Therapeutic Potential of Stem Cells in Neurodegenerative Diseases

55

One of the leading PD-derived PSC studies was published by Soldner

and colleagues. Actually, they inserted the different point mutations (c.A53T

(p.G209) and c.G188A (p.E46K)) into the SNCA gene and obtained mod-

eled human ESCs to observe the pathological effects of these mutations on

dopaminergic neuron differentiation. Moreover, they directly generated an

iPSC line from the PD patient carrying the c.A53T mutation to validate

the results in ESCs. Afterward, this mutation in ESCs and iPSCs was cor-

rected by using zinc finger nuclease (ZFN)-mediated genome engineering. The

results were significant, showing that genetically engineered PSCs could pro-

vide a basis for cell replacement therapies [110]. iPSC-derived DOPA neurons

from sporadic and LRRK2-associated PD patients showed similar epigenetic

alterations and an abnormal DNA methylation profile compared to healthy

controls. Thus, the association between sporadic or monogenic PD pathology

and the epigenomic landscape was documented for the first time in the iPSC

model [111]. iPSC-derived 3D organoids are also convenient for recapitulating

the complex interactions in the PD-suffered brain. A human midbrain-specific

organoid comprised of iPSC-derived neural progenitor cells (from PD patients

with the LRRK2-G2019S mutation) provided an efficient platform to differ-

entiate high numbers of functional DOPA neurons. Thereby, iPSC-derived

organoid mimicking complexity in the human midbrain served as a repro-

ducible model to track neurodevelopmental defects in PD [112]. A similar hu-

man midbrain organoid was also clarified by Kim’s group. They distinguished

the pathological signature and expressional changes in PD patient-specific

midbrain organoids bearing the LRRK2-G2019S mutation [113].

2.3.2.2

Stem Cell-based Preclinical Studies and Clinical Trials for

PD

Stem cells and stem cell-differentiated neural cells serve for preclinical studies

and clinical trials for the treatment of PD. A group of scientists at the Center

for iPS Cell Research and Application (CiRA) in Japan has recently manu-

factured clinical-grade iPSC-derived DOPA neurons from a healthy individ-

ual under GMP regulations. Upon quality and safety checks for the iPSC line

(QHJI01s04) via genetic and epigenetic analyses, iPSC-DOPA neurons were

injected into the striatum of rat and monkey PD models. Engraftment ensured

miraculous improvements in the behaviors and brain histology of subjected

animals [114]. This study also received approval for a clinical trial (JMA-

IIA00384, UMIN000033564) in Japan. Researchers from International Stem

Cell Corporation (Carlsbad, CA, USA) commenced another clinical trial at

phase I (ClinicalTrials.gov: NCT02452723). First, they manufactured GMP-

level neural progenitors from human parthenogenetic pluripotent stem cells.

After they ensured functionality, toxicity, tumorigenicity, and biodistribution

through in vivo assays, clinical trials were started in Australia [115]. An-

other pre-clinical study and clinical trial subjecting clinical-grade partheno-

genetic ESC-derived neurons have been conducted in China. The clinical trial