Construction of Cynomologus Monkey Model for Hereditary Retinal Diseases : Diseases Mechanisms and Therapeutic

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17H06276
• Research Institution: 独立行政法人国立病院機構(東京医療センター臨床研究センター)
• Principal Investigator: 岩田 岳 独立行政法人国立病院機構(東京医療センター臨床研究センター), 分子細胞生物学研究部, 部長 (90374157)
• Co-Investigator(Kenkyū-buntansha): 溝田 淳 帝京大学, 医学部, 教授 (10239262) ; 下澤 律浩 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 霊長類医科学研究センター, 主任研究員 (50300786)
• Project Period (FY): 2017-06-30 – 2020-03-31
• Keywords: 医歯薬学 / 外科系臨床医学 / 眼科学 / 眼生化学・分子生物学 / ドルーゼン

Outline of Annual Research Achievements

日本人の主な失明原因である緑内障、加齢黄斑変性、遺伝性網膜疾患について、通常使われる実験動物（マウス、ラット、ウサギ、ブタなど）では眼の構造が異なるために、ヒトの疾患を正確に再現することは困難である。近年、それぞれの疾患について新たな原理による治療法が数多く開発されており、これを試験する疾患動物モデルがこれまで以上に求められている。この研究によって、より患者の病態に近い眼疾患モデル動物の作製が期待され、これまでのマウスを中心とした遺伝子解析動物よりも精度の高い情報が得られると期待される。当初の想定に反し、CRISPR/Cas9による作成法ではカニクイザルでのゲノム編集効率が低いことが判明し、広島大学の山本卓先生が開発されたプラチナTALEN法によるゲノム編集技術に変更した。その結果、CRISPR/Cas9と比較して大幅なゲノム編集効率の改善が観察された。プラチナTALENは特に両アレルの配列を同時に破壊することによるトランケーション・ホモ変異を作成することを得意とする。両アレルを同時編集はCRISPR/Cas9ではできなかったことである。ヘテロマウスからホモマウスを作製するための時間は数か月であるが、カニクイザルにおいては数年の時間がかかる。また、受精卵の確保がマウスと比較して難しいカニクイザルにおいて、一回のゲノム編集によって目的とするトランケーション変異が両アレルで得られることは作製時間の大幅な短縮となる。全ての遺伝性眼疾患において両アレルのトラケーション変異は報告されており、網膜色素変性の原因遺伝子EYS、緑内障の原因遺伝子MYOC、黄斑ジストロフィの原因遺伝子ELOVL4、レーベル先天黒内障の原因遺伝子LCA5の作製を開始した。すでに網膜色素変性EYS遺伝子の両アレル変異の妊娠が確認され、出産が2021年の夏に予定されている。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Spatial Functional Characteristics of East Asian Patients With Occult Macular Dystrophy (Miyake Disease); EAOMD Report No. 2 (2021)
  • Author(s): Yang Lizhu、Joo Kwangsic、Tsunoda Kazushige、Kondo Mineo、Fujinami-Yokokawa Yu、Arno Gavin、Pontikos Nikolas、Liu Xiao、Nakamura Natsuko、Kurihara Toshihide、Tsubota Kazuo、Iwata Takeshi、Li Hui、Zou Xuan、Wu Shijing、Sun Zixi、Ahn Seong Joon、Kim Min Seok、Mun Yong Seok、Park Kyu Hyung、et al.
  • Journal Title: American Journal of Ophthalmology Volume: 221 Pages: 169～180
  • DOI: 10.1016/j.ajo.2020.07.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Serine Protease HTRA-1 Is a Biomarker for ROP and Mediates Retinal Neovascularization (2020)
  • Author(s): Owen Leah A.、Shirer Kinsey、Collazo Samuel A.、Szczotka Kathryn、Baker Shawna、Wood Blair、Carroll Lara、Haaland Benjamin、Iwata Takeshi、Katikaneni Lakshmi D.、DeAngelis Margaret M.
  • Journal Title: Frontiers in Molecular Neuroscience Volume: 13 Pages: 605918
  • DOI: 10.3389/fnmol.2020.605918
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families (2020)
  • Author(s): Hayashi Takaaki、Kameya Shuhei、Mizobuchi Kei、Kubota Daiki、Kikuchi Sachiko、Yoshitake Kazutoshi、Mizota Atsushi、Murakami Akira、Iwata Takeshi、Nakano Tadashi
  • Journal Title: Scientific Reports Volume: 10 Pages: 15883
  • DOI: 10.1038/s41598-020-72623-1
  • Peer Reviewed / Open Access
• [Journal Article] RP2 ‐associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype?phenotype association (2020)
  • Author(s): Fujinami Kaoru、Liu Xiao、Ueno Shinji、Mizota Atsushi、Shinoda Kei、Kuniyoshi Kazuki、Fujinami‐Yokokawa Yu、Yang Lizhu、Arno Gavin、Pontikos Nikolas、Kameya Shuhei、Kominami Taro、Terasaki Hiroko、Sakuramoto Hiroyuki、Nakamura Natsuko、Kurihara Toshihide、et al.
  • Journal Title: American Journal of Medical Genetics Part C: Seminars in Medical Genetics Volume: 184 Pages: 675～693
  • DOI: 10.1002/ajmg.c.31830
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D-Associated Retinal Disorder (2020)
  • Author(s): Liu Xiao、Fujinami Kaoru、Kuniyoshi Kazuki、Kondo Mineo、Ueno Shinji、Hayashi Takaaki、Mochizuki Kiyofumi、Kameya Shuhei、Yang Lizhu、Fujinami-Yokokawa Yu、Arno Gavin、Pontikos Nikolas、Sakuramoto Hiroyuki、Kominami Taro、Terasaki Hiroko、Katagiri Satoshi、Mizobuchi Kei、Nakamura Natsuko、et al.
  • Journal Title: Translational Vision Science & Technology Volume: 9 Pages: 2～2
  • DOI: 10.1167/tvst.9.6.2
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and genetic characteristics of 10 Japanese patients with PROM1 ‐associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population (2020)
  • Author(s): Fujinami Kaoru、Oishi Akio、Yang Lizhu、Arno Gavin、Pontikos Nikolas、Yoshitake Kazutoshi、Fujinami‐Yokokawa Yu、Liu Xiao、Hayashi Takaaki、Katagiri Satoshi、Mizobuchi Kei、Mizota Atsushi、Shinoda Kei、Nakamura Natsuko、Kurihara Toshihide、Tsubota Kazuo、Miyake Yozo、Iwata Takeshi、et al.
  • Journal Title: American Journal of Medical Genetics Part C: Seminars in Medical Genetics Volume: 184 Pages: 656～674
  • DOI: 10.1002/ajmg.c.31826
  • Peer Reviewed / Open Access
• [Journal Article] Progress of macular atrophy during 30 months’ follow-up in a patient with spinocerebellar ataxia type1 (SCA1) (2020)
  • Author(s): Hirose Ayane、Katagiri Satoshi、Hayashi Takaaki、Matsuura Tomokazu、Nagai Norihiro、Fujinami Kaoru、Iwata Takeshi、Tsunoda Kazushige
  • Journal Title: Documenta Ophthalmologica Volume: 142 Pages: 87～98
  • DOI: 10.1007/s10633-020-09782-z
  • Peer Reviewed
• [Journal Article] Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association (2020)
  • Author(s): Fujinami-Yokokawa Yu、Japan Eye Genetics Consortium、Fujinami Kaoru、Kuniyoshi Kazuki、Hayashi Takaaki、Ueno Shinji、Mizota Atsushi、Shinoda Kei、Arno Gavin、Pontikos Nikolas、Yang Lizhu、Liu Xiao、Sakuramoto Hiroyuki、et al.
  • Journal Title: Scientific Reports Volume: 10 Pages: 9531
  • DOI: 10.1038/s41598-020-65737-z
  • Peer Reviewed / Open Access
• [Journal Article] Novel homozygous CLN3 missense variant in isolated retinal dystrophy: A case report and electron microscopic findings (2020)
  • Author(s): Mizobuchi Kei、Hayashi Takaaki、Yoshitake Kazutoshi、Fujinami Kaoru、Tachibana Toshiaki、Tsunoda Kazushige、Iwata Takeshi、Nakano Tadashi
  • Journal Title: Molecular Genetics & Genomic Medicine Volume: 8 Pages: e1308
  • DOI: 10.1002/mgg3.1308
  • Peer Reviewed / Open Access
• [Journal Article] RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort (2020)
  • Author(s): Katagiri Satoshi、Hayashi Takaaki、Nakamura Masaki、Mizobuchi Kei、Gekka Tamaki、Komori Shiori、Ueno Shinji、Terasaki Hiroko、Sakuramoto Hiroyuki、Kuniyoshi Kazuki、Kusaka Shunji、Nagashima Ryunosuke、Kondo Mineo、Fujinami Kaoru、Tsunoda Kazushige、Matsuura Tomokazu、Kondo Hiroyuki、Yoshitake Kazutoshi、et al.
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 61 Pages: 53～53
  • DOI: 10.1167/iovs.61.3.53
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency (2020)
  • Author(s): Yang Lizhu、JEGC study group、Fujinami Kaoru、Ueno Shinji、Kuniyoshi Kazuki、Hayashi Takaaki、Kondo Mineo、Mizota Atsushi、Naoi Nobuhisa、Shinoda Kei、Kameya Shuhei、Fujinami-Yokokawa Yu、et al.
  • Journal Title: Scientific Reports Volume: 10 Pages: 5497
  • DOI: 10.1038/s41598-020-62119-3
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Variants Associated With the Onset and Progression of Primary Open-Angle Glaucoma (2020)
  • Author(s): Mabuchi Fumihiko、Mabuchi Nakako、Sakurada Yoichi、Yoneyama Seigo、Kashiwagi Kenji、Iijima Hiroyuki、Yamagata Zentaro、Takamoto Mitsuko、Aihara Makoto、Iwata Takeshi、Hashimoto Kazuki、Sato Kota、Shiga Yukihiro、Nishiguchi Koji M.、Nakazawa Toru、Akiyama Masato、et al.
  • Journal Title: American Journal of Ophthalmology Volume: 215 Pages: 135～140
  • DOI: 10.1016/j.ajo.2020.03.014
  • Peer Reviewed
• [Journal Article] Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with DRAM2-Associated Retinopathy (2020)
  • Author(s): Kuniyoshi Kazuki、Hayashi Takaaki、Kameya Shuhei、Katagiri Satoshi、Mizobuchi Kei、Tachibana Toshiaki、Kubota Daiki、Sakuramoto Hiroyuki、Tsunoda Kazushige、Fujinami Kaoru、Yoshitake Kazutoshi、Iwata Takeshi、Nakano Tadashi、Kusaka Shunji
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Pages: 1331～1331
  • DOI: 10.3390/ijms21041331
  • Peer Reviewed / Open Access
• [Journal Article] Correction to: Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants (2020)
  • Author(s): Mawatari Go、on behalf of the JEGC study group、Fujinami Kaoru、Liu Xiao、Yang Lizhu、Fujinami-Yokokawa Yu、Komori Shiori、Ueno Shinji、Terasaki Hiroko、Katagiri Satoshi、Hayashi Takaaki、Kuniyoshi Kazuki、Miyake Yozo、Tsunoda Kazushige、Yoshitake Kazutoshi、Iwata Takeshi、Nao-i Nobuhisa
  • Journal Title: Human Genome Variation Volume: 7 Pages: 1-3
  • DOI: 10.1038/s41439-019-0086-2
  • Peer Reviewed / Open Access
• [Journal Article] Heterozygous GGC repeat expansion of NOTCH2NLC in a patient with neuronal intranuclear inclusion disease and progressive retinal dystrophy (2020)
  • Author(s): Hayashi Takaaki、Katagiri Satoshi、Mizobuchi Kei、Yoshitake Kazutoshi、Kameya Shuhei、Matsuura Tomokazu、Iwata Takeshi、Nakano Tadashi
  • Journal Title: Ophthalmic Genetics Volume: 41 Pages: 93～95
  • DOI: 10.1080/13816810.2020.1723119
  • Peer Reviewed
• [Journal Article] Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy (2020)
  • Author(s): Li Huiping、Yuan Shiqin、Minegishi Yuriko、Suga Akiko、Yoshitake Kazutoshi、Sheng Xunlun、Ye Jianping、Smith Stuart、Bunkoczi Gabor、Yamamoto Megumi、Iwata Takeshi
  • Journal Title: Human Molecular Genetics Volume: 29 Pages: 444～458
  • DOI: 10.1093/hmg/ddz311
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Malonyl-CoA-Acyl Carrier Protein Transacylase Provoke Autosomal Recessive Optic Neuropathy (2020)
  • Author(s): Takeshi Iwata, Huiping Li, Shiqin Yuan, Yuriko Minegishi, Akiko Suga, Kazutoshi Yoshitake, Xunlun Sheng, Jianping Ye, Stuart Smith, Gabor Bunkoczi, Megumi Yamamoto.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) Virtual Meeting
  • Int'l Joint Research
• [Presentation] GEGC research plans in Africa and the Middle East. (2020)
  • Author(s): Takeshi Iwata.
  • Organizer: World Ophthalmology Congress (WOC) Virtual Meeting
  • Int'l Joint Research / Invited
• [Presentation] シンポジウム5 網膜視神経細胞死のメカニズム：ゲノム解析から発症分子機序の解明 (2020)
  • Author(s): 岩田岳
  • Organizer: 第31回バーチャル日本緑内障学会
  • Invited
• [Presentation] 遺伝性網膜疾患の症例・ゲノム情報の収集：日本から世界への展開 (2020)
  • Author(s): 岩田岳
  • Organizer: 第74回バーチャル・国立病院総合医学会
  • Invited
• [Presentation] Novel Mutations in Malonyl-CoA-Acyl Carrier Protein Transacylase Provoke Autosomal Recessive Optic Neuropathy (2020)
  • Author(s): Takeshi Iwata, Huiping Li, Shiqin Yuan, Yuriko Minegishi, Akiko Suga, Kazutoshi Yoshitake, Xunlun Sheng, Jianping Ye, Stuart Smith, Gabor Bunkoczi, Megumi Yamamoto.
  • Organizer: American Society for Human Genetics (ASHG) Virtual Meeting
  • Int'l Joint Research
• [Remarks] 独立行政法人国立病院機構東京医療センター 感覚器センター 分子細胞生物学研究部
  • URL: http://www.kankakuki.go.jp/lab_e.html
• [Remarks] Iwata Laboratory
  • URL: http://www.iwatalab.org/