Deep layer cortical projecting neurons that form the corticospinal tract are a vulnerable cell population to neurodegeneration and have reduced capacity for repair in human CNS injuries. Discovery and treatment development have been halted by the lack of suitable model systems that faithfully recapitulate the human aspects of pathobiology. To overcome these limitations, my laboratory developed a state-of-the-art human stem cell-derived corticospinal organoid system for pathomechanistic and therapeutic discoveries. My talk will cover our latest findings obtained by using this platform in combination with single cell transcriptomic approaches and biological perturbation assays, providing a view to therapeutic advancement.