AUG 30, 2016 08:00 AM PDT

Challenge toward Clinical Trial for Spinal Cord Injury using iPS Cell

Speakers
  • Dean, Professor, Department of Physiology, Keio University School of Medicine, Japan
    Biography
      Professor Hideyuki Okano is Dean of Keio University School of Medicine and Team Leader of Laboratory for Marmoset Neural Architecture, Brain Science Institute RIKEN. In addition, Dr. Okano holds important posts, including University of New South Wales Visiting Professor (Since 2009), University of Queensland Honorary Professor in the Queensland Brain Institute (Since 2008), and Professor of Department of Physiology, Keio University School of Medicine (Since 2001). In the past he served as Professor of Osaka University Graduate School of Medicine (Department of Neuroscience, 1997-2001) and Professor of University of Tsukuba (Department of Molecular Neurobiology, Institute of Basic Medical Sciences, 1994-1997). He also did research at the University ofTokyo and The Johns Hopkins University School of Medicine as instructor. Dr. Okano has been the recipient of numerous awards, most recently including the Molecular Brain Award (2016), Balz Award (2014) and the Medal with Purple Ribbon (from the Emperor of Japan, 2009). His scientific research area is basic neuroscience, stem cell, and regenerative medicine including iPSC, NSC, and clinical applications for spinal cord injury.

    Abstract:
    In our previous preclinical studies, when neural stem progenitor cells (NS/PCs)-derived from hiPSCs were transplanted into mouse or non-human primate spinal cord injury (SCI) models, long-term restoration of motor function was induced without tumorigenicity, by selecting suitable hiPSCs-lines (Nori et al., 2011; Okano et al., 2013; Okano and Yamanaka, 2014). However, NS/PCs derived from certain iPSC-lines gave rise to late-onset tumorigenicity after transplantation (Tsuji et al., 2010; Nori et al., 2015). Here, to preclude these risks before clinical application, we developed molecular characterization of hiPSCs and hiPSC-derived NS/PCs together with transplantation to injured spinal cord of immune-deficient mice (Nori et al., 2015; Sugai et al., 2016). We investigated global methylation status of tumorigenic hiPSC-NS/PCs and found that aberrant hypermethylation of a tumor suppressor gene was induced along the passage. For addressing the safety issue, remnant immature cells or tumor-initiating cells should be removed or induced into more mature cell types to avoid adverse effects of hiPSC-NS/PC transplantation. Because Notch signaling plays a role in maintaining NS/PCs, we evaluated the effects of γ-secretase inhibitor (GSI) and found that pretreating hiPSC-NS/PCs with GSI promoted neuronal differentiation and maturation in vitro, and GSI pretreatment also reduced the overgrowth of transplanted hiPSC-NS/PCs and inhibited the deterioration of motor function in vivo (Okubo et al., 2016). Based on these findings, we are establishing methods of production, selection and transplantation of clinical grade NS/PCs stocks-derived from human iPSC stocks generated from HLA-homozygous super-donors by CiRA. We aim to commence clinical research (Phase I–IIa) trials for treatments of sub-acute phase SCI using hiPSCs-derived NS/PCs in the near future.
     

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