Advances in Central Nervous System Organoids: A Focus on Organoid-Based Models for Motor Neuron Disease.

Despite their large societal burden, the development of therapeutic treatments for neurodegenerative diseases (NDDs) has been relatively unsuccessful. This is, in part, due to a lack of representative experimental models that reveal fundamental aspects of human brain pathology. Recently, assays for in vitro modeling of the human central nervous system (CNS) have significantly improved with the development of brain and spinal cord organoids. Coupled with induced-pluripotent stem cell and genome editing technologies, CNS organoids are a promising tool for studying neurodegeneration in a patient-specific manner. An extensive array of protocols for the generation of organoids for different brain regions has been developed and used for studying neurodegenerative and other brain diseases. However, their application in the field of motor neuron disease (MND) has been limited due to a lack of adequate organoid models. The development of protocols to derive spinal cord and trunk organoids and progress in the field of assembloids are providing new opportunities for modeling MND. In this study here we review recent advances in the development of CNS organoid models, their application in NDDs, and technical limitations. Finally, we discuss future perspectives for the development of organoid-based systems for MND and provide a framework for their development. Impact statement Animal models and two-dimensional cultures are currently the main platforms for studying neurodegenerative diseases (NDDs). However, central nervous system (CNS) organoid technology offers novel possibilities for studying these diseases. Organoid modeling in combination with emerging organ-on-a-chip approaches, induced-pluripotent stem cell technology, and genome editing render in vitro modeling of NDDs more robust and physiologically relevant. In this study, we review the principles underlying CNS organoid generation, their use in NDD research, and future perspectives in organoid technology. Finally, we discuss how advances in different fields could be combined to generate a multisystem organoid-on-a-chip model to investigate a specific class of NDDs, motor neuron diseases.