Preclinical and dose-ranging assessment of hESC-derived dopaminergic progenitors for a clinical trial on Parkinson's disease
Sang Hyun 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, Jung-Il Lee, Sieun Kim, Dohun Kim, Dohun Kim, Chul‐Yong Park, Su Jin Kim, Ho‐Young Lee, Myung Soo Cho, Dae‐Sung Kim, Dae‐Sung Kim, Dong‐Wook Kim, Dong‐Wook Kim
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.