Development of treatment for autism spectrum disorder relating with oxytocin and miRNA

• Project/Area Number: 19K08258
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Jichi Medical University
• Principal Investigator: 山形 崇倫 自治医科大学, 医学部, 客員教授 (00239857)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 自閉スペクトラム症 / MECP2 / MECP2重複症候群 / Rett症候群 / miRNA / 遺伝子治療 / 神経発達症 / MECP2関連疾患 / 概日リズム関連遺伝子 / 治療 / オキシトシン

Outline of Research at the Start

自閉スペクトラム症（ASD）の治療法開発を、オキシトシン神経系とmiRNAに焦点を絞り実施する。①独自に開発したオキシトシン神経系を活性化する内服薬の治療効果と作用を臨床研究により確認する。②miRNAのASDへの関与を解析するため、aCGH解析などにより、疾患関連miRNAを抽出する。③ASDに関連すると確認されたmiRNAについて、脳での発現解析や細胞導入による作用の確認等により作用を解析するとともに、治療二用いる可能性を探る。その一端として、MECP2重複例で、miRNA導入によりMECP2発現量を減らし治療可能となるかを解析する。

Outline of Annual Research Achievements

自閉スペクトラム症(ASD)等の神経発達症と関連疾患のRett症候群／MECP2重複症候群の病態解析と治療開発研究を行った。治療開発として、オキシトシン神経系を賦活する機能性糖質のASDと肥満に対する効果と、MECP2関連疾患のmiRNAを用いた治療や遺伝子治療を検討している。
機能性糖質の臨床研究は、治療薬群と非治療薬群の二重盲検試験実施後、治療群と非治療群を交代して実施した。10名治療実施し、2024年6月にキーオープンの予定である。大きな有害事象はなく、有効性が示されれば、治験に進む予定である。
MECP2発現を抑制するmiRNA同定研究を行った。検索アルゴリズムでMECP2抑制の可能性が高く、他遺伝子に作用する可能性が低いものなど、50種類のmiRNAを選択し、培養神経細胞でスクリーニングした。ヒトとマウス両方でMECP2発現を0.5-0.8程度抑制するmiRNAを4個選択し、MECP2重複症候群モデルマウスの海馬由来神経細胞とヒトiPS細胞由来神経細胞で、Mecp2発現をそれぞれ60-84%に抑制することを確認した。しかし、神経細胞と神経芽細胞でも作用の程度が異なることも示され、さらに、網羅的にオフターゲット作用を確認しており、治療薬候補miRNA選択を進めていく。
低発現で神経細胞特異的に発現するsynIプロモーターを用いたMECP2導入ベクター(AAV9)を作製し、Rett症候群モデルマウス大槽に注入し、治療効果を確認した。オスマウスでは生存期間が80日から100-120日間、さらにそれ以上の長期生存例も得られた。ヘテロのメスでは、１年間観察し、運動機能改善等の効果が明らかになった。さらに解析を進め、治療薬として確立していく。同時にdCasシステムを用い、不活化されている正常MECP2の活性化による治療も進めている。

Research Products

• [Journal Article] Apomorphine is a potent inhibitor of ferroptosis independent of dopaminergic receptors (2024)
  • Author(s): Miyauchi Akihiko、Watanabe Chika、Yamada Naoya、Jimbo Eriko F.、Kobayashi Mizuki、Ohishi Natsumi、Nagayoshi Atsuko、Aoki Shiho、Kishita Yoshihito、Ohtake Akira、Ohno Nobuhiko、Takahashi Masafumi、Yamagata Takanori、Osaka Hitoshi
  • Journal Title: Scientific Reports Volume: 14 Issue: 1 Pages: 4820-4820
  • DOI: 10.1038/s41598-024-55293-1
  • Peer Reviewed / Open Access
• [Journal Article] Unfavorable switching of skewed X chromosome inactivation leads to Menkes disease in a female infant (2024)
  • Author(s): Matsumoto Ayumi、Kano Shintaro、Kobayashi Natsumi、Matsuki Mitsuru、Furukawa Rieko、Yamagishi Hirokazu、Yoshinari Hiroki、Nakata Waka、Wakabayashi Hiroko、Tsuda Hidetoshi、Watanabe Kazuhisa、Takahashi Hironori、Yamagata Takanori、Matsumura Takayoshi、Osaka Hitoshi、Mori Harushi、Iwamoto Sadahiko
  • Journal Title: Scientific Reports Volume: 14 Issue: 1 Pages: 440-440
  • DOI: 10.1038/s41598-023-50668-2
  • Peer Reviewed / Open Access
• [Journal Article] Development of emotion comprehension in children with autism spectrum disorder and Williams syndrome (2023)
  • Author(s): Ikeda Ayaka、Hakuno Yoko、Asada Kosuke、Ikeda Takahiro、Yamagata Takanori、Hirai Masahiro
  • Journal Title: Autism Research Volume: 16 Issue: 12 Pages: 2378-2390
  • DOI: 10.1002/aur.3053
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of the Social Responsiveness Scale-2 among Individuals with Autism Spectrum Disorder and Williams Syndrome in Japan (2022)
  • Author(s): Hirai Masahiro、Asada Kosuke、Kato Takeo、Ikeda Takahiro、Hakuno Yoko、Ikeda Ayaka、Matsushima Kanae、Awaya Tomonari、Okazaki Shin、Kato Toshihiro、Funabiki Yasuko、Murai Toshiya、Heike Toshio、Hagiwara Masatoshi、Yamagata Takanori、Tomiwa Kiyotaka、Kimura Ryo
  • Journal Title: Journal of Autism and Developmental Disorders Volume: - Issue: 8 Pages: 3176-3184
  • DOI: 10.1007/s10803-022-05740-7
  • Peer Reviewed / Open Access
• [Journal Article] The ATRX splicing variant c.21-1G>A is asymptomatic (2022)
  • Author(s): Kojima Karin、Wada Takahito、Shimbo Hiroko、Ikeda Takahiro、Jimbo Eriko F.、Saitsu Hirotomo、Matsumoto Naomichi、Yamagata Takanori
  • Journal Title: Human Genome Variation Volume: 9 Issue: 1 Pages: 33-33
  • DOI: 10.1038/s41439-022-00212-x
  • Peer Reviewed / Open Access
• [Journal Article] A TUBB4A Met363Thr variant in pediatric hypomyelination without atrophy of the basal ganglia (2022)
  • Author(s): Hashiguchi Marina、Monden Yukifumi、Nozaki Yasuyuki、Watanabe Kazuki、Nakashima Mitsuko、Saitsu Hirotomo、Yamagata Takanori、Osaka Hitoshi
  • Journal Title: Human Genome Variation Volume: 9 Issue: 1 Pages: 19-19
  • DOI: 10.1038/s41439-022-00198-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recurrent pneumonia in three patients with MECP2 duplication syndrome with aspiration as the possible cause (2022)
  • Author(s): Sugitate Ryo、Muramatsu Kazuhiro、Ogata Tomomi、Goto Masahide、Hayashi Shin、Sawaura Noriko、Kawada-Nagashima Masako、Matsui Atsushi、Yamagata Takanori
  • Journal Title: Brain and Development Volume: 44 Issue: 7 Pages: 486-491
  • DOI: 10.1016/j.braindev.2022.03.005
  • Peer Reviewed
• [Journal Article] Developmental changes of the neural mechanisms underlying level 2 visual perspective‐taking: A functional near‐infrared spectroscopy study (2022)
  • Author(s): Hirai Masahiro、Sakurada Takeshi、Ikeda Takahiro、Monden Yukifumi、Shimoizumi Hideo、Yamagata Takanori
  • Journal Title: Developmental Psychobiology Volume: 64 Issue: 1 Pages: 1-20
  • DOI: 10.1002/dev.22229
  • Peer Reviewed / Open Access
• [Journal Article] Low donor chimerism may be sufficient to prevent demyelination in adrenoleukodystrophy. (2021)
  • Author(s): Ikeda T, Kawahara Y, Miyauchi A, Niijima H, Furukawa R, Shimozawa N, Morimoto A, Osaka H, Yamagata T.
  • Journal Title: JIMD Rep. Volume: 63 Issue: 1 Pages: 19-24
  • DOI: 10.1002/jmd2.12259
  • Peer Reviewed / Open Access
• [Journal Article] Valine metabolites analysis in ECHS1 deficiency (2021)
  • Author(s): Kuwajima M, Kojima K, Osaka H, Hamada Y, Jimbo E, Watanabe M, Aoki S, Sato-Shirai I, Ichimoto K, Fushimi T, Murayama K, Ohtake A, Kohda M, Kishita Y, Yatsuka Y, Uchino S, Mimaki M, Miyake N, Matsumoto N, Okazaki Y, Ogata T, Yamagata T, Muramatsu K.
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 29 Pages: 100809-100809
  • DOI: 10.1016/j.ymgmr.2021.100809
  • Peer Reviewed / Open Access
• [Journal Article] Dopaminergic restoration of prefrontal cortico-putaminal network in gene therapy for aromatic l-amino acid decarboxylase deficiency (2021)
  • Author(s): Onuki Yoshiyuki、Ono Sayaka、Nakajima Takeshi、Kojima Karin、Taga Naoyuki、Ikeda Takahiro、Kuwajima Mari、Kurokawa Yoshie、Kato Mitsuhiro、Kawai Kensuke、Osaka Hitoshi、Sato Toshihiko、Muramatsu Shin-ichi、Yamagata Takanori
  • Journal Title: Brain Communications Volume: － Issue: 3
  • DOI: 10.1093/braincomms/fcab078
  • Peer Reviewed / Open Access
• [Journal Article] Intellectual disability and microcephaly associated with a novel CHAMP1 mutation (2021)
  • Author(s): Asakura Yuta、Osaka Hitoshi、Aoi Hiromi、Mizuguchi Takeshi、Matsumoto Naomichi、Yamagata Takanori
  • Journal Title: Human Genome Variation Volume: 8 Issue: 1 Pages: 34-34
  • DOI: 10.1038/s41439-021-00165-7
  • Peer Reviewed / Open Access
• [Journal Article] Greater reliance on proprioceptive information during a reaching task with perspective manipulation among children with autism spectrum disorders (2021)
  • Author(s): Hirai Masahiro、Sakurada Takeshi、Izawa Jun、Ikeda Takahiro、Monden Yukifumi、Shimoizumi Hideo、Yamagata Takanori
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 15974-15974
  • DOI: 10.1038/s41598-021-95349-0
  • Peer Reviewed / Open Access
• [Journal Article] Two cases of DYNC1H1 mutations with intractable epilepsy (2021)
  • Author(s): Matsumoto Ayumi、Kojima Karin、Miya Fuyuki、Miyauchi Akihiko、Watanabe Kazuhisa、Iwamoto Sadahiko、Kawai Kensuke、Kato Mitsuhiro、Takahashi Yukitoshi、Yamagata Takanori
  • Journal Title: Brain and Development Volume: 43 Issue: 8 Pages: 857-862
  • DOI: 10.1016/j.braindev.2021.05.005
  • Peer Reviewed
• [Journal Article] MCT8 deficiency in a patient with a novel frameshift variant in the SLC16A2 gene (2021)
  • Author(s): Wakabayashi Kei、Osaka Hitoshi、Kojima Karin、Imaizumi Taichi、Yamamoto Toshiyuki、Yamagata Takanori
  • Journal Title: Human Genome Variation Volume: 8 Issue: 1 Pages: 10-10
  • DOI: 10.1038/s41439-021-00142-0
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings (2021)
  • Author(s): Ohashi K, Fukuhara S, Miyachi T, Asai T, Imaeda M, Goto M, Kurokawa Y, Anzai T, Tsurusaki Y, Miyake N, Matsumoto N, Yamagata T, Saitoh S
  • Journal Title: J Autism Dev Disord Volume: なし Issue: 12 Pages: 4655-4662
  • DOI: 10.1007/s10803-021-04910-3
  • Peer Reviewed
• [Journal Article] Gene Therapy in a Mouse Model of Niemann?Pick Disease Type C1 (2021)
  • Author(s): Kurokawa Yoshie、Osaka Hitoshi、Kouga Takeshi、Jimbo Eriko、Muramatsu Kazuhiro、Nakamura Sachie、Takayanagi Yuki、Onaka Tatsushi、Muramatsu Shin-ichi、Yamagata Takanori
  • Journal Title: Human Gene Therapy Volume: 32 Issue: 11-12 Pages: 589-598
  • DOI: 10.1089/hum.2020.175
  • Peer Reviewed / Open Access
• [Journal Article] Intra-cisterna magna delivery of an AAV vector with the GLUT1 promoter in a pig recapitulates the physiological expression of SLC2A1 (2021)
  • Author(s): Nakamura Sachie、Osaka Hitoshi、Muramatsu Shin-ichi、Takino Naomi、Ito Mika、Jimbo Eriko F.、Watanabe Chika、Hishikawa Shuji、Nakajima Takeshi、Yamagata Takanori
  • Journal Title: Gene Therapy Volume: 28 Issue: 6 Pages: 329-338
  • DOI: 10.1038/s41434-020-00203-z
  • Peer Reviewed
• [Journal Article] Does Culture Shape Face Perception in Autism? Cross-cultural Evidence of the Own-Race Advantage From the UK and Japan (2020)
  • Author(s): Hanley, M., Riby, DM., Derges, MJ, Douligeri, A., Philyaw, Z., Ikeda, T., Monden, Y., Shimoizumi, H., Yamagata, T., Hirai, M.
  • Journal Title: Developmental Science Volume: 25 Issue: 5 Pages: 1-20
  • DOI: 10.1111/desc.12942
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy (2019)
  • Author(s): Negishi Yutaka、Ieda Daisuke、Hori Ikumi、Nozaki Yasuyuki、Yamagata Takanori、Komaki Hirofumi、Tohyama Jun、Nagasaki Keisuke、Tada Hiroko、Saitoh Shinji
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 14 Issue: 1 Pages: 277-277
  • DOI: 10.1186/s13023-019-1249-4
  • Peer Reviewed / Open Access
• [Journal Article] Role of Per3, a circadian clock gene, in embryonic development of mouse cerebral cortex.? (2019)
  • Author(s): Noda M, Iwamoto I, Tabata H, Yamagata T, Ito H, Nagata K.
  • Journal Title: Sci. Rep. Volume: 9 Issue: 1 Pages: 5874-5874
  • DOI: 10.1038/s41598-019-42390-9
  • Peer Reviewed / Open Access
• [Presentation] Gene therapy for Niemann-Pick disease type C1 (NPC1) using AAV.GTX-NPC1. (2023)
  • Author(s): Karin Kojima, Yoshie Kurokawa, Chika Watanabe, Takanori Yamagata.
  • Organizer: 第29回日本遺伝子細胞治療学会学術集会 シンポジウムGenetic Diseases
  • Invited
• [Presentation] 小児難治性神経疾患に対する遺伝子治療 (2021)
  • Author(s): 山形 崇倫
  • Organizer: 第124回日本小児科学会学術集会
  • Invited
• [Presentation] 遺伝子治療開発における臨床試験の実際 (2021)
  • Author(s): 山形 崇倫
  • Organizer: 第63回日本小児神経学会学術集会
  • Invited
• [Presentation] Gene therapy of genetic neurological disorders (2021)
  • Author(s): Osaka H,Nakamura S,Kurokawa Y,Kojima K, Miyauchi A,Muramatsu K,Jimbo E,Nakajima T,Mizukami H,Muramatsu SI,Yamagata T
  • Organizer: 第27回日本遺伝子細胞治療学会
  • Invited
• [Presentation] Circadian-relevant gene PERIOD3 is related to autism spectrum disorder and has function neuronal development (2019)
  • Author(s): Miyauchi A, Noda M, Matsumoto A, Goto M, Kojima K, Osaka H, Jimbo E, Nagata K, Yamagata T
  • Organizer: The American Society of Human Genetics 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] First report of FER1L6 as the gene responsible for hypotonia and intellectual disability (2019)
  • Author(s): Matsumoto A, Nagao Y, Saitsu H, Osaka H, Iwamoto S, Yamagata T
  • Organizer: 日本人類遺伝学会 第64回大会