Concise Review: Laying the Groundwork for a First‐In‐Human Study of an Induced Pluripotent Stem Cell‐Based Intervention for Spinal Cord Injury

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Abstract

There have been numerous attempts to develop stem cell transplantation approaches to promote the regeneration of spinal cord injury (SCI). Our multicenter team is currently planning to launch a first‐in‐human clinical study of an induced pluripotent stem cell (iPSC)‐based cell transplant intervention for subacute SCI. This trial was conducted as class I regenerative medicine protocol as provided for under Japan's Act on the Safety of Regenerative Medicine, using neural stem/progenitor cells derived from a clinical‐grade, integration‐free human “iPSC stock” generated by the Kyoto University Center for iPS Cell Research and Application. In the present article, we describe how we are preparing to initiate this clinical study, including addressing the issues of safety and tumorigenesis as well as practical problems that must be overcome to enable the development of therapeutic interventions for patients with chronic SCI. stem cells 2019;37:6–13

Abstract

Ash1l can epigenetically promote the expression of essential osteogenic and chondrogenic transcription factors in C3H10T1/2 cells. It exerts this impact via modifications in the enrichment of H3K4me3 on their promoter regions. Ash1l hampered adipogenesis by enhancing H3K4me3 enrichment in promoter of Creb gene, which was reported to be a repressive gene of PPARγ.

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Variation in the safety of induced pluripotent stem cell lines.

Kyoko Miura, Yohei Okada, Takashi Aoi … (2009)

We evaluated the teratoma-forming propensity of secondary neurospheres (SNS) generated from 36 mouse induced pluripotent stem (iPS) cell lines derived in 11 different ways. Teratoma-formation of SNS from embryonic fibroblast-derived iPS cells was similar to that of SNS from embryonic stem (ES) cells. In contrast, SNS from iPS cells derived from different adult tissues varied substantially in their teratoma-forming propensity, which correlated with the persistence of undifferentiated cells.

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Direct reprogramming of mouse fibroblasts to neural progenitors.

Janghwan Kim, Jem A Efe, Saiyong Zhu … (2011)

The simple yet powerful technique of induced pluripotency may eventually supply a wide range of differentiated cells for cell therapy and drug development. However, making the appropriate cells via induced pluripotent stem cells (iPSCs) requires reprogramming of somatic cells and subsequent redifferentiation. Given how arduous and lengthy this process can be, we sought to determine whether it might be possible to convert somatic cells into lineage-specific stem/progenitor cells of another germ layer in one step, bypassing the intermediate pluripotent stage. Here we show that transient induction of the four reprogramming factors (Oct4, Sox2, Klf4, and c-Myc) can efficiently transdifferentiate fibroblasts into functional neural stem/progenitor cells (NPCs) with appropriate signaling inputs. Compared with induced neurons (or iN cells, which are directly converted from fibroblasts), transdifferentiated NPCs have the distinct advantage of being expandable in vitro and retaining the ability to give rise to multiple neuronal subtypes and glial cells. Our results provide a unique paradigm for iPSC-factor-based reprogramming by demonstrating that it can be readily modified to serve as a general platform for transdifferentiation.

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A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury

Erik Curtis, Joseph Ciacci, Martin Marsala … (2018)

We tested the feasibility and safety of human-spinal-cord-derived neural stem cell (NSI-566) transplantation for the treatment of chronic spinal cord injury (SCI). In this clinical trial, four subjects with T2-T12 SCI received treatment consisting of removal of spinal instrumentation, laminectomy, and durotomy, followed by six midline bilateral stereotactic injections of NSI-566 cells. All subjects tolerated the procedure well and there have been no serious adverse events to date (18-27 months post-grafting). In two subjects, one to two levels of neurological improvement were detected using ISNCSCI motor and sensory scores. Our results support the safety of NSI-566 transplantation into the SCI site and early signs of potential efficacy in three of the subjects warrant further exploration of NSI-566 cells in dose escalation studies. Despite these encouraging secondary data, we emphasize that this safety trial lacks statistical power or a control group needed to evaluate functional changes resulting from cell grafting.

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Author and article information

Contributors

Hideyuki Okano:

ORCID: https://orcid.org/0000-0001-7482-5935

hidokano@keio.jp

Journal

Journal ID (nlm-ta): Stem Cells

Journal ID (iso-abbrev): Stem Cells

Journal ID (doi): 10.1002/(ISSN)1549-4918

Journal ID (publisher-id): STEM

Title: Stem Cells (Dayton, Ohio)

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Print): 1066-5099

ISSN (Electronic): 1549-4918

Publication date (Electronic): 12 November 2018

Publication date (Print): January 2019

Volume: 37

Issue: 1 ( doiID: 10.1002/stem.v37.1 )

Pages: 6-13

Affiliations

[ ¹ ] Department of Orthopaedic Surgery Keio University School of Medicine Tokyo Japan

[ ² ] Department of Physiology Keio University School of Medicine Tokyo Japan

[ ³ ] Regenerative & Cellular Medicine Office Sumitomo Dainippon Pharma Co., Ltd. Kobe Japan

[ ⁴ ] Department of Rehabilitation Medicine Keio University School of Medicine Tokyo Japan

[ ⁵ ] Department of Orthopaedic Surgery National Hospital Organization Murayama Medical Center Tokyo Japan

[ ⁶ ] Department of Biomedical Research and Innovation Institute for Clinical Research and Department of Neurosurgery, Osaka National Hospital, National Hospital Organization Osaka Japan

[ ⁷ ] Center for iPS Cell Research and Application (CiRA) Kyoto University Kyoto Japan

Author notes

[*] [* ]Correspondence: Hideyuki Okano, M.D., Ph.D., Department of Physiology, Keio University School of Medicine, Tokyo, Japan. Telephone: +81‐3‐5363‐3746; e‐mail: hidokano@ 123456keio.jp

Author information

Osahiko Tsuji https://orcid.org/0000-0002-4584-1757

Keiko Sugai https://orcid.org/0000-0002-8539-1797

Hideyuki Okano https://orcid.org/0000-0001-7482-5935

Article

Publisher ID: STEM2926

DOI: 10.1002/stem.2926

PMC ID: 7379555

PubMed ID: 30371964

SO-VID: 3782e7b9-a55f-4530-bd50-d6d141a1dca1

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 26 April 2018

Date revision received : 16 August 2018

Date accepted : 22 September 2018

Page count

Figures: 2, Tables: 0, Pages: 8, Words: 7225

Funding

Funded by: Research Center Network for Realization of Regenerative Medicine

Funded by: Centers for Clinical Application Research on Specific Disease/Organ

Award ID: 18bm0204001h0006

Award ID: 18bk01045h003

Funded by: Research Project for Practical Applications of Regenerative Medicine

Funded by: Japan Agency for Medical Research and Development (AMED) , open-funder-registry 10.13039/100009619;

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source-schema-version-number 2.0

cover-date January 2019

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:24.07.2020

ScienceOpen disciplines: Molecular medicine

Keywords: cell transplantation,clinical trials,induced pluripotent stem cells,spinal cord injury

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ScienceOpen disciplines: Molecular medicine

Keywords: cell transplantation, clinical trials, induced pluripotent stem cells, spinal cord injury

Concise Review: Laying the Groundwork for a First‐In‐Human Study of an Induced Pluripotent Stem Cell‐Based Intervention for Spinal Cord Injury

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Drug Repurposing

Most cited references 55

Variation in the safety of induced pluripotent stem cell lines.

Direct reprogramming of mouse fibroblasts to neural progenitors.

A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury

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