Modulation of repeat size in trinucleotide repeat expansion disorders

• Project/Area Number: 25713034
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: NAKAMORI Masayuki 大阪大学, 医学(系)研究科(研究院), 助教 (60630233)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000); Fiscal Year 2015: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2014: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000); Fiscal Year 2013: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
• Keywords: 筋強直性ジストロフィー / ハンチントン病 / トリプレットリピート / リピート不安定性 / 脊髄小脳失調症 / ミスマッチ修復 / 脊髄小脳変性症 / CAGリピート / CTGリピート

Outline of Final Research Achievements

Triplet repeat disorders are caused by abnormal expansion of trinucleotide repeat sequences (repeat), and the longer the repeat the more severe the condition. These repeats also lengthen with age, contributing to progression of the disease. Therefore, controlling the repeat length is important from a treatment perspective. Here we conducted research with the aim of elucidating the repeat expansion mechanism as well as developing therapies to stabilize or shorten the repeat length. As a result, we have identified factors that affect repeat expansion, using repeat disorder model cells and patient-derived iPS cells. We also discovered a compound that stabilizes or shortens the repeat length, the effect has been demonstrated in cell models, and we can expect future clinical application of this discovery.

Research Products

• [Int'l Joint Research] フロリダ大学/ロチェスター大学(米国)
• [Int'l Joint Research] トロント大学(カナダ)
• [Int'l Joint Research] IGBMC(フランス)
• [Int'l Joint Research] アダム・ミツキェヴィチ大学(ポーランド)
• [Int'l Joint Research] フロリダ大学/ロチェスター大学(米国)
• [Int'l Joint Research] IGBMC(フランス)
• [Int'l Joint Research] アダム・ミツキェヴィチ大学(ポーランド)
• [Int'l Joint Research] トロント大学(カナダ)
• [Int'l Joint Research] The Hospital for Sick Children(カナダ)
• [Int'l Joint Research] University of Oregon/University of Florida/Ｕｎｉｖｅｒｓｉｔｙ of Rochester(米国)
• [Int'l Joint Research] ＩＧＢＭＣ(フランス)
• [Int'l Joint Research] Adam Mickiewicz University(ポーランド)
• [Journal Article] Myotonic Dystrophy: Advances in Translational Research (2017)
  • Author(s): Nakamori M, Takahashi MP.
  • Journal Title: BRAIN and NERVE Volume: 69 Issue: 1 Pages: 61-69
  • DOI: 10.11477/mf.1416200637
  • ISSN: 1344-8129, 1881-6096
  • Year and Date: 2017-01-01
• [Journal Article] Myotonic dystrophy type 1 patient-derived iPSCs for the investigation of CTG repeat instability. (2017)
  • Author(s): Ueki J, Nakamori M, Nakamura M, Nishikawa M, Yoshida Y, Tanaka A, Morizane A, Kamon M, Araki T, Takahashi MP, Watanabe A, Inagaki N, Sakurai H.
  • Journal Title: Sci Rep. Volume: 13 Issue: 1 Pages: 42522-42522
  • DOI: 10.1038/srep42522
  • Peer Reviewed / Open Access
• [Journal Article] Renal dysfunction can be a common complication in patients with myotonic dystrophy 1. (2016)
  • Author(s): Matsumura T, Saito T, Yonemoto N, Nakamori M, Sugiura T, Nakamori A, et al.
  • Journal Title: J Neurol Sci Volume: 368 Pages: 266-71
  • DOI: 10.1016/j.jns.2016.07.036
  • Peer Reviewed
• [Journal Article] 筋強直性ジストロフィーの新規治療開発の動向と標準的医療の意義 (2016)
  • Author(s): 中森雅之, 高橋正紀
  • Journal Title: 神経内科 Volume: 85 Pages: 240-6
• [Journal Article] 筋強直性ジストロフィーの治療戦略 (2016)
  • Author(s): 中森雅之, 高橋正紀
  • Journal Title: 医学のあゆみ Volume: 259 Pages: 58-64
• [Journal Article] 筋強直性ジストロフィー治療薬開発の現状と患者登録 (2016)
  • Author(s): 中森雅之, 高橋正紀
  • Journal Title: 難病と在宅ケア Volume: 22 Pages: 9-9
• [Journal Article] Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. (2016)
  • Author(s): Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, Kino Y,.......Zimmer T, Furling D, Takahashi MP, Charlet-Berguerand N.
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 11067-11067
  • DOI: 10.1038/ncomms11067
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Oral administration of erythromycin decreases RNA toxicity in myotonic dystrophy. (2016)
  • Author(s): Nakamori M, Taylor K, Mochizuki H, Sobczak K, Takahashi MP.
  • Journal Title: Ann Clin Transl Neurol. Volume: 3 Issue: 1 Pages: 42-54
  • DOI: 10.1002/acn3.271
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Large expansion of CTG*CAG repeats is exacerbated by MutSbeta in human cells. (2015)
  • Author(s): Nakatani R, Nakamori M, Fujimura H, Mochizuki H, Takahashi MP.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 11020-11020
  • DOI: 10.1038/srep11020
  • Peer Reviewed / Open Access
• [Journal Article] Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models. (2015)
  • Author(s): Siboni RB, Bodner MJ, Khalifa MM, Docter AG, Choi JY, Nakamori M, Haley MM, Berglund JA.
  • Journal Title: J Med Chem. Volume: 58 Issue: 15 Pages: 5770-80
  • DOI: 10.1021/acs.jmedchem.5b00356
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models. (2015)
  • Author(s): Siboni RB, Nakamori M, Wagner SD, Struck AJ, Coonrod LA, Harriott SA, Cass DM, Tanner MK, Berglund JA.
  • Journal Title: Cell Rep. Volume: 13 Issue: 11 Pages: 2386-94
  • DOI: 10.1016/j.celrep.2015.11.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 神経変性疾患のRNA創薬は5年以内に成功するか (2015)
  • Author(s): 中森雅之, 望月秀樹
  • Journal Title: Frontiers in Parkinson Disease. Volume: 8 Pages: 141-3
• [Journal Article] Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects. (2014)
  • Author(s): Hoskins JW, Ofori LO, Chen CZ, Kumar A, Sobczak K, Nakamori M, Southall N, Patnaik S, Marugan JJ, Zheng W, Austin CP, Disney MD, Miller BL, Thornton CA.
  • Journal Title: Nucleic Acids Res Volume: 42 Issue: 10 Pages: 6591-602
  • DOI: 10.1093/nar/gku275
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Kir3.4 mutation causes Andersen–Tawil syndrome by an inhibitory effect on Kir2.1. (2014)
  • Author(s): Kokunai Y, Nakata T, Furuta M, Sakata S, Kimura H, Aiba T, Yoshinaga M, Osaki Y, Nakamori M, Itoh H, Sato T, Kubota T, Kadota K, Shindo K, Mochizuki H, Shimizu W, Horie M, Okamura Y, Ohno K, Takahashi MP
  • Journal Title: Neurology Volume: 82 Issue: 12 Pages: 1058-64
  • DOI: 10.1212/wnl.0000000000000239
  • Peer Reviewed / Open Access
• [Journal Article] A simple questionnaire for screening patients with myotonic dystrophy type 1. (2014)
  • Author(s): Matsumura T, Kimura T, Kokunai Y, Nakamori M, Ogata K, Fujimura H, Takahashi MP, Mochizuki H, and Sakoda S.
  • Journal Title: Neurology and Clinical Neuroscience Volume: 2 Pages: 97-103
  • Peer Reviewed
• [Journal Article] 筋強直性ジストロフィーの治療開発 (2014)
  • Author(s): 高橋正紀, 中森雅之, 望月秀樹.
  • Journal Title: 臨床神経 Volume: 54 Pages: 1077-79
• [Journal Article] 筋強直性ジストロフィーにおける筋強直、心臓伝導障害とイオンチャネル異常 (2014)
  • Author(s): 久保田智哉、中森雅之、高橋正紀
  • Journal Title: 臨床病理 Volume: 62 Pages: 246-254
• [Journal Article] Splicing biomarkers of disease severity in myotonic dystrophy. (2013)
  • Author(s): Nakamori M, Sobczak K, Puwanant A, Welle S, Eichinger K, Pandya S, Dekdebrun J, Heatwole CR, McDermott MP, Chen T, Cline M, Tawil R, Osborne RJ, Wheeler TM, Swanson MS, Moxley RT 3rd, Thornton CA.
  • Journal Title: Annals of Neurology Volume: 74 Issue: 6 Pages: 862-72
  • DOI: 10.1002/ana.23992
  • Peer Reviewed
• [Journal Article] Reducing levels of toxic RNA with small molecules. (2013)
  • Author(s): Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, Siboni RB, Docter AG, Haley MM, Thornton CA, Berglund JA.
  • Journal Title: ACS Chemical Biology Volume: 8 Issue: 11 Pages: 2528-37
  • DOI: 10.1021/cb400431f
  • Peer Reviewed
• [Journal Article] Detection of slipped-DNAs at the trinucleotide repeats of the myotonic dystrophy type I disease locus in patient tissues. (2013)
  • Author(s): Axford MM, Wang YH, Nakamori M, Zannis-Hadjopoulos M, Thornton CA, Pearson CE.
  • Journal Title: PLoS Genetics Volume: 9 Issue: 12 Pages: e1003866-e1003866
  • DOI: 10.1371/journal.pgen.1003866
  • Peer Reviewed
• [Journal Article] 核スプライシング障害とトリプレットリピート病 (2013)
  • Author(s): 中森雅之, 高橋正紀.
  • Journal Title: 脳21 Volume: 16 Pages: 71-77
• [Presentation] Oral administration of erythromycin decreases RNA toxicity in myotonic dystrophy. (2016)
  • Author(s): Nakamori M
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
• [Presentation] Gene therapy with antisense oligonucleotides for neurological and neuromuscular disorders. (2016)
  • Author(s): Nakamori M
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Invited
• [Presentation] Antisense oligonucleotides therapy for neurological and neuromuscular disorders. (2016)
  • Author(s): Nakamori M
  • Organizer: 第22回日本遺伝子細胞治療学会学術集会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 筋強直性ジストロフィーの新しい治療 (2016)
  • Author(s): 中森雅之
  • Organizer: 第4回北海道東北筋強直性ジストロフィー臨床研究会
  • Place of Presentation: 旭川
  • Invited
• [Presentation] ハンチントン病の将来の治療 (2016)
  • Author(s): 中森雅之
  • Organizer: 第10回 パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 京都
  • Invited
• [Presentation] Phenotype-genotype correlation in congenital myotonic dystrophy. (2015)
  • Author(s): Nakamori M.
  • Organizer: The 8th International Conference on Unstable Microsatellites and Human Disease
  • Place of Presentation: Guanacaste, Costa Rica
  • Year and Date: 2015-01-18
  • Int'l Joint Research / Invited
• [Presentation] Aberrant methylation of the CTCF binding site is associated with antisense transcription and disease severity in congenital myotonic dystrophy. (2015)
  • Author(s): Nakamori M
  • Organizer: 10th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: Paris, France.
  • Int'l Joint Research
• [Presentation] Myotonic dystrophy: toxic RNA and spliceopathy. (2015)
  • Author(s): Nakamori M
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 埼玉
  • Invited
• [Presentation] Phenotype-genotype correlation in congenital myotonic dystrophy. (2015)
  • Author(s): Nakamori M
  • Organizer: 10th Brain Research Conference: RNA Metabolism in Neurological Disease
  • Place of Presentation: Chicago, U.S.A.
  • Int'l Joint Research
• [Presentation] 先天性筋強直性ジストロフィー症の筋未熟性とCpGメチル化異常 (2015)
  • Author(s): 中森雅之
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟
• [Presentation] 筋強直性ジストロフィーの治療戦略 (2015)
  • Author(s): 中森雅之
  • Organizer: 第2回筋ジストロフィー医療研究会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] 筋強直性ジストロフィーにおける網羅的スプライシング解析とスプライシングバイオマーカーの確立 (2014)
  • Author(s): 中森雅之
  • Organizer: 日本人類遺伝学会 第59回大会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-21
• [Presentation] 筋強直性ジストロフィーにおけるスプライシングバイオマーカーの確立 (2014)
  • Author(s): 中森雅之
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-22
• [Presentation] トリプレットリピート病におけるリピート長伸長機構の解明と制御 (2013)
  • Author(s): 中森雅之
  • Organizer: 第58回日本人類遺伝学会大会
  • Place of Presentation: 江陽グランドホテル（宮城県）
  • Year and Date: 2013-11-21
• [Presentation] Phenotype-genotype correlation in congenital myotonic dystrophy. (2013)
  • Author(s): Masayuki Nakamori
  • Organizer: 8th Brain Research Conference
  • Place of Presentation: San Diego (U.S.A.)
  • Year and Date: 2013-11-07
• [Presentation] Pentamidine and analogs as inhibitors of transcription. (2013)
  • Author(s): Coonrod L, Nakamori M
  • Organizer: 9th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: Donostia San Sebastian (Spain)
  • Year and Date: 2013-10-18
• [Presentation] Actinomycin D inhibits transcription of CUG RNA in a DM1 model. (2013)
  • Author(s): Siboni R, Nakamori M
  • Organizer: 9th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: Donostia San Sebastian (Spain)
  • Year and Date: 2013-10-18
• [Presentation] Phenotype-genotype correlation in congenital myotonic dystrophy. (2013)
  • Author(s): Masayuki Nakamori
  • Organizer: 9th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: Donostia San Sebastian (Spain)
  • Year and Date: 2013-10-17
• [Presentation] トリプレットリピート病におけるリピート長の制御 (2013)
  • Author(s): 中森雅之
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム（東京都）
  • Year and Date: 2013-05-30
• [Book] Translational research in muscular dystrophy (2016)
  • Author(s): Nakamori M, Takahashi MP.
  • Total Pages: 23
  • Publisher: Springer Japan
• [Book] 筋疾患診療ハンドブック (2013)
  • Author(s): 中森雅之, 高橋正紀
  • Publisher: 中外医学社
• [Patent(Industrial Property Rights)] 筋強直性ジストロフィー治療薬 (2016)
  • Inventor(s): 中森雅之
  • Industrial Property Rights Holder: 中森雅之
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-07-07
  • Overseas
• [Patent(Industrial Property Rights)] 筋強直性ジストロフィー治療薬 (2015)
  • Inventor(s): 中森雅之
  • Industrial Property Rights Holder: 中森雅之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-140599
  • Filing Date: 2015-07-14