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Summary: Myelin defects cause a collection of myelin disorders in the brain. The lack of human models has limited us from better understanding pathological mechanisms of myelin diseases. While human induced pluripotent stem cell (hiPSC)-derived spheroids or organoids have been used to study brain development and disorders, it has been difficult to recapitulate mature myelination in these structures. Here, we have developed a method to generate three-dimensional (3D) myelin spheroids from hiPSCs in a robust and reproducible manner. Using this method, we generated myelin spheroids from patient iPSCs to model Canavan disease (CD), a demyelinating disorder. By using CD patient iPSC-derived myelin spheroids treated with N-acetyl-aspartate (NAA), we were able to recapitulate key pathological features of the disease and show that high-level NAA is sufficient to induce toxicity on myelin sheaths. Our study has established a 3D human cellular platform to model human myelin diseases for mechanistic studies and drug discovery.