Large-scale generation of high-purity midbrain dopaminergic progenitor cells from human embryonic stem cells

Recently, researchers from Yonsei University School of Medicine generated high-purity midbrain dopaminergic (mDA) progenitor cells on a large scale from clinical-grade human embryonic stem cells (hESC), and verified the safety and effectiveness of mDA progenitor cells in vitro and in vivo.

mDA progenitor cells dose-dependently improve disease-related behavior in a rat model of Parkinson's disease. Based on these preclinical study results, the research team obtained approval from the South Korea Department of Food and Drug Safety to conduct a Phase 1/2a clinical trial of cell therapy for Parkinson's disease and initiated treatment in 12 patients with Parkinson's disease.

In a groundbreaking study reported in the New England Journal of Medicine (NEJM), researchers at Massachusetts General Hospital reported that a patient with Parkinson's disease who received an autologous transplant of hiPSC-derived mDA progenitor cells showed stabilization or improvement in clinical symptoms at 24 months post-implantation. Now, this method has been further developed, and hiPSC-derived hESC-derived mDA progenitor cells are beginning to enter the early stage of clinical trials.

The first step in the clinical application of cell transplantation for Parkinson's disease is to fully define the cell product characteristics. It is critical to determine whether cells are produced using clinical-grade materials under GMP conditions and whether they meet the criteria for intended clinical use. Subsequently, preclinical studies should produce convincing evidence of efficacy through large-scale animal experiments and systematically examine long-term safety-related issues such as toxicity, biodistribution, and tumorigenicity. In addition, preclinical studies are needed to determine the optimal cell dose range for transplantation as a reference for human trials. Most importantly, the entire study design must be meticulous and the results must be assessed in an impartial manner. This usually requires working with the CRO firm and extensive discussions with regulators.

This paper describes the process and results of a preclinical study to use human embryonic stem cell (hESC)-derived midbrain dopaminergic (mDA) neurons for human clinical trials for the treatment of Parkinson's disease.

The cell differentiation method used in this study has been optimized for clinical application to ensure compliance with GMP standards. This optimized method enables large-scale production of high-purity, cryopreserved mDA progenitor cells while maintaining strict quality control. A year-long large-scale transplantation study using immunodeficient rats by independent CRO companies showed that the transplanted mDA neurons did not result in tumorigenicity, significant toxicity, or ectopic integration outside the injection site. In addition, clinical mDA precursor cells showed therapeutic potential and dose range, producing therapeutic effects in toxin-induced hemi-parkinsonian rats. These findings provide essential information about the appropriate cell dose for human trials.

The method of large-scale extraction of high-purity mDA progenitor cells from clinical-grade hESCs under strict GMP conditions was also evaluated for toxicity, biodistribution, and tumorigenicity of these cells in immunodeficient rats in a facility conforming to Good Laboratory Practice (GLP). Different doses of mDA progenitor cells were transplanted into a hemiparkinsonian rat model, and a significant dose-dependent behavioral improvement was observed at the minimum effective dose range of 5000-10000 mDA progenitor cells. These results provide insights for determining the low cell dose (3.15 million cells) for human clinical trials.

Based on these experimental results, the research team obtained the approval of the South Korea Food and Drug Safety Department to conduct a phase 1/2a clinical trial of Parkinson's disease cell therapy and began a clinical trial for the treatment of Parkinson's disease patients.