Preclinical and dose-ranging assessment of hESC-derived dopaminergic progenitors for a clinical trial on Parkinson's disease

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Authors: Sanghyun Park ; Chan Wook Park ; Jang Hyeon Eom ; Mi-Young Jo ; Hye-Jin Hur ; Sung Kyoung Choi ; Jae Souk Lee ; Seung Taek Nam ; Ki-Sang Jo ; Young Woo Oh ; Jungil Lee ; Sieun Kim ; Do-Hun Kim ; Chul-Yong Park ; Su Jin Kim ; Ho-Young Lee ; Myung Soo Cho ; Dae-Sung Kim ; Dong-Wook Kim

MeSH: Animals ; Cell Differentiation ; Dopamine ; Dopaminergic Neurons ; Human Embryonic Stem Cells* ; Humans ; Mesencephalon ; Parkinson Disease* / therapy ; Rats ; Stem Cell Transplantation / methods ; Tissue Distribution

Keywords: Parkinson’s disease ; cell transplantation ; dose-escalation study ; efficacy study ; human embryonic stem cells ; midbrain dopaminergic neurons ; preclinical study ; safety study ; stem-cell-based cell therapy

Abstract: Human embryonic stem cell (hESC)-derived midbrain dopaminergic (mDA) cell transplantation is a promising therapeutic strategy for Parkinson's disease (PD). Here, we present the derivation of high-purity mDA progenitors from clinical-grade hESCs on a large scale under rigorous good manufacturing practice (GMP) conditions. We also assessed the toxicity, biodistribution, and tumorigenicity of these cells in immunodeficient rats in good laboratory practice (GLP)-compliant facilities. Various doses of mDA progenitors were transplanted into hemi-parkinsonian rats, and a significant dose-dependent behavioral improvement was observed with a minimal effective dose range of 5,000-10,000 mDA progenitor cells. These results provided insights into determining a low cell dosage (3.15 million cells) for human clinical trials. Based on these results, approval for a phase 1/2a clinical trial for PD cell therapy was obtained from the Ministry of Food and Drug Safety in Korea, and a clinical trial for treating patients with PD has commenced.