大谷木 正貴 (オオヤギ マサキ)

Ohyagi, Masaki

写真a

所属(所属キャンパス)

医学部 微生物学・免疫学教室 (信濃町)

職名

特任助教(有期)

学歴 【 表示 / 非表示

  • 2002年04月
    -
    2008年03月

    東京医科歯科大学, 医学部, 医学科

    大学, 卒業

  • 2015年04月
    -
    2020年03月

    東京医科歯科大学

    大学, 修了, 博士

学位 【 表示 / 非表示

  • 博士(医学), 東京医科歯科大学, 課程, 2020年03月

 

論文 【 表示 / 非表示

  • Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve.

    Hidetoshi Kaburagi, Tetsuya Nagata, Mitsuhiro Enomoto, Takashi Hirai, Masaki Ohyagi, Kensuke Ihara, Kie Yoshida-Tanaka, Satoe Ebihara, Ken Asada, Hiroyuki Yokoyama, Atsushi Okawa, Takanori Yokota

    Molecular therapy. Nucleic acids 28   910 - 919 2022年06月

    査読有り

     概要を見る

    Neuropathic pain, a heterogeneous condition, affects 7%-10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its therapeutic utility. ASO therapy for neuropathic pain and peripheral nerve disease requires efficient gene delivery and knockdown in both the dorsal root ganglion (DRG) and sciatic nerve, key tissues for pain signaling. We previously developed a new DNA/RNA heteroduplex oligonucleotide (HDO) technology that achieves highly efficient gene knockdown in the liver. Here, we demonstrated that intravenous injection of HDO, comprising an ASO and its complementary RNA conjugated to α-tocopherol, silences endogenous gene expression more than 2-fold in the DRG, and sciatic nerve with higher potency, efficacy, and broader distribution than ASO alone. Of note, we observed drastic target suppression in all sizes of neuronal DRG populations by in situ hybridization. Our findings establish HDO delivery as an investigative and potentially therapeutic platform for neuropathic pain and peripheral nerve disease.

  • Regulation of activated microglia and macrophages by systemically administered DNA/RNA heteroduplex oligonucleotides.

    Rieko Nishi, Masaki Ohyagi, Tetsuya Nagata, Yo Mabuchi, Takanori Yokota

    Molecular therapy : the journal of the American Society of Gene Therapy 2022年02月

    筆頭著者, 査読有り

     概要を見る

    Microglial activation followed by recruitment of blood-borne macrophages into the central nervous system (CNS) aggravates neuroinflammation. Specifically, in multiple sclerosis (MS) as well as in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, activated microglia and macrophages (Mg/Mφ) promote proinflammatory responses and expand demyelination in the CNS. However, a potent therapeutic approach through the systemic route for regulating their functions has not yet been developed. Here, we demonstrated that a systemically injected DNA/RNA heteroduplex oligonucleotide (HDO), composed of an antisense oligonucleotide (ASO) and its complementary RNA, conjugated to cholesterol (Chol-HDO) distributed more efficiently to demyelinating lesions of the spinal cord in EAE mice with significant gene silencing than the parent ASO. Importantly, systemic administration of Cd40-targeting Chol-HDO improved clinical signs of EAE with significant downregulation of Cd40 in Mg/Mφ. Furthermore, we successfully identified that macrophage scavenger receptor 1 (MSR1) is responsible for the uptake of Chol-HDO by Mg/Mφ of EAE mice. Overall, our findings demonstrate the therapeutic potency of systemically administered Chol-HDO to regulate activated Mg/Mφ in neuroinflammation.

  • DNA/RNA heteroduplex oligonucleotide technology for regulating lymphocytes in vivo.

    Masaki Ohyagi, Tetsuya Nagata, Kensuke Ihara, Kie Yoshida-Tanaka, Rieko Nishi, Haruka Miyata, Aya Abe, Yo Mabuchi, Chihiro Akazawa, Takanori Yokota

    Nature communications 12 ( 1 ) 7344 - 7344 2021年12月

    筆頭著者, 査読有り

     概要を見る

    Manipulating lymphocyte functions with gene silencing approaches is promising for treating autoimmunity, inflammation, and cancer. Although oligonucleotide therapy has been proven to be successful in treating several conditions, efficient in vivo delivery of oligonucleotide to lymphocyte populations remains a challenge. Here, we demonstrate that intravenous injection of a heteroduplex oligonucleotide (HDO), comprised of an antisense oligonucleotide (ASO) and its complementary RNA conjugated to α-tocopherol, silences lymphocyte endogenous gene expression with higher potency, efficacy, and longer retention time than ASOs. Importantly, reduction of Itga4 by HDO ameliorates symptoms in both adoptive transfer and active experimental autoimmune encephalomyelitis models. Our findings reveal the advantages of HDO with enhanced gene knockdown effect and different delivery mechanisms compared with ASO. Thus, regulation of lymphocyte functions by HDO is a potential therapeutic option for immune-mediated diseases.

  • Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS

    Tetsuya Nagata, Chrissa A. Dwyer, Kie Yoshida-Tanaka, Kensuke Ihara, Masaki Ohyagi, Hidetoshi Kaburagi, Haruka Miyata, Satoe Ebihara, Kotaro Yoshioka, Takashi Ishii, Kanjiro Miyata, Kenichi Miyata, Berit Powers, Tomoko Igari, Syunsuke Yamamoto, Naoto Arimura, Hideki Hirabayashi, Toshiki Uchihara, Rintaro Iwata Hara, Takeshi Wada, C. Frank Bennett, Punit P. Seth, Frank Rigo, Takanori Yokota

    Nature Biotechnology (Springer Science and Business Media LLC)  39 ( 12 ) 1529 - 1536 2021年12月

    査読有り,  ISSN  1087-0156

     概要を見る

    Achieving regulation of endogenous gene expression in the central nervous system (CNS) with antisense oligonucleotides (ASOs) administered systemically would facilitate the development of ASO-based therapies for neurological diseases. We demonstrate that DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol or α-tocopherol at the 5' end of the RNA strand reach the CNS after subcutaneous or intravenous administration in mice and rats. The HDOs distribute throughout the brain, spinal cord and peripheral tissues and suppress the expression of four target genes by up to 90% in the CNS, whereas single-stranded ASOs conjugated to cholesterol have limited activity. Gene knockdown was observed in major CNS cell types and was greatest in neurons and microglial cells. Side effects, such as thrombocytopenia and focal brain necrosis, were limited by using subcutaneous delivery or by dividing intravenous injections. By crossing the blood-brain barrier more effectively, cholesterol-conjugated HDOs may overcome the limited efficacy of ASOs targeting the CNS without requiring intrathecal administration.

  • Intrathecal IgG Synthesis and Persistent Inflammation Are Associated with White Matter Lesions in HIV-negative Patients with Cryptococcal Meningoencephalitis

    Ohyagi, M., Irioka, T., Ohkubo, T., Ishibashi, S., Takahashi, Y. K., Amano, E., Machida, A., Kuwahara, H. and Yokota, T.

    Intern Med 58 ( 21 ) 3077 - 3082 2019年11月

    査読有り,  ISSN  0918-2918

     概要を見る

    Objective Cryptococcal meningoencephalitis (CM) causes significant morbidity and mortality in human immunodeficiency virus (HIV)-negative and HIV-positive populations. White matter lesions (WMLs) have been reported in both populations of CM patients; however, the mechanisms underlying WML formation remain unknown. We herein report the relationship between the intrathecal immune response and the development of WMLs in HIV-negative patients with CM. Methods Eleven consecutive HIV-negative patients with CM who presented at one of three emergency hospitals in Japan from April 2001 to March 2018 were enrolled. For all patients, we retrospectively assessed the relationships between clinical and laboratory information and the presence of WMLs. Results At presentation, 6 patients had WMLs on magnetic resonance imaging (MRI). The cerebrospinal fluid immunoglobulin G (CSF IgG) index was significantly higher in the patients with WMLs than in those without WMLs (mean, 1.34 vs. 0.70, p=0.017). The time from the symptom onset to initial neuroimaging was also significantly longer in the patients with WMLs than in those without WMLs (median, 31.5 vs. 7.0 days; p=0.008). The clinical outcome was comparable among the patients with and without WMLs. Conclusion In HIV-negative patients with CM, a persistent, aberrant immune response to Cryptococcus, such as intrathecal IgG synthesis, may induce WML formation.

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競争的研究費の研究課題 【 表示 / 非表示

  • アルツハイマー病の早期アミロイド病理において脳内浸潤T細胞の果たす役割の解明

    2021年04月
    -
    2024年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 大谷木 正貴, 若手研究, 補助金,  研究代表者

  • アルツハイマー病の脳内炎症における制御性T細胞の意義の解明

    2020年09月
    -
    2022年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 大谷木 正貴, 研究活動スタート支援, 補助金,  研究代表者

受賞 【 表示 / 非表示

  • the Oral Presentation Silver Award

    2021年04月, 第17回アジア・オセアニア神経学会議, New therapeutic strategy for multiple sclerosis (MS) by DNA/RNA heteroduplex oligonucleotide technology

  • AOCN2021演題発表支援トラベルグラント

    2020年09月, 日本神経学会, New therapeutic strategy for multiple sclerosis by DNA/RNA heteroduplex oligonucleotide technology

  • Young Neuroimmunologist Award

    2019年09月, 日本神経免疫学会, DNA/RNAヘテロ2本鎖核酸によるリンパ球制御を介した神経免疫疾患の新規治療法の開発