分子病態治療研究センター

瀬原 吉英

セハラ ヨシヒデ  (Yoshihide Sehara)

基本情報

所属
自治医科大学 分子病態治療研究センター 遺伝子治療研究部 講師
学位
医学博士(岡山大学大学院)

J-GLOBAL ID
201301061949126420
researchmap会員ID
7000006422

論文

 44
  • Yoshihide Sehara, Yuki Hashimotodani, Ryota Watano, Kenji Ohba, Ryosuke Uchibori, Kuniko Shimazaki, Kensuke Kawai, Hiroaki Mizukami
    Molecular neurobiology 2024年4月27日  査読有り筆頭著者責任著者
    It is established that neurogenesis of dentate gyrus is increased after ischemic insult, although the regulatory mechanisms have not yet been elucidated. In this study, we focused on Ezh2 which suppresses gene expression through catalyzing trimethylation of lysine 27 of histone 3. Male gerbils were injected with adeno-associated virus (AAV) carrying shRNA targeting to Ezh2 into right dentate gyrus 2 weeks prior to forebrain ischemia. One week after ischemia, animals were injected with thymidine analogue to label proliferating cells. Three weeks after ischemia, animals were killed for histological analysis. AAV-mediated knockdown of Ezh2 significantly decreased the ischemia-induced increment of proliferating cells, and the proliferated cells after ischemia showed significantly longer migration from subgranular zone (SGZ), compared to the control group. Furthermore, the number of neural stem cells in SGZ significantly decreased after ischemia with Ezh2 knockdown group. Of note, Ezh2 knockdown did not affect the number of proliferating cells or the migration from SGZ in the non-ischemic condition. Our data showed that, specifically after ischemia, Ezh2 knockdown shifted the balance between self-renewal and differentiation toward differentiation in adult dentate gyrus.
  • Yuka Hayashi, Yoshihide Sehara, Ryota Watano, Kenji Ohba, Yuki Takayanagi, Yoshio Sakiyama, Kazuhiro Muramatsu, Hiroaki Mizukami
    Human Gene Therapy 2024年2月22日  査読有り責任著者
  • Yuka Hayashi, Yoshihide Sehara, Ryota Watano, Kenji Ohba, Yuki Takayanagi, Kazuhiro Muramatsu, Yoshio Sakiyama, Hiroaki Mizukami
    The Journal of Gene Medicine e3560 2023年6月30日  査読有り責任著者
    BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A) encoded by the GLA gene. The symptoms of FD occur as a result of the accumulation of globotriaosylceramide (Gb3), comprising a substrate of α-Gal A, in the organs. Adeno-associated virus (AAV)-mediated gene therapy is a promising treatment for FD. METHODS: α-Gal A knockout (GLAko) mice were injected intravenously with AAV2 (1 × 1011 viral genomes [vg]) or AAV9 (1 × 1011 or 2 × 1012 vg) vectors carrying human GLA (AAV-hGLA), and plasma, brain, heart, liver and kidney were tested for α-Gal A activity. The vector genome copy numbers (VGCNs) and Gb3 content in each organ were also examined. RESULTS: The plasma α-Gal A enzymatic activity was three-fold higher in the AAV9 2 × 1012 vg group than wild-type (WT) controls, which was maintained for up to 8 weeks after injection. In the AAV9 2 × 1012 vg group, the level of α-Gal A expression was high in the heart and liver, intermediate in the kidney, and low in the brain. VGCNs in the all organs of the AAV9 2 × 1012 vg group significantly increased compared to the phosphate-buffered-saline (PBS) group. Although Gb3 in the heart, liver and kidney of the AAV9 2 × 1012 vg was reduced compared to PBS group and AAV2 group, and the amount of Gb3 in the brain was not reduced. CONCLUSIONS: Systemic injection of AAV9-hGLA resulted in α-Gal A expression and Gb3 reduction in the organs of GLAko mice. To expect a higher expression of α-Gal A in the brain, the injection dosage, administration route and the timing of injection should be reconsidered.
  • Kenji Ohba, Yoshihide Sehara, Tatsuji Enoki, Junichi Mineno, Keiya Ozawa, Hiroaki Mizukami
    iScience 106487-106487 2023年3月  査読有り
  • Yoshihide Sehara, Kyoichiro Tsuchiya, Ichizo Nishino, Hirotake Sato, Yoshihito Ando
    Internal medicine (Tokyo, Japan) 2022年2月1日  査読有り筆頭著者責任著者
    A 72-year-old woman presented with gradually-worsening myalgia and muscle weakness of the proximal lower limbs as well as elevated serum creatine kinase level. Based on a clinicoseropathological examination including a muscle biopsy, she was diagnosed with anti-signal recognition particle (SRP) myopathy. Although the myopathy relapsed two times in two years under oral prednisolone and intravenous immunoglobulin therapy, the myopathy remained in remission for more than three years after resection of gastric cancer. Although the anti-SRP myopathy is not considered to be cancer-associated in general, we should note that some cases of anti-SRP myopathy may be ameliorated with appropriate cancer treatment.

共同研究・競争的資金等の研究課題

 14