Developing a Novel Therapy through Retinal Ganglion Cell Dendrite Regeneration

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16961
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: KITAMURA Yuta 公益財団法人東京都医学総合研究所, 疾患制御研究分野, 研究員 (90868259)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 緑内障 / TrkB / AAV / 細胞死

Outline of Final Research Achievements

We developed a molecule F-iTrkB that can constantly activate TrkB signaling, which successfully induced neuroprotection and axonal regeneration of retinal ganglion cells (RGCs) in optic neuropathy and normal tension glaucoma models by gene therapy using AAV2-F-iTrkB (Nishijima et al., Molecular Therapy, 2023). We also found that RGC-specific TrkB deficiency in adult mice induced relatively rapid RGC cell death, which was preceded by RGC dendrite regression, retinal function impairment and axonal degeneration. Furthermore, we found that αRGC, a subtype of RGC, most likely causes cell death due to TrkB deficiency. In addition, in order to visualize the distribution of mitochondria inside RGC dendrites with 3D images, we expressed a fluorescent protein that binds to mitochondria using AAV-vector. We found that the number of mitochondria inside dendrites was significantly reduced before RGC cell death.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

TrkB floxマウスにAAV-Creを眼球内投与して、網膜組織中の細胞から内在性の BDNF-TrkBシグナルを消失させたところ、主にRGCの細胞死が誘導されることがわかった。 さらに、RGCの多くのサブタイプで細胞死が生じていたが、ipRGCでは比較的細胞死が抑制されていることが判明した。緑内障マウスの早期作成ができることが示唆され、今後の緑内障の研究に活用することが期待できる。