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Development of novel therapy due to correcting splicing error of patients with galactosialidosis

Research Project

Project/Area Number 19K17298
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionKobe University

Principal Investigator

Bo Ryosuke  神戸大学, 医学部附属病院, 助教 (10749188)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywordsガラクトシアリドーシス / CTSA遺伝子 / ライソソーム病 / 先天代謝異常 / 先天代謝異常症 / スプライシング調整 / スプライシング異常 / アンチセンス
Outline of Research at the Start

ガラクトシアリドーシス(GS)はライソゾーム保護性タンパク質/カテプシンAをコードするCTSA遺伝子の異常で発症するが、根本的な治療法は確立していない。日本人GS患者ではCTSA遺伝子にIVS7+3A>Gを高頻度に有するが、本遺伝子変異は成熟mRNAへのスプライシング過程でexon7の欠失を引き起こす。我々は、この日本人高頻度変異に対して、アンチセンスオリゴヌクレオチド(AO)を用いた修正が根本治療となり得ることに着目した。本研究は、変異をトランスフェクションさせたHeLa細胞に対して、AOを様々な種類、濃度で設計し投与することで、スプライシングの修正が可能であるかを明らかにする。

Outline of Final Research Achievements

Galactosialiodosis is a rare lysosomal disease, caused by mutation in the CTSA gene. In Japanese cases, common variant, IVS7+3A>G, has been identified, which was related to the milder phenotype. However, this mechanism of genotype and phenotype was not fully declared. At first, we analyzed the splicing pattern of this variant both in vivo and vitro. In previous report, this common variant produced exon 7 skipping and normal mRNA. However, our study revealed normal mRNA was not obtained in both. Furthermore, novel alternative splicing product including gt insertion was demonstrated. Skipping of exon 7 (92 bases) was assumed to cause nonsense medicated decay, but this product could be strongly related to the milder phenotype. We planed to clarify whether the specific antisense nucleotide can modify the splicing pattern of CTSA gene or not, but we can not obtain any sufficient effect However, this new splicing variant could be the novel target of therapy with galactosialidosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、日本人ガラクトシアリドーシス患者に多くみられる遺伝子変異に関して検討をおこなった。従来本変異による軽症化の機序は、通常のmRNA産物が一部で産生されるためと考えられていた。しかし本研究から、本変異からの正常mRNAは確認できず、exon7が欠失したうえで2塩基の挿入がみられる新規のスプライシング産物が認められた。これは従来想定されていたものとは異なる機序で臨床像に影響を与えている可能性を示唆している。本研究ではスプライシングを修正し正常化させる薬剤の同定まではできなかったが、新規の治療対象となりうる軽症化のメカニズムに関しての新たな知見が得られた。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (13 results)

All 2022 2021 2020 2019

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (4 results) Book (2 results)

  • [Journal Article] Frequent recurrence of pancreatitis in a patient with Leigh syndrome.2022

    • Author(s)
      Nakashima K, Bo R, Awano H, Nishiyama M, Iijima K.
    • Journal Title

      Pediatric International

      Volume: 64 Issue: 1

    • DOI

      10.1111/ped.15021

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The perioperative transition of serum biomarkers of a 1.5-year-old boy with very-long-chain acyl-CoA dehydrogenase deficiency2021

    • Author(s)
      Bo Ryosuke、Awano Hiroyuki、Yamada Kenji、Ooi Mayu、Okata Yuichi、Bitoh Yuko、Mizobuchi Satoshi、Iijima Kazumoto
    • Journal Title

      Molecular Genetics and Metabolism Reports

      Volume: 27 Pages: 100760-100760

    • DOI

      10.1016/j.ymgmr.2021.100760

    • NAID

      120007097082

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ピポキシル基含有抗生剤内服中の母体より出生したイソ吉草酸血症の一例2021

    • Author(s)
      増田知佳, 坊亮輔, 粟野宏之, 小林弘典, 但馬剛, 飯島一誠
    • Journal Title

      特殊ミルク情報

      Volume: 31 Pages: 41-47

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] False positive cases of elevated tetradecenoyl carnitine in newborn mass screening showed significant loss of body weight2020

    • Author(s)
      Bo Ryosuke、Awano Hiroyuki、Nishida Kosuke、Fujioka Kazumichi、Nishiyama Atsushi、Miyake Osamu、Iijima Kazumoto
    • Journal Title

      Molecular Genetics and Metabolism Reports

      Volume: 24 Pages: 100634-100634

    • DOI

      10.1016/j.ymgmr.2020.100634

    • NAID

      120006882475

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Need for strict clinical management of patients with carnitine palmitoyltransferase II deficiency: Experience with two cases detected by expanded newborn screening2020

    • Author(s)
      Bo Ryosuke、Musha Ikuma、Yamada Kenji、Kobayashi Hironori、Hasegawa Yuki、Awano Hiroyuki、Arao Masato、Kikuchi Toru、Taketani Takeshi、Ohtake Akira、Yamaguchi Seiji、Iijima Kazumoto
    • Journal Title

      Molecular Genetics and Metabolism Reports

      Volume: 24 Pages: 100611-100611

    • DOI

      10.1016/j.ymgmr.2020.100611

    • NAID

      120006882474

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Preliminary Effectiveness and Safety of High Frequency Oscillation in Addition to Mechanical Insufflation and Exsufflation for Intratracheal Mucus Removal in Patients With Neuromuscular Disease: Protocol for a Prospective Study.2019

    • Author(s)
      Hiroyuki Awano, Masashi Nagai , Ryosuke Bo, Mariko Murao, Yusuke Ishida, Tsukasa Tanaka, Kazumi Tomioka, Masahiro Nishiyama, Hiroaki Nagase , Kazumoto Iijima
    • Journal Title

      JMIR Res Protoc.

      Volume: 27 Issue: 6 Pages: e12102-e12102

    • DOI

      10.2196/12102

    • NAID

      120006709591

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The prescription rates of glucagon for hypoglycemia by pediatricians and physicians are low in Japan.2019

    • Author(s)
      Matsumoto M, Awano H, Hirota Y, Nagai M, Bo R, Matsuoka A, Hamaguchi T, Takeuchi T, Nakagawa Y, Ogawa W, Iijima K.
    • Journal Title

      Endocrine

      Volume: 64 Issue: 2 Pages: 233-238

    • DOI

      10.1007/s12020-018-1793-z

    • NAID

      120006645707

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] 極低出生体重児におけるビオチンおよびビオチン関連代謝産物の推移2021

    • Author(s)
      坊亮輔, 山田健治, 洪聖媛, 南部静紀, 藤岡一路, 小林弘典, 長谷川有紀, 渡邊敏明, 野津寛大, 粟野宏之
    • Organizer
      日本先天代謝異常学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 3歳時から6歳時にかけて早期にインスリン抵抗性が顕在化したSHORT症候群の一例2021

    • Author(s)
      坊亮輔, 松本真明, 曽根原晶子, 洪聖媛, 南部静紀, 廣田勇士, 小川渉, 野津寛大, 粟野宏之
    • Organizer
      日本小児内分泌学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Alternative splicing derived by a common mutation of CTSA in Japanese galactosialidosis in vivo and in vitro.2019

    • Author(s)
      Ryosuke Bo, Hiroyuki Awano, Tomohiko Yamamura, Kandai Nozu, Kazumoto Iijima10.2196/12102
    • Organizer
      先天代謝異常学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 新生児マススクリーニングにおけるC14:1偽陽性例では出生後の体重減少が大きい2019

    • Author(s)
      坊亮輔
    • Organizer
      日本マススクリーニング学会
    • Related Report
      2019 Research-status Report
  • [Book] 特殊ミルク治療ガイドブック2020

    • Author(s)
      日本小児医療保健協議会(四者協)治療用ミルク安定供給委員会
    • Total Pages
      152
    • Publisher
      診断と治療社
    • ISBN
      9784787823878
    • Related Report
      2020 Research-status Report
  • [Book] 小児の救急・搬送医療2019

    • Author(s)
      坊亮輔
    • Total Pages
      880
    • Publisher
      東京医学者
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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