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AUG 30, 2016 8:00 AM PDT

Challenge toward Clinical Trial for Spinal Cord Injury using iPS Cell

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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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