Engineered three-dimensional (3D) in vitro and ex vivo neural tissues, also known as “mini brains and spinal cords in a dish,” can be derived from different types of human stem cells via several differentiation protocols. In general, human mini brains are micro-scale physiological systems consisting of mixed populations of neural progenitor cells, glial cells, and neurons that may represent key features of human brain anatomy and function. To date, these specialized 3D tissue structures can be characterized into spheroids, organoids, assembloids, organ-on-a-chip and their various combinations based on generation procedures and cellular components. These 3D CNS models incorporate complex cell-cell interactions and play an essential role in bridging the gap between two-dimensional human neuroglial cultures and animal models. Indeed, they provide an innovative platform for disease modeling and therapeutic cell replacement, especially shedding light on the potential to realize personalized medicine for neurological disorders when combined with the revolutionary human induced pluripotent stem cell technology. In this review, we highlight human 3D CNS models developed from a variety of experimental strategies, emphasize their advances and remaining challenges, evaluate their state-of-the-art applications in recapitulating crucial phenotypic aspects of many CNS diseases, and discuss the role of contemporary technologies in the prospective improvement of their composition, consistency, complexity, and maturation.

Mutations of the SPAST gene that encodes the microtubule-severing enzyme called spastin are the chief cause of Hereditary Spastic Paraplegia. Growing evidence indicates that pathogenic mutations functionally compromise the spastin protein and endow it with toxic gain-of-function properties. With each of these two factors potentially relevant to disease etiology, the present article discusses possible therapeutic strategies that may ameliorate symptoms in patients suffering from SPAST-based Hereditary Spastic Paraplegia, which is usually termed SPG4-HSP.