Human autologous iPSC-derived dopaminergic progenitors restore motor function in Parkinson's disease models

• Published in: The Journal of clinical investigation Vol. 130; no. 2; pp. 904 - 920
• Main Authors: Song, Bin, Cha, Young, Ko, Sanghyeok, Jeon, Jeha, Lee, Nayeon, Seo, Hyemyung, Park, Kyung-Joon, Lee, In-Hee, Lopes, Claudia, Feitosa, Melissa, Luna, María José, Jung, Jin Hyuk, Kim, Jisun, Hwang, Dabin, Cohen, Bruce M, Teicher, Martin H, Leblanc, Pierre, Carter, Bob S, Kordower, Jeffrey H, Bolshakov, Vadim Y, Kong, Sek Won, Schweitzer, Jeffrey S, Kim, Kwang-Soo
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2020
• Subjects: Animal models; Autografts; Backup software; Biomedical research; Cell culture; Cell therapy; Diseases; Dopamine; Dopamine receptors; Fibroblasts; Gene expression; Health aspects; Inhibitory postsynaptic potentials; Mesencephalon; Metabolism; MicroRNA; MicroRNAs; miRNA; Morphology; Movement disorders; Mutation; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neurons; Parkinson disease; Parkinson's disease; Phenols (Class of compounds); Pluripotency; Quality; Recovery of function; Respiration; Stem cell transplantation; Stem cells; Substantia nigra; Surgery; Transplantation; Tumors; Stem cell transplantation; Neuroscience; Parkinson’s disease; Stem cells
• DOI: 10.1172/JCI130767
• ISSN: 0021-9738

Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. To establish human induced pluripotent stem cell-based (hiPSC-based) autologous cell therapy, we report a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, we developed a method to more efficiently generate clinical-grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, we established a "spotting"-based in vitro differentiation methodology to generate functional and healthy mDA cells in a scalable manner. Third, we developed a chemical method that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restores motor function and reinnervates host brain, while showing no evidence of tumor formation or redistribution of the implanted cells. We propose that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.