TOPICS

2024 2023 2022 2021 2020 2019 2018 2017 2016 2015

8 Dec 2022
Takayuki Harada and his colleagues at Visual Research Project published an article entitled “Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors” in Molecular Therapy.

Japanese Page

Gene therapy using a short-form neurotrophin receptor stimulates neuroprotection and optic nerve regeneration in mouse models of glaucoma

<Title of the paper>
Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors
<Authors>
Euido Nishijima#, Sari Honda#, Yuta Kitamura#, Kazuhiko Namekata#, Atsuko Kimura, Xiaoli Guo, Yuriko Azuchi, Chikako Harada, Akira Murakami, Akira Matsuda, Tadashi Nakano, Luis F. Parada, and Takayuki Harada
# These authors contributed equally to this work.
<Journal>
Molecular Therapy
DOI:https://doi.org/10.1016/j.ymthe.2022.11.018

Outline of Research

Glaucoma is the leading cause of irreversible blindness due to optic nerve damage and the death of retinal ganglion cells (RGCs). Presently, reducing intraocular pressure is the sole evidence-based therapy for glaucoma patients, but this therapy is ineffective in a considerable proportion of glaucoma patients, especially those with normal tension glaucoma. Thus, other strategies for suppressing further degeneration of RGCs, such as neuroprotection through activation of neurotrophic factor signaling, have been investigated. For example, brain-derived neurotrophic factor (BDNF) stimulates RGC protection through its high-affinity receptor TrkB. However, the transient nature of ligand-dependent activation limits the effectiveness of this treatment.

The research group solved the problem of transient activation by inventing a system that forces membrane localization of the intracellular domain of TrkB through farnesylation (F-iTrkB). This results in constitutive TrkB activation in the absence of ligands. The small size of F-iTrkB allows it to be packaged in adeno-associated virus (AAV) and allows high expression of the transgene.

Intraocular injection of AAV-F-iTrkB significantly enhanced the survival of RGCs in both high and normal intraocular pressure mouse glaucoma models. AAV-F-iTrkB also protected RGCs and induced robust optic nerve regeneration in an optic nerve injury model. In an optic tract transection model, in which visual pathway in the brain (superior colliculus) were damaged, intraocular injection of AAV-F-iTrkB induced axon regeneration at the injury site and restored connections to brain targets, resulting in partial recovery of visual behavior.

With further characterization and enhancement of delivery, AAV-F-iTrkB may become an effective gene therapy tool for treatment of axonal damage and some neurodegenerative diseases, including glaucoma.

Major funding for this research

This work was supported by JSPS KAKENHI Grants-in-Aid for Scientific Research, the Takeda Science Foundation, the Suzuken Memorial Foundation, the Naito Foundation, and the Uehara Memorial Foundation.

Figure
Image title: Schematic model of sustained activation of TrkB signaling in the absence of BDNF

2024 2023 2022 2021 2020 2019 2018 2017 2016 2015