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

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          Abstract

          Following intensive efforts since their discovery little more than 10 years ago, cell replacement therapy using induced pluripotent stem (iPS) cells is now becoming reality. However, there remain several obstacles in the translation of basic research to clinical application, obstacles known as the “Valley of Death”. With regards to regenerative medicine using iPS cells for Parkinson's disease, we have developed a method for the 1) efficient induction of dopaminergic neurons from human iPS cells and 2) sorting dopaminergic progenitor cells using a floor plate marker, CORIN. The grafted CORIN + cells survived well and functioned as midbrain dopaminergic neurons in the Parkinson's disease model rats and monkeys, and showed minimal risk of tumor formation. Based on these results, we performed a pre-clinical study using a clinical-grade iPS cell line and finally started a clinical trial to treat Parkinson's disease patients in August 2018. Here, I discuss the key issues to crossing the Valley of Death: scientific rationale, pre-clinical study, and clinical trial.

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          Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling

          Stuart Chambers, Christopher Fasano, Eirini P. Papapetrou … (2009)
          Current neural induction protocols in human ES cells (hESCs) rely on embryoid body formation, stromal feeder co-culture, or selective survival conditions; each strategy displaying significant drawbacks such as poorly defined culture conditions, protracted differentiation and low yield. Here we report that the synergistic action of two inhibitors of SMAD signaling, Noggin and SB431542, is sufficient for inducing rapid and complete neural conversion of hESCs under adherent culture conditions. Temporal fate analysis reveals a transient FGF5+ epiblast-like stage followed by PAX6+ neural cells competent of rosette formation. Initial cell density determines the ratio of CNS versus neural crest progeny. Directed differentiation of human iPSCs into midbrain dopamine and spinal motoneurons confirm robustness and general applicability of the novel induction protocol. Noggin/SB431542 based neural induction should greatly facilitate the use of hESC and hiPSCs in regenerative medicine and disease modeling and obviate the need for stromal feeder or embryoid body based protocols.
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            Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development.

            Charles E. Murry, Gordon Keller (2008)
            The potential to generate virtually any differentiated cell type from embryonic stem cells (ESCs) offers the possibility to establish new models of mammalian development and to create new sources of cells for regenerative medicine. To realize this potential, it is essential to be able to control ESC differentiation and to direct the development of these cells along specific pathways. Embryology has offered important insights into key pathways regulating ESC differentiation, resulting in advances in modeling gastrulation in culture and in the efficient induction of endoderm, mesoderm, and ectoderm and many of their downstream derivatives. This has led to the identification of new multipotential progenitors for the hematopoietic, neural, and cardiovascular lineages and to the development of protocols for the efficient generation of a broad spectrum of cell types including hematopoietic cells, cardiomyocytes, oligodendrocytes, dopamine neurons, and immature pancreatic beta cells. The next challenge will be to demonstrate the functional utility of these cells, both in vitro and in preclinical models of human disease.
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              A more efficient method to generate integration-free human iPS cells.

              Satoshi Okamoto, Annabelle A. Okada, Yaejee H. Hong … (2011)
              We report a simple method, using p53 suppression and nontransforming L-Myc, to generate human induced pluripotent stem cells (iPSCs) with episomal plasmid vectors. We generated human iPSCs from multiple donors, including two putative human leukocyte antigen (HLA)-homozygous donors who match ∼20% of the Japanese population at major HLA loci; most iPSCs are integrated transgene-free. This method may provide iPSCs suitable for autologous and allologous stem-cell therapy in the future.
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                Author and article information

                Contributors
                Jun Takahashi
                Journal
                Journal ID (nlm-ta): Regen Ther
                Journal ID (iso-abbrev): Regen Ther
                Title: Regenerative Therapy
                Publisher: Japanese Society for Regenerative Medicine
                ISSN (Electronic): 2352-3204
                Publication date PMC-release: 15 September 2020
                Publication date Collection: March 2020
                Publication date (Electronic): 15 September 2020
                Volume: 13
                Pages: 18-22
                Affiliations
                [1]Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo, Kyoto, 606-8507, Japan
                Article
                Publisher Item ID: S2352-3204(20)30061-4
                DOI: 10.1016/j.reth.2020.06.002
                PMC ID: 7794047
                PubMed ID: 33490319
                SO-VID: ae4a7c4a-f292-4d3f-97b4-a3635cf98986
                Copyright © © 2020 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 17 June 2020
                Date accepted : 18 June 2020
                Categories
                Subject: Original Article

                Keywords: parkinson's disease,induced pluripotent stem cell,dopaminergic neuron,transplantation,translational research,clinical trial
                Data availability:
                Keywords: parkinson's disease, induced pluripotent stem cell, dopaminergic neuron, transplantation, translational research, clinical trial

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