Human in vitro models for studying motor neuron disease

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons, resulting in muscle weakness, paralysis, and ultimately respiratory failure. Despite significant advances in our understanding of ALS pathogenesis, effective disease-modifying therapies remain limited. Human induced pluripotent stem cell (hiPSC)-derived in vitro models have emerged as powerful experimental platforms for modeling the cellular and molecular mechanisms underlying ALS in a patient-based context. Recent developments in modeling technology have enabled the generation of increasingly sophisticated neural systems, including spinal cord and cortico-spinal organoids, neuromuscular assembloids, and organoid slice cultures that support long-term live imaging, electrophysiological recordings, and circuit-level analyses. 

These models recapitulate key aspects of ALS pathology and facilitate the investigation of complex interactions between neurons, glial cells, and interconnected neural circuits. 

In this presentation, I will review recent advances in the development and application of human in vitro models to ALS research, highlighting their contributions to understanding disease mechanisms, identifying cell type-specific vulnerabilities, and evaluating novel therapeutic strategies. I will also discuss current limitations, as well as future opportunities. 

Finally, I will present our recent work on the development of next-generation in vitro models that enable the investigation of disease-relevant cellular interactions and functional network activity. These advances provide new opportunities to dissect ALS pathogenesis and establish scalable human platforms for therapeutic target discovery and preclinical drug evaluation.