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Proof of concept study of a novel excess chromosome elimination therapy to ameliorate and prevent trisomy 21 associated complications

Research Project

Project/Area Number 16K09964
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionMie University

Principal Investigator

Hashizume Ryotaro  三重大学, 医学系研究科, 助教 (50456662)

Co-Investigator(Kenkyū-buntansha) 宮川 世志幸  日本医科大学, 医学部, 講師 (90415604)
緒方 藍歌  名古屋大学, 医学系研究科, 特任助教 (70718311)
高成 広起  徳島大学, 病院, 特任講師 (70723253)
Research Collaborator Wakita Sachiko  
Kokubo Yasumasa  
Okamoto Takayuki  
Hara Mari  
Ichishi Masako  
Kawano Mitsuo  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsダウン症候群 / トリソミー / 染色体工学 / iPS細胞 / CRISPR/Cas / ゲノム編集 / 染色体 / 再生医学 / 遺伝学 / トリソミックレスキュー
Outline of Final Research Achievements

Down syndrome is a chromosomal condition caused by an excess of chromosome 21, leading to an array of lifelong complications. The elimination of extra chromosome 21 could be directly linked to a primary intervention in this context for a person with Down syndrome. The overexpression of ZSCAN4 protein, a transcription factor previously reported as an aneuploidy correction effector, showed no significant extra chromosome elimination rate compared with no-treatment control trisomy 21 iPS cells in our in vitro setting. In an effort to delete extra chromosome, we next employ CRSPR/Cas9 system for DNA double-strand breaks on a single targeted chromosome 21, and found that 7% of entire chromosome loss rate on average by FISH analysis. The strategy to induce single chromosome cleavages at a multiple site using CRISPR/Cas9 thus may contribute to both basic and clinical science for aneuploidy-associated pathological condition, including Down syndrome and other autosomal trisomies.

Academic Significance and Societal Importance of the Research Achievements

細胞内にある複数の相同染色体のうち、単一の染色体をCRISPR/Cas9システムを用いてアレル特異的に切断することにより、標的染色体を細胞内から消去可能であることを示した点は、学術的意義があると判断される。オフターゲット、Cas9蛋白の抗原性、DNAの変異誘導と蓄積、デリバリー法等、臨床応用には複数の解決すべき課題が複数あるも、これまで染色体の消去が困難ないし不可能であった背景に照らし合わせれば、本原理は過剰染色体を後天的に消去する基盤技術として臨床的展開が見込める技術と判断され、人口の0.1%弱の人がDown症候群を有する事実に鑑みれば、十分に社会的意義のある成果といえる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (17 results)

All 2019 2018 Other

All Journal Article (12 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 12 results,  Open Access: 9 results) Presentation (3 results) Remarks (2 results)

  • [Journal Article] Direct free radical scavenging effects of water-soluble HMG-CoA reductase inhibitors2019

    • Author(s)
      Umeda Ryohei、Takanari Hiroki、Ogata Kazue、Matsumoto Shigekiyo、Kitano Takaaki、Ono Katsushige、Tokumaru Osamu
    • Journal Title

      Journal of Clinical Biochemistry and Nutrition

      Volume: 64 Issue: 1 Pages: 20-26

    • DOI

      10.3164/jcbn.18-48

    • NAID

      130007542260

    • ISSN
      0912-0009, 1880-5086
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Renal papillary tip extract stimulates BNP production and excretion from cardiomyocytes2018

    • Author(s)
      Goto I, Okamoto R, Hashizume R, Suzuki N, Ito R, Yamanaka K, Saito H, Kiyonari H, Tawara I, Kageyama Y, Ogihara Y, Ali Y, Yamada N, Katayama N, Ito M
    • Journal Title

      PLoS One

      Volume: 13 Issue: 5 Pages: e0197078-e0197078

    • DOI

      10.1371/journal.pone.0197078

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Possibility of venoarteriual extracorporeal membranous oxygenator being a bridging therapy for hemodynamic deterioration of pulmonary tumor thrombotic microangiopathy prior to initiating chemotherapy2018

    • Author(s)
      Iwashita Y, Maruyama K. et al.
    • Journal Title

      Medicine

      Volume: 37 Issue: 37 Pages: e12169-e12169

    • DOI

      10.1097/md.0000000000012169

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cellular Antisilencing Elements Support Transgene Expression from Herpes Simplex Virus Vectors in the Absence of Immediate Early Gene Expression2018

    • Author(s)
      Han Fang、Miyagawa Yoshitaka、Verlengia Gianluca、Ingusci Selene、Soukupova Marie、Simonato Michele、Glorioso Joseph C.、Cohen Justus B.
    • Journal Title

      Journal of Virology

      Volume: 92 Issue: 17 Pages: 00536-18

    • DOI

      10.1128/jvi.00536-18

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Herpes Simplex Virus Vectors for Gene Transfer to the Central Nervous System2018

    • Author(s)
      Artusi Sara、Miyagawa Yoshitaka、Goins William、Cohen Justus、Glorioso Joseph
    • Journal Title

      Diseases

      Volume: 6 Issue: 3 Pages: 74-74

    • DOI

      10.3390/diseases6030074

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epstein?Barr virus-associated hemophagocytic syndrome in a patient with ulcerative colitis during treatment with azathioprine: A case report and review of literature2018

    • Author(s)
      Miyaguchi Kazuya、Yamaoka Minoru、Tsuzuki Yoshikazu、Ashitani Keigo、Ohgo Hideki、Miyagawa Yoshitaka、Ishizawa Keisuke、Kayano Hidekazu、Nakamoto Hidetomo、Imaeda Hiroyuki
    • Journal Title

      World Journal of Clinical Cases

      Volume: 6 Issue: 14 Pages: 776-780

    • DOI

      10.12998/wjcc.v6.i14.776

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Highly Efficient Ultracentrifugation-free Chromatographic Purification of Recombinant AAV Serotype 92018

    • Author(s)
      Tomono T, Hirai Y, Okada H, Miyagawa Y, Adachi 1, Sakamoto S, Kawano Y, Chono H, Mineno J, Ishii A, Shimada T, Onodera M, Tamaoka A, Okada T.
    • Journal Title

      Mol Ther Methods Clin Dev

      Volume: 11 Pages: 180-190

    • DOI

      10.1016/j.omtm.2018.10.015

    • NAID

      120007128300

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The oral administration of clarithromycin prevents the progression and rupture of aortic aneurysm2018

    • Author(s)
      Uchida W, Narita Y, Yamawaki-Ogata A, Tokuda Y, Mutsuga M1 Lee Fujimoto K, Abe T, Oshima H, Usui A
    • Journal Title

      J Vasc Surg

      Volume: epub Issue: 6 Pages: 82S-92S.e2

    • DOI

      10.1016/j.jvs.2017.12.047

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation of the bactericidal and fungicidal activities of poly([2-(methacryloyloxy)ethyl]trimethyl ammonium chloride)(poly(METAC))-based materials2018

    • Author(s)
      Toshiki Shiga, Hiromitsu Mori, Keiichi Uemura, Ryota Moriuchi, Hideo Dohra, Aika Yamawaki-Ogata, Yuji Narita, Akihiro Saito, Yohei Kotsuchibashi
    • Journal Title

      Polymers

      Volume: 10 Issue: 9 Pages: 947-947

    • DOI

      10.3390/polym10090947

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Testosterone-mediated upregulation of delayed rectifier potassium channel in cardiomyocytes causes abbreviation of QT intervals in rats.2018

    • Author(s)
      Masuda K, Takanari H, Morishima M, Ma F, Wang Y, Takahashi N, Ono K.
    • Journal Title

      J Physiol Sci

      Volume: Jan 13 Issue: 6 Pages: 1-9

    • DOI

      10.1007/s12576-017-0590-4

    • NAID

      40021720520

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo.2018

    • Author(s)
      Baburin I, Varkevisser R, Schramm A, Saxena P, Beyl S, Szkokan P, Linder T, Stary-Weinzinger A, van der Heyden MAG, Houtman M, Takanari H, Jonsson M, Beekman JHD, Hamburger M, Vos MA, Hering S.
    • Journal Title

      Pharmacol Res

      Volume: 131 Pages: 150-163

    • DOI

      10.1016/j.phrs.2018.02.024

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Interleukin 10 Treatment Ameliorates High-Fat Diet-Induced Inflammatory Atrial Remodeling and Fibrillation.2018

    • Author(s)
      Kondo H, Abe I, Gotoh K, Fukui A, Takanari H, Ishii Y, Ikebe Y, Kira S, Oniki T, Saito S, Aoki K, Tanino T, Mitarai K, Kawano K, Miyoshi M, Fujinami M, Yoshimura S, Ayabe R, Okada N, Nagano Y, Akioka H, Shinohara T, Akiyoshi K, Masaki T, Teshima Y, Yufu K, Nakagawa M, Takahashi N.
    • Journal Title

      Circ Arrhythm Electrophysiol

      Volume: 11 Issue: 5

    • DOI

      10.1161/circep.117.006040

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] 染色体消去によるtrisomy 21のhaplotype phasing方法構築2019

    • Author(s)
      橋詰 令太郎、脇田 幸子、原 万里、柴山 道登、宮川 世志幸
    • Organizer
      第18回日本再生医療学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 染色体消去による21番染色体の chromosome phasingの試み-Haplotype phasing of trisomy 21 by chromosome elimination-2018

    • Author(s)
      脇田幸子、原万理、橋詰令太郎
    • Organizer
      遺伝子診療学会(25)
    • Related Report
      2018 Annual Research Report
  • [Presentation] ゲノム編集技術を用いた染色体再編成による染色体排除は、トリソミー細胞の染色体に対する高精度phasingを可能とする2018

    • Author(s)
      脇田幸子、原万里、吉田利通、橋詰令太郎
    • Organizer
      日本人類遺伝学会第63回大会
    • Related Report
      2018 Annual Research Report
  • [Remarks] 基礎医学系講座 修復再生病理学 -Pathology and Matrix biology-

    • URL

      https://www.medic.mie-u.ac.jp/organization/course/pathol_matrix/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 修復再生病理学 - 三重大学 大学院医学系研究科・医学部

    • Related Report
      2017 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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