Treatment of congenital hypomyelinating leukodystrophy using the gene suppression effect of morpholino

• Project/Area Number: 25670485
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Inoue Ken 国立研究開発法人国立精神・神経医療研究センター, 神経研究所疾病研究第二部, 室長 (30392418)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: トランスレーショナルリサーチ / 脳神経疾患 / アンチセンス / 発現抑制 / 治療法開発 / トランスレーショナルリサーチレーショナルリサーチ / 発現制御

Outline of Final Research Achievements

Pelizaeus-Merzbacher disease is a hypomyelinating leukodystrophy characterized by failure of myelination. the most frequent mutation is PLP1 duplication that lead to gene overexpression, but no cure is available. In this study, we employed a synthetic antisense oligonucleotide-like reagent, morpholino, to develop a therapy for PLP1 duplication. We designed and produced modified morpholino that can specifically suppress PLP1 expression. We treated PLP1 trasngenic mice by injecting morpholino into ventricle or cerebral parenchyma. However, we found that morpholino is toxic to brain tissue and concluded that morpholino is inappropriate to use in the treatment of PLP1 duplication.

Research Products

• [Journal Article] The magnetic resonance imaging spectrum of Pelizaeus-Merzbacher disease: A multicenter study of 19 patients. (2016)
  • Author(s): Sumida K, Inoue K, Takanashi JI, Sasaki M, Watanabe K, Suzuki M, Kurahashi H, Omata T, Tanaka M, Yokochi K, Iio J, Iyoda K, Kurokawa T, Matsuo M, Sato T, Iwaki A, Osaka H, Kurosawa K, Yamamoto T, Matsumoto N, Maikusa N, Mastuda H, Sato N
  • Journal Title: Brain Dev Volume: in press Issue: 6 Pages: 571-80
  • DOI: 10.1016/j.braindev.2015.12.007
  • Peer Reviewed
• [Journal Article] A splicing mutation of proteolipid protein 1 in Pelizaeus-Merzbacher disease. (2016)
  • Author(s): Omata T, Nagai J, Shimbo H, Koizume S, Miyagi Y, Kurosawa K, Yamashita S, Osaka H, Inoue K.
  • Journal Title: Brain & Development Volume: 38 Issue: 6 Pages: 581-584
  • DOI: 10.1016/j.braindev.2015.12.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH (2015)
  • Author(s): Ito Y, Inoue N, Inoue YU, Nakamura S, Matsuda Y, Inagaki M, Okubo T, Asami J, Terakawa YW, Kohsaka S, Goto Y, Akazawa C, Inoue T, Inoue K
  • Journal Title: Neurobiology of Disease Volume: In Press Pages: 1-14
  • DOI: 10.1016/j.nbd.2015.04.013
  • Peer Reviewed
• [Journal Article] Pathophysiology and emerging therapeutic strategies in Pelizaeus-Merzbacher Disease. (2015)
  • Author(s): Osaka H, Inoue K.
  • Journal Title: Expert Opinion on Orphan Drugs. Volume: 3 Issue: 12 Pages: 1447-1458
  • DOI: 10.1517/21678707.2015.1106315
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Attenuation of endoplasmic reticulum stress in Pelizaeus-Merzbacher disease by an anti-malaria drug, chloroquine. (2014)
  • Author(s): Morimura T, Numata Y, Nakamura S, Hirano E, Gotoh L, Goto YI, Urushitani M, Inoue K.
  • Journal Title: Exp Biol Med Volume: 239 Issue: 4 Pages: 489-501
  • DOI: 10.1177/1535370213520108
  • Peer Reviewed
• [Journal Article] Epidemiological, clinical, and genetic landscapes of hypomyelinating leukodystrophies. (2014)
  • Author(s): Numata Y, Gotoh L, Iwaki A, Kurosawa K, Takanashi J, Deguchi K, Yamamoto T, Osaka H, Inoue K.
  • Journal Title: J Neurol. Volume: 261(4) Issue: 4 Pages: 752-758
  • DOI: 10.1007/s00415-014-7263-5
  • Peer Reviewed
• [Journal Article] Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes (2014)
  • Author(s): Numasawa-Kuroiwa Y, Okada Y, Shibata S, Kishi N, Akamatsu W, Shoji M, Nakanishi A, Oyama M, Oasaka H, Inoue K, Takahashi K, Yamanaka S, Kosaki K, Takahashi T, Okano H
  • Journal Title: Stem Cell Rep Volume: 2 Issue: 5 Pages: 1-14
  • DOI: 10.1016/j.stemcr.2014.03.007
  • Peer Reviewed / Open Access
• [Journal Article] SLC16A2 mutations in two Japanese patients with Allan–Herndon–Dudley syndrome. (2014)
  • Author(s): Yamamoto T, Shimojima K, Umemura A, Uematsu M, Nakayama T, Inoue K.
  • Journal Title: HumGenVar Volume: 1 Issue: 1 Pages: 14010-14010
  • DOI: 10.1038/hgv.2014.10
  • Peer Reviewed / Open Access
• [Journal Article] Three new PLP1 splicing mutations demonstrate pathogenic and phenotypic diversity of Pelizaeus-Merzbacher disease. (2014)
  • Author(s): Lassuthova P, Zaliova M, Inoue K, Haberlova J, Sixtova K, Sakmaryova I,Paderova K, Mazanec R, Zamecnik J, Siskova D, Garbern J, Seeman P.
  • Journal Title: J Child Neurol Volume: 0 Issue: 7 Pages: 0-0
  • DOI: 10.1177/0883073813492387
  • Peer Reviewed
• [Journal Article] GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease. (2014)
  • Author(s): Gotoh L, Inoue K, Helman G, Mora S, Maski K, Soul JS, Bloom M, Evans SH, Goto Y, Caldovic L, Hobson GM, Vanderver A.
  • Journal Title: Mol Genet Metab. Volume: 111 Issue: 3 Pages: 393-8
  • DOI: 10.1016/j.ymgme.2013.12.001
  • Peer Reviewed
• [Journal Article] Partial PLP1 deletion causing X-linked dominant spastic paraplegia type 2. (2013)
  • Author(s): Matsufuji M, Osaka H, Gotoh L, Shimbo H, Takashima S, Inoue K
  • Journal Title: Pediatric Neurology Volume: 49 Issue: 6 Pages: 477-81
  • DOI: 10.1016/j.pediatrneurol.2013.07.012
  • Peer Reviewed
• [Journal Article] Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations. (2013)
  • Author(s): 98. Takanashi JI, Osaka H, Saitsu H, Sasaki M, Mori H, Shibayama H, Tanaka M,
  • Journal Title: Brain Dev. Volume: May 3 Issue: 3 Pages: 259-263
  • DOI: 10.1016/j.braindev.2013.03.006
  • Peer Reviewed
• [Journal Article] 先天性大脳白質形成不全症：ゲノム解析から診断、治療への取り組み (2013)
  • Author(s): 井上 健，岩城明子，黒澤健司，高梨潤一，出口貴美子，山本俊至，小坂 仁
  • Journal Title: 脳と発達 Volume: 45 Pages: 122-126
  • NAID: 10031156273
  • Peer Reviewed
• [Presentation] Seeking drugs for Pelizaeus-Merzbacher disease using drug repositioning approach targeting a novel cellular pathology. (2015)
  • Author(s): K Inoue, P.R. Mangalika, A Nishizawa, H Li, Y Numata, S Nakamura, T Morimura, H Saya, Y Goto.
  • Organizer: The 65th American Society of Human Genetics Annual Meeting
  • Place of Presentation: Baltimore Convention Center, Baltimore, USA
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Presentation] 既存薬ドラッグ・リポジショニングによるPelizaeus-Merzbacher病の治療候補薬の探索 (2015)
  • Author(s): 井上 健、マンガリイ・プリアンティ、西澤絢子、李珩、沼田有里佳、中村祥子、守村敏史、佐谷秀行、後藤雄一
  • Organizer: 第57回日本小児神経学会総会
  • Place of Presentation: 大阪（帝国ホテル大阪）
  • Year and Date: 2015-05-28
• [Presentation] PLP1点変異の新規分子病態を標的としたドラッグ・リポジショニングによるPelizaeus-Merzbacher病の治療法開発 (2014)
  • Author(s): 井上 健、マンガリイ・プリアンティ、沼田有里佳、中村祥子、守村敏史、佐谷秀行、後藤雄一
  • Organizer: 第59回日本人類遺伝学会
  • Place of Presentation: 東京（タワーホール船堀）
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] dditive toxicity of SOX10 mutation underlies a complex neurological phenotype of PCWH (2014)
  • Author(s): Inoue K, Ito Y, Inoue N, Inoue YU, Nakamura S, Matsuda Y, Inagaki M, Ohkubo T, Asami J, Terakawa YW, Kohsaka S, Goto Y, Akazawa C, Inoue T.
  • Organizer: The 64th American Society of Human Genetics Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, USA
  • Year and Date: 2014-10-18 – 2014-10-22
• [Presentation] bronx waltzerマウス変異遺伝子Srrm4の脳内発現とGABAergic interneuronへの影響 (2014)
  • Author(s): 白川 由佳、泉 仁美、中村 祥子、井上 健、後藤 雄一、稲垣 真澄
  • Organizer: 第37回神経科学会大会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] PLP1 missense mutations impair subcellular organelle dynamics that impact clinical severity of Pelizaeus-Merzbacher disease. (2014)
  • Author(s): Inoue K, Numata Y, Morimura T, Nakamura S, Goto Y
  • Organizer: 20th Biennial Meeting of the International Society for Developmental Neuroscience
  • Place of Presentation: Hilton Montreal Bonaventure, Montreal, Canada
  • Year and Date: 2014-07-19 – 2014-07-24
• [Presentation] Abnormal neuronal migration with ischemic brain injury in extremely preterm infants underlies subsequent cognitive impairment. (2014)
  • Author(s): K. Deguchi , K Kubo, K Nakajima K. Inoue.
  • Organizer: 20th Biennial Meeting of the International Society for Developmental Neuroscience
  • Place of Presentation: Hilton Montreal Bonaventure, Montreal, Canada
  • Year and Date: 2014-07-19 – 2014-07-24
• [Presentation] Pelizaeus-Merzbacher-like病：GJC2遺伝子の新規プロモーター変異とその分子病態 (2014)
  • Author(s): 井上 健、後藤玲央、Helman G, Mora S, Maski K, Soul JS, Bloom M, Evans SH, 後藤雄一, Caldovic L, Hobson GM, Vanderver A.
  • Organizer: 第56回日本小児神経学会総会
  • Place of Presentation: 浜松（アクトシティ浜松）
  • Year and Date: 2014-05-29 – 2014-05-31
• [Presentation] Preclinical studies for the treatment of Pelizaeus-Merzbacher disease with clinically applicable compounds, curumin and chloroquine. (2013)
  • Author(s): Inoue K, Morimura T, Numata Y, Yu L-H, Gotoh L, Yamamoto R, Inoue N, Antalfy B, Deguchi K, Osaka H, Goto Y.
  • Organizer: 23rd Meeting of the European Neurological Society
  • Place of Presentation: Barcelona, Spain（Fira de Barcelona）
• [Presentation] Abnormal neuronal migration with ischaemic brain injuries may cause cognitive dysfunction in extremely preterm infants. (2013)
  • Author(s): Deguchi K, Kubo K, Armstrong D, Nakajima K, Inoue K.
  • Organizer: 23rd Meeting of the European Neurological Society
  • Place of Presentation: Barcelona, Spain（Fira de Barcelona）
• [Presentation] Brain N-acetylaspartate is Increased in mouse models of Pelizaeus-Merzbacher disease: implication for human imaging findings. (2013)
  • Author(s): Inoue K, Itoh Y, Saito S, Aoki I, Barkovich J, Takanashi J.
  • Organizer: 62rd Annual meeting of the American Society of Human Genetics
  • Place of Presentation: Boston, USA（Boston Convention & Exhibition Center）
• [Presentation] More than ER stress: molecular mechanism for misfolded PLP1 that impacts subcellular dynamics and clinical severity of Pelizaeus-Merzbacher disease. (2013)
  • Author(s): Numata Y, Morimura T, Nakamura S, Hirano E, Kure S, Goto Y, Inoue K.
  • Organizer: 62rd Annual meeting of the American Society of Human Genetics
  • Place of Presentation: Boston, USA（Boston Convention & Exhibition Center）
• [Presentation] 先天性大脳白質形成不全症の脳MRI画像データベース構築への取り組み
  • Author(s): 井上 健、高梨潤一、小坂 仁、佐藤典子
  • Organizer: 第55回日本小児神経学会総会
  • Place of Presentation: 大分（大分オアシスタワーホテル）
• [Presentation] Pelizaeus-Merzbacher病の細胞内分子病態：小胞体ストレスとシャペロンダイナミクス
  • Author(s): 沼田有里佳、呉繁夫、後藤雄一、井上健
  • Organizer: 第55回日本小児神経学会総会
  • Place of Presentation: 大分（大分オアシスタワーホテル）