Vision protection and axon regeneration by gene therapy of constitutive active TrkB

• Project/Area Number: 20K07751
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: NAMEKATA Kazuhiko 公益財団法人東京都医学総合研究所, 疾患制御研究分野, 副参事研究員 (70392355)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 神経再生 / TrkB / AAV / 緑内障 / 軸索再生 / 遺伝子治療 / 神経保護・再生 / TrkBシグナル

Outline of Research at the Start

本研究では網膜の神経に注目し、TrkBを用いた遺伝子治療によって神経再生を強力に促し、軸索損傷によって失明したマウスの視機能回復に挑戦する。具体的には、アデノ随伴ウィルス（AAV）による遺伝子発現、組織透明化による細胞の立体画像解析、optogeneticsによるタンパク発現制御、遺伝子改変マウスなど様々なツールを利用して、神経保護と軸索再生療法の可能性に挑戦する。また、その分子機序解明のために、細胞内シグナル、微小管形成、軸索輸送などの検討を行う。本研究から得られた知見は緑内障や脊髄損傷など、軸索変性を引き起こす多くの神経変性疾患において、広く有益な成果となることが期待される。

Outline of Final Research Achievements

In this study, we investigated the possibility of recovering visual function in blind mice by promoting the neuroprotective effect and axonal regeneration of retinal ganglion cells (RGC) by gene therapy using our originally developed constitutive active TrkB. We found that constitutive active TrkB strongly suppressed cell death induced by optic nerve crush. The regenerated axons also reached the optic chiasm. Furthermore, in glaucoma model mice, suppression of visual function decline was observed, as well as neuroprotective effect.

Academic Significance and Societal Importance of the Research Achievements

これらの成果から、常時活性型TrkB分子は、細胞内のシグナル活性化を介してin vivoにおけるマウス網膜神経節細胞の保護・再生を強力に促進することが判明した。したがってアデノ随伴ウィルスなどの遺伝子治療との併用することで、緑内障などの網膜神経変性に対する新たな治療法となる可能性に期待が持たれる。

Research Products

• [Journal Article] Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors (2023)
  • Author(s): Nishijima Euido、Honda Sari、Kitamura Yuta、Namekata Kazuhiko、Kimura Atsuko、Guo Xiaoli、Azuchi Yuriko、Harada Chikako、Murakami Akira、Matsuda Akira、Nakano Tadashi、Parada Luis F.、Harada Takayuki
  • Journal Title: Molecular Therapy Volume: 31 Issue: 3 Pages: 810-824
  • DOI: 10.1016/j.ymthe.2022.11.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of constitutively active K-Ras on axon regeneration after optic nerve injury (2023)
  • Author(s): Kiyota Naoki、Namekata Kazuhiko、Nishijima Euido、Guo Xiaoli、Kimura Atsuko、Harada Chikako、Nakazawa Toru、Harada Takayuki
  • Journal Title: Neuroscience Letters Volume: 799 Pages: 137124-137124
  • DOI: 10.1016/j.neulet.2023.137124
  • Peer Reviewed / Open Access
• [Journal Article] Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy (2022)
  • Author(s): Shinozaki Youichi、Leung Alex、Namekata Kazuhiko、Saitoh Sei、Nguyen Huy Bang、Takeda Akiko、Danjo Yosuke、Morizawa Yosuke M.、Shigetomi Eiji、Sano Fumikazu、Yoshioka Nozomu、Takebayashi Hirohide、Ohno Nobuhiko、Segawa Takahiro、Miyake Kunio、Kashiwagi Kenji、Harada Takayuki、Ohnuma Shin-ichi、Koizumi Schuichi
  • Journal Title: Science Advances Volume: 8 Issue: 44 Pages: 1081-1081
  • DOI: 10.1126/sciadv.abq1081
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ASK1 signaling regulates phase-specific glial interactions during neuroinflammation (2022)
  • Author(s): Guo Xiaoli、Kimura Atsuko、Namekata Kazuhiko、Harada Chikako、Arai Nobutaka、Takeda Kohsuke、Ichijo Hidenori、Harada Takayuki
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 119 Issue: 6
  • DOI: 10.1073/pnas.2103812119
  • Peer Reviewed / Open Access
• [Journal Article] Genetic inhibition of collapsin response mediator protein‐2 phosphorylation ameliorates retinal ganglion cell death in normal‐tension glaucoma models (2022)
  • Author(s): Brahma Musukha Mala、Takahashi Kazuya、Namekata Kazuhiko、Harada Takayuki、Goshima Yoshio、Ohshima Toshio
  • Journal Title: Genes to Cells Volume: 27 Issue: 8 Pages: 526-536
  • DOI: 10.1111/gtc.12971
  • Peer Reviewed / Open Access
• [Journal Article] Effects of lighting environment on the degeneration of retinal ganglion cells in glutamate/aspartate transporter deficient mice, a mouse model of normal tension glaucoma (2022)
  • Author(s): Ohashi Tsutomu、Namekata Kazuhiko、Guo Xiaoli、Kimura Atsuko、Harada Chikako、Harada Takayuki
  • Journal Title: Biochemistry and Biophysics Reports Volume: 29 Pages: 101197-101197
  • DOI: 10.1016/j.bbrep.2021.101197
  • Peer Reviewed / Open Access
• [Journal Article] Ocular expression of cyclin-dependent kinase 5 in patients with proliferative diabetic retinopathy. (2021)
  • Author(s): Hiroki Sano, Kazuhiko Namekata, Masanori Niki, Kentaro Semba, Fumiko Murao, Takayuki Harada, Yoshinori Mitamura
  • Journal Title: Journal of Diabetes Investigation Volume: 13 Issue: 4 Pages: 628-628
  • DOI: 10.1111/jdi.13702
  • Peer Reviewed / Open Access
• [Journal Article] Loss of P2Y ₁ receptors triggers glaucoma‐like pathology in mice (2021)
  • Author(s): Hamada Kentaro、Shinozaki Youichi、Namekata Kazuhiko、Matsumoto Mami、Ohno Nobuhiko、Segawa Takahiro、Kashiwagi Kenji、Harada Takayuki、Koizumi Schuichi
  • Journal Title: British Journal of Pharmacology Volume: 178 Issue: 22 Pages: 4552-4571
  • DOI: 10.1111/bph.15637
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of the DOCK-D family proteins in a mouse model of neuroinflammation (2020)
  • Author(s): Namekata Kazuhiko、Guo Xiaoli、Kimura Atsuko、Azuchi Yuriko、Kitamura Yuta、Harada Chikako、Harada Takayuki
  • Journal Title: Journal of Biological Chemistry Volume: in press Issue: 19 Pages: 6710-6720
  • DOI: 10.1074/jbc.ra119.010438
  • Peer Reviewed / Open Access
• [Journal Article] Topical ripasudil stimulates neuroprotection and axon regeneration in adult mice following optic nerve injury (2020)
  • Author(s): Nishijima Euido、Namekata Kazuhiko、Kimura Atsuko、Guo Xiaoli、Harada Chikako、Noro Takahiko、Nakano Tadashi、Harada Takayuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15709-15709
  • DOI: 10.1038/s41598-020-72748-3
  • Peer Reviewed / Open Access
• [Journal Article] EAAT1 variants associated with glaucoma (2020)
  • Author(s): Yanagisawa Michiko、Namekata Kazuhiko、Aida Tomomi、Katou Sayaka、Takeda Takuya、Harada Takayuki、Fuse Nobuo、the Glaucoma Gene Research Group、Tanaka Kohichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 529 Issue: 4 Pages: 943-949
  • DOI: 10.1016/j.bbrc.2020.06.099
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of Oxidative Stress as Potential Therapeutic Approach for Normal Tension Glaucoma (2020)
  • Author(s): Harada Chikako、Noro Takahiko、Kimura Atsuko、Guo Xiaoli、Namekata Kazuhiko、Nakano Tadashi、Harada Takayuki
  • Journal Title: Antioxidants Volume: 9 Issue: 9 Pages: 874-874
  • DOI: 10.3390/antiox9090874
  • Peer Reviewed / Open Access
• [Presentation] DOCKファミリー分子が視神経炎症を重症化する分子メカニズムの解明 (2022)
  • Author(s): 行方和彦
  • Organizer: 第126回日本眼科学会総会
  • Invited
• [Presentation] Constitutively active Ras promotes protection and axon regeneration in retinal ganglion cells after optic nerve injury. (2022)
  • Author(s): Kiyota N, Namekata K, Guo X, Kimura A, Nakazawa T, Harada T
  • Organizer: ARVO2022 meeting
  • Int'l Joint Research
• [Presentation] 活性型TrkBを活用した遺伝子治療による神経保護と軸索再生. (2021)
  • Author(s): 行方和彦、西島義道、北村裕太、本田紗里、郭曉麗、木村敦子、原田知加子、原田高幸.
  • Organizer: 第９４回日本生化学会大会
• [Presentation] AAV-mediated delivery of constitutively active TrkB promotes CNS axon regeneration and neuroprotection. (2021)
  • Author(s): Kimura A, Nishijima E, Kitamura Y, Honda S, Guo X, Harada C, Namekata K, Harada T.
  • Organizer: Neuroscience Meeting 2021
• [Presentation] Microglial DOCK8 and neurodegeneration. (2021)
  • Author(s): Kimura A, Namekata K, Guo X, Arai N, Harada C, Harada T.
  • Organizer: The 4th International Conference on Applied Biochemistry and Biotechnology (ABB 2021).
  • Invited
• [Presentation] The renin-angiotensin system regulates neurodegeneration in a mouse model of optic neuritis. (2021)
  • Author(s): Guo X, Namekata K, Kimura A, Harada C, Harada T.
  • Organizer: 3rd Annual Global Conference on Neuroscience and Neurology.
  • Invited
• [Presentation] Gene therapy with modified TrkB induces neuroprotection and axon regeneration. (2021)
  • Author(s): Kimura A, Nishijima E, Kitamura Y, Honda S, Guo X, Harada C, Namekata K, Harada T.
  • Organizer: 第４４回日本神経科学大会
• [Presentation] Gene therapy with mutant TrkB receptor protects retinal ganglion cell and retinal function in a mouse model of normal tension glaucoma. (2021)
  • Author(s): Nishijima E, Honda S, Namekata K, Kimura A, Guo X, Harada C, Nakano T, Harada T.
  • Organizer: World Glaucoma Congress 2021
• [Presentation] Gene therapy with mutant TrkB receptors protects retinal neurons and promotes optic nerve regeneration without ligands. (2021)
  • Author(s): Nishijima E, Namekata K, Kimura A, Kitamura Y, Honda S, Guo X, Harada C, Nakano T, Harada T.
  • Organizer: ARVO 2021 meeting
• [Presentation] 活性型Rasの遺伝子治療による視神経保護と再生への影響. (2020)
  • Author(s): 金義道、本田紗里、北村裕太、郭暁麗、木村敦子、行方和彦、中野匡、原田高幸
  • Organizer: 第１２４回日本眼科学会総会
• [Presentation] Loss of astrocytic ABCA1 induces normal tension glaucoma. (2020)
  • Author(s): Shinozaki, Y., Namekata, K., Kashiwagi, K., Ohno, N., Segawa, T., Harada, T., Koizumi, S.
  • Organizer: FENS 2020 Virtual Forum
  • Int'l Joint Research
• [Presentation] GLAST欠損マウスによる網膜神経節細胞樹状突起の解析. (2020)
  • Author(s): 北村裕太、行方和彦、木村敦子、郭暁麗、山本修一、原田高幸.
  • Organizer: 第３１回日本緑内障学会
• [Presentation] 失明からの視機能回復に向けた新規遺伝子治療ベクターの開発. (2020)
  • Author(s): 金義道、行方和彦、本田紗里、木村敦子、北村裕太、中野匡、原田高幸.
  • Organizer: 第１９回日本再生医療学会総会
• [Presentation] TrkB欠損マウスにおける網膜神経節細胞の変性過程の検討. (2020)
  • Author(s): 北村裕太、安土ゆり子、行方和彦、木村敦子、郭暁麗、山本修一、原田高幸.
  • Organizer: 第７４回日本臨床眼科学会
• [Remarks] 公益財団法人東京都医学総合研究所 視覚病態プロジェクト
  • URL: https://www.igakuken.or.jp/retina/