite these challenges, organoids surpassed traditional models, offering mechanistic insights and translational promise. Key research gaps include modeling chronic disease, integrating sensory-motor circuits, and improving vascularization.DiscussionSMA organoids enable patient-specific drug testing and uncover novel mechanisms, but face limitations in vascularization, maturity, and heterogeneity. Despite challenges, they surpass traditional models and drive a shift toward multifaceted SMA therapeutics. However, a standardized protocol is necessary to improve reproducibility, minimize batch variability, and enable reliable cross-study comparisons in SMA organoid research—ultimately enhancing their translational utility in drug discovery and personalized medicine.