医学部 生化学講座 病態生化学部門

早川 盛禎

ハヤカワ モリサダ  (Morisada Hayakawa)

基本情報

所属
自治医科大学 医学部・医学研究科 生化学講座 病態生化学部門/遺伝子治療研究センター 准教授
学位
博士(医学)(2000年3月 自治医科大学)

J-GLOBAL ID
200901040571142546
researchmap会員ID
1000300010

外部リンク

委員歴

 3

論文

 46
  • Tomoki Togashi, Nemekhbayar Baatartsogt, Yasumitsu Nagao, Yuji Kashiwakura, Morisada Hayakawa, Takafumi Hiramoto, Takayuki Fujiwara, Eriko Morishita, Osamu Nureki, Tsukasa Ohmori
    Arteriosclerosis, thrombosis, and vascular biology 44(12) 2616-2627 2024年12月  
    BACKGROUND: PC (protein C) is a plasma anticoagulant encoded by PROC; mutation in both PROC alleles results in neonatal purpura fulminans-a fatal systemic thrombotic disorder. In the present study, we aimed to develop a genome editing treatment to cure congenital PC deficiency. METHODS: We generated an engineered APC (activated PC) to insert a furin-cleaving peptide sequence between light and heavy chains. The engineered PC was expressed in the liver of mice using an adeno-associated virus vector or CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9)-mediated genome editing using an adeno-associated virus vector in vivo. RESULTS: The engineered PC could be released in its activated form and significantly prolonged the plasma coagulation time independent of the cofactor activity of PS (protein S) in vitro. The adeno-associated virus vector-mediated expression of the engineered PC, but not wild-type PC, prolonged coagulation time owing to the inhibition of activated coagulation FV (factor V) in a dose-dependent manner and abolished pathological thrombus formation in vivo in C57BL/6J mice. The insertion of EGFP (enhanced green fluorescent protein) sequence conjugated with self-cleaving peptide sequence at Alb locus via neonatal in vivo genome editing using adeno-associated virus vector resulted in the expression of EGFP in 7% of liver cells, mainly via homology-directed repair, in mice. Finally, we succeeded in improving the survival of PC-deficient mice by expressing the engineered PC via neonatal genome editing in vivo. CONCLUSIONS: These results suggest that the expression of engineered PC via neonatal genome editing is a potential cure for severe congenital PC deficiency.
  • Takafumi Hiramoto, Hiroshi Inaba, Nemekhbayar Baatartsogt, Yuji Kashiwakura, Morisada Hayakawa, Nobuhiko Kamoshita, Hiroshi Nishimasu, Osamu Nureki, Ei Kinai, Tsukasa Ohmori
    Blood advances 7(22) 7017-7027 2023年11月28日  
    The importance of genetic diagnosis for patients with hemophilia has been recently demonstrated. However, the pathological variant cannot be identified in some patients. Here, we aimed to identify the pathogenic intronic variant causing hemophilia A using induced pluripotent stem cells (iPSCs) from patients and genome editing. We analyzed siblings with moderate hemophilia A and without abnormalities in the F8 exon. Next-generation sequencing of the entire F8 revealed 23 common intron variants. Variant effect predictor software indicated that the deep intronic variant at c.5220-8563A>G (intron 14) might act as a splicing acceptor. We developed iPSCs from patients and used genome editing to insert the elongation factor 1α promoter to express F8 messenger RNA (mRNA). Then, we confirmed the existence of abnormal F8 mRNA derived from aberrant splicing, resulting in a premature terminal codon as well as a significant reduction in F8 mRNA in iPSCs due to nonsense-mediated RNA decay. Gene repair by genome editing recovered whole F8 mRNA expression. Introduction of the intron variant into human B-domain-deleted F8 complementary DNA suppressed factor VIII (FVIII) activity and produced abnormal FVIII lacking the light chain in HEK293 cells. Furthermore, genome editing of the intron variant restored FVIII production. In summary, we have directly proven that the deep intronic variant in F8 results in aberrant splicing, leading to abnormal mRNA and nonsense-mediated RNA decay. Additionally, genome editing targeting the variant restored F8 mRNA and FVIII production. Our approach could be useful not only for identifying causal variants but also for verifying the therapeutic effect of personalized genome editing.
  • Yuji Kashiwakura, Kazuhiro Endo, Atsushi Ugajin, Tomohiro Kikuchi, Shuji Hishikawa, Hitoyasu Nakamura, Yuko Katakai, Nemekhbayar Baatartsogt, Takafumi Hiramoto, Morisada Hayakawa, Nobuhiko Kamoshita, Shoji Yamazaki, Akihiro Kume, Harushi Mori, Naohiro Sata, Yoichi Sakata, Shin-ichi Muramatsu, Tsukasa Ohmori
    Molecular Therapy - Methods & Clinical Development 30 502-514 2023年8月  
  • 冨樫 朋貴, ネメフバヤル・バータルツォグト, 長尾 恭光, 柏倉 裕志, 早川 盛禎, 鴨下 信彦, 平本 貴史, 藤原 隆行, 森下 英理子, 濡木 理, 大森 司
    日本血栓止血学会誌 34(2) 257-257 2023年5月  
  • 柏倉 裕志, 遠藤 和洋, 宇賀神 敦, 菊地 智博, 菱川 修司, 中村 仁康, 片貝 祐子, Nemekhbayar Baatartsogt, 平本 貴史, 早川 盛禎, 鴨下 信彦, 山崎 晶司, 久米 晃啓, 森 墾, 佐田 尚宏, 坂田 洋一, 村松 慎一, 大森 司
    日本血栓止血学会誌 34(2) 240-240 2023年5月  

MISC

 20
  • 早川 盛禎, 尾崎 裕美, 大森 司
    臨床免疫・アレルギー科 75 355-362 2021年3月  招待有り筆頭著者責任著者
  • 早川 盛禎
    コスメトロジー研究報告 23 93-97 2015年9月  
    IL-33デコイ受容体(ST2L)による皮膚炎症の制御について検討した。分泌型ST2を過剰発現するトランスジェニックマウス(ST2-Tgマウス)を作製した。ST2-Tgマウスを用いて、ハプテン塗布による接触皮膚炎モデル、およびダニ抗原塗布によるアトピー性皮膚炎モデルを作製し、皮膚炎症に対する分泌型ST2の作用を中心に検討した。FITC塗布による接触皮膚炎モデルでは、野生型とST2-Tgマウスにおける皮膚樹状細胞の遊走能と皮膚炎症に大きな違いは見られなかった。接触皮膚炎モデルでは、ST2-Tgマウスの皮膚炎症及びTh2型免疫応答は野生型マウスに比べて減弱した。IL-33トランスジェニックマウスを用いた解析で、IL-33の発現亢進により皮膚炎症が誘発されることが示された。
  • 早川 盛禎
    ファルマシア 50(8) 815-815 2014年8月  招待有り筆頭著者責任著者
  • 早川裕子, 早川盛禎
    FASEB JOURNAL 27 835.4 2013年4月  
  • 早川 盛禎
    日本生化学会会誌 83 253 2011年  招待有り筆頭著者責任著者

講演・口頭発表等

 82

担当経験のある科目(授業)

 11

共同研究・競争的資金等の研究課題

 11