Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease

Abstract

Induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons are an expected source for cell-based therapies for Parkinson’s disease (PD). The regulatory criteria for the clinical application of these therapies, however, have not been established. Here we show the results of our pre-clinical study, in which we evaluate the safety and efficacy of dopaminergic progenitors (DAPs) derived from a clinical-grade human iPSC line. We confirm the characteristics of DAPs by in vitro analyses. We also verify that the DAP population include no residual undifferentiated iPSCs or early neural stem cells and have no genetic aberration in cancer-related genes. Furthermore, in vivo studies using immunodeficient mice reveal no tumorigenicity or toxicity of the cells. When the DAPs are transplanted into the striatum of 6-OHDA-lesioned rats, the animals show behavioral improvement. Based on these results, we started a clinical trial to treat PD patients in 2018.

iPS cell-based therapy for Parkinson's disease: A Kyoto trial

“…As a next step towards clinical application, we performed a pre-clinical study to confirm the safety and efficacy of a clinical grade human iPS cell line (QHJI-01) [ 24 ]. This cell line was established at our institute from a healthy individual who has most common human leukocyte antigen (HLA) haplotype in the Japanese population [ 25 ].…”

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

“…The development of human iPSC technology has opened the doors to modeling complex brain diseases. Established protocols are available to generate various brain cell types from patient derived iPSCs in two dimensional (2D) monolayer cultures and use these to model AD [ 197 , 198 ], ALS [ 199 , 200 , 201 ] and PD [ 202 , 203 ]. The possibility of introducing genome editing in iPSCs (e.g., via CRISPR/CAS9) further increases the potential of these cells to study the specific roles of individual genes.…”

Direct Reprogramming of Human Fetal- and Stem Cell-Derived Glial Progenitor Cells into Midbrain Dopaminergic Neurons

“…The potential of cell replacement therapy as a means of treating PD has been established through clinical trials using human fetal ventral midbrain tissue ( Barker et al., 2015 ), and efforts are currently underway with the aim of assessing hPSCs as a source of transplantable DA progenitors ( Barker et al., 2017 ; Doi et al., 2020 ; Schweitzer et al., 2020 ). In vivo direct reprogramming of resident glia into DA neurons is similarly based on DA neuronal replacement but circumvents cell transplantation, as the new neurons are generated by reprogramming resident cells in situ ( Grealish et al., 2016 ; Vignoles et al., 2019 ).…”