Pluripotent stem cell-based therapies and their path to the clinic

概要

Stem Cell Reports
Editorial

Pluripotent stem cell-based therapies and their path to the clinic
Welcome to this special issue, focusing on the potential of
pluripotent stem cell (PSC)-based therapies and their paths
toward clinical application. Since the establishment of human embryonic stem (ES) and induced pluripotent stem
(iPS) cells in 1998 and 2007, respectively, significant progress has been made in differentiating PSCs into a broad
range of somatic cells. We are now closer than ever before
to having highly functional PSC-derived somatic cells
at purity for transplantation therapies to complement
damaged or diseased organs and restore their physiologic
functions. Like organ transplantation, PSC-based therapies
have the potential to regenerate damaged organs that
cannot otherwise be healed by using small-molecule or
antibody-based drugs.
In this issue, Kobold et al. present an overview of the history and current status of clinical studies utilizing human
PSCs. Since the early 2010s, many clinical studies employing human ES cells have been initiated. By 2018, the number of such studies using human iPS cells had skyrocketed.
Many PSC-based therapies are currently being tested to
treat various pathologic conditions, including different
neoplasms and diseases of the eye, adnexa, and circulatory
system. However, there are still many diseases that require
further efforts to interrogate the true potential of PSCbased therapies. To advance the use of PSC-based therapy
to treat a wider range of pathologic conditions in the
future, we must continue with extensive basic and clinical
research to establish both efficacy and safety for such new
therapies.
Although clinical research on PSC-based therapy for liver
diseases has not received as much attention, there is much
hope for it to become a real alternative to living-donor liver
transplantation. Cardinale et al. provided a comprehensive
summary of the recent studies on cell-based therapy
for liver diseases. In addition, artificial livers generated
through bioengineering efforts are now considered to be
a viable option. Aside from traditional cell or organ transplantation to restore impaired liver function, transplantation aimed at treating the microenvironment, such as
inflammation, in the liver is also an effective therapeutic
strategy. Concurrent research efforts in both basic and clinical studies will be crucial in making PSC-based therapy for
liver diseases a reality.
This special issue includes three research papers reporting basic research on the development of PSC-based therapy. (1) Martinez-Curiel et al. demonstrated the in vitro
and in vivo production of myelinating oligodendrocytes
from a human iPSC-derived long-term neuroepithelial
stem cell (NES) line, which also gives rise to neurons

with the capacity to integrate into stroke-injured, adult
rat cortical networks. This long-term NES cell line holds
promise for repairing both damaged neural circuits and
demyelinated axons. Such a strategy has potential as a
new treatment for neurological disorders and injuries,
such as ischemic stroke. (2) To successfully carry out
PSC-based therapy, it is of utmost importance to ensure
not only its efficacy but also its safety. The exclusion of
unwanted cells, such as undifferentiated cells, is vital to
ensuring the safety of PSC-derived somatic cells for transplantation. Taga et al. report a method for purifying

Stem Cell Reports j Vol. 18 j 1547–1548 j August 8, 2023 j ª 2023 The Author(s). 1547
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Stem Cell Reports
Editorial

adrenocorticotropic hormone-secreting PSC-derived pituitary cells based on epithelial cell adhesion molecule, a
cell-surface marker for pituitary cells. In the study, they
successfully purified pituitary cells and kept off-target cells
to a minimum. The transplantation of purified pituitary
cells offers an effective and safe solution to treating hypopituitarism. (3) To maximize the therapeutic efficacy of
PSC-based therapy, combining it with gene therapy is
one of the major focuses in the development of so-called
next-generation cell therapy. Transplanting cells transduced with specific genes to modify their functions or
properties could be an effective means to enhance
their therapeutic effects. Laperle et al. demonstrated the
effectiveness of glial cell-derived neurotrophic factor
(GDNF)-transduced iPS cell-derived neural progenitor cells
(iNPC-GDNFs) as a novel approach to treating neurodegenerative diseases. The transplantation of iNPC-GDNFs
into the subretinal space of a Royal College of Surgeons
rodent model of retinal degeneration was shown to preserve photoreceptors and visual functions. Prolonged motor neuron protection was also observed in an SOD1G93A
amyotrophic lateral sclerosis (ALS) rat model upon
receiving iNPC-GDNF transplants in the spinal cord. As
such, the authors illustrated the potential of using such
PSC-derived cells to impart significant neuroprotection
in these debilitating models of retinal degeneration and
ALS. By using gene transfer technology to improve or
even generate new functionalities of somatic cells derived
from PSCs, it is up to the imagination of stem cell scientists to find creative new ways to enhance the therapeutic
potential of PSC-based implants.
As basic research on PSC-based therapy continues to
forge ahead, clinical research is also striving forward synchronously at a rapid pace. Nonetheless, the necessity for
stringent rules to evaluate the safety and efficacy of novel
therapies remains. Hirai et al. recently highlighted how
cell-based therapeutic products (CTPs) should not be assessed using the same criteria as those for small molecule
drugs and antibodies, thus necessitating the creation of
new evaluation methods. As PSC-based therapies often
employ emerging technologies, such as gene therapy, it is
essential to update our evaluation methods and standard
guidelines continuously to accompany new technological
advances. Furthermore, it will be vital to establish international standardization for the testing and implementation
of PSC-based therapies that can be applied universally
across all countries.
In order to properly evaluate PSC-based therapies during
clinical trials, various challenges—such as determining

1548 Stem Cell Reports j Vol. 18 j 1547–1548 j August 8, 2023

the efficacy and safety of CTPs—must be addressed. The
ISSCR Clinical Translation Committee outlined key considerations that the scientific and medical communities must
contemplate to advance PSC-based therapies forward: (1)
choosing the appropriate stem cell line and meticulously assessing the genomes of both the starting and final product;
(2) acclimatizing to GMP manufacturing, reagent validation, and supply chain management; (3) enduring product
delivery issues and additional regulatory challenges; (4) understanding the relationship between clinical trial design
and preclinical studies; and (5) realizing market approval requirements, pathways, and partnerships needed.
Expectations surrounding PSC-based therapy are higher
than ever as it holds promise to overcome a wide range of
intractable diseases. However, such heightened anticipation has also led to issues related to unproven stem cell usage. As described by Dulak and Pecyna and Kawam et al.,
unproven stem cell interventions necessitate vigilance
from healthcare professionals, researchers, and patients
to avert their use. It is essential to impart a better understanding of PSC-based therapy, including its advantages
and drawbacks, how it fares against other available options, and its financial costs. For individuals to readily access and comprehend this information, all stakeholder
groups must consistently convey clear and concise
information.
At present, the market size for PSC-based therapy is
smaller than that for small molecule, protein-based, and
antibody-based drugs. Nevertheless, we are confident that
with the emergence of innovative PSC-based therapy, the
market size will rapidly expand, analogous to how RNAbased medicine boomed in the past few years. For PSCbased therapy to become more widespread and readily
available, we must overcome many obstacles. It is unimaginable that it has only been 25 and 16 years since human ES
and iPS cells were established, respectively. Finally, we have
arrived at the stage of testing these new therapeutic modalities in clinical trials. Our mission is to continue to persistently run so that we can create a future in which lifethreatening illnesses are no longer life threatening because
PSC-based therapies will be available to treat any pathologic conditions where traditional approaches have failed. ...

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