Abstract
Quality of life gradually declined with aging due to deterioration of various bodily functions such as motor function and immune response. Glaucoma, the leading cause of blindness, is a neurodegenerative disease and the incidence increases with age. Currently, more than 180,000 people in Japan are blindness, and more than 25% of these cases are caused by retinal neurodegeneration due to glaucoma. Neuroprotection and regeneration therapies are essential for neurodegenerative diseases, such as glaucoma.
We have been investigating new therapy for glaucoma via neuroprotective and axon regenerative approaches using mouse models. We focused on TrkB molecule, a neurotrophic factor receptor, and have attempted to enhance TrkB signaling in neurons without ligand, BDNF. We found that artificially modified TrkB, which was truncated form of intracellular region and artificially attached the plasma membrane localization signal, possess the effect of neuroprotection and axon regeneration. This modified TrkB is localized to the plasma membrane, allowing for constitutive activation of intracellular signaling, such as ERK and AKT, in the absence of ligands. In addition, gene therapy with the modified TrkB in a mouse model of glaucoma maintained visual function through its neuroprotective effects. Furthermore, the modified TrkB promoted axon regeneration in an optic nerve crush mouse model. These results suggests that intracellular signal activation utilizing gene therapy is a good approach for developing neuroprotective and regenerative therapies.
