Systematic review validates iPSC-derived organoids as models for ALS pathology compared to traditional 2D or animal models.

A systematic review assessed the utility of induced pluripotent stem cell (iPSC)-derived organoids, specifically spinal and neuromuscular subtypes, as models for Amyotrophic Lateral Sclerosis (ALS). The study population consisted of human-specific neural and neuromuscular subtypes derived from iPSCs, utilized within an in vitro setting involving organoid models. These interventions were benchmarked against traditional animal and 2D cell models to determine their fidelity in representing disease pathophysiology.

The primary outcome focused on the validation and benchmarking of these organoid models. Secondary outcomes included the recapitulation of key pathological features, such as protein mis-localization, neuromuscular junction defects, synaptic impairments, and glial contributions, alongside potential applications in drug screening, mechanistic studies, and personalized therapeutic discovery. The review noted that traditional animal and 2D cell models often fail to fully capture the human-specific and multicellular aspects of disease pathophysiology, suggesting organoids offer a more accurate representation of these complex interactions.

Regarding safety and tolerability, adverse events, serious adverse events, discontinuations, and overall tolerability were not reported, as the study was conducted entirely in vitro. Consequently, no clinical safety signals were identified. The main limitation highlighted is that the evidence is restricted to preclinical models and does not establish efficacy or safety in human patients. The practice relevance is currently theoretical, as the findings support the use of these models for research rather than direct clinical application. Causality cannot be inferred from these observational comparisons of model systems.