Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors

Activation of neurotrophic factor signaling is a promising ther-apy for neurodegeneration. However, the transient nature of ligand-dependent activation limits its effectiveness. In this study, we solved this problem by inventing a system that forces membrane localization of the intracellular domain of tropomy-osin receptor kinase B (iTrkB), which results in constitutive activation without ligands. Our system overcomes the small size limitation of the genome packaging in adeno-associated vi-rus (AAV) and allows high expression of the transgene. Using AAV-mediated gene therapy in the eyes, we demonstrate that iTrkB expression enhances neuroprotection in mouse models of glaucoma and stimulates robust axon regeneration after op-tic nerve injury. In addition, iTrkB expression in the retina was also effective in an optic tract transection model, in which the injury site is near the superior colliculus. Regenerating axons successfully formed pathways to their brain targets, resulting in partial recovery of visual behavior. Our system may also be applicable to other trophic factor signaling pathways and lead to a significant advance in the field of gene therapy for neuro-trauma and neurodegenerative disorders, including glaucoma.

Automated summary

In this study, a system was developed to achieve constitutive activation of iTrkB without ligands, by forcing its membrane localization. This system overcomes the limitations of packaging size in AAV and allows high expression of the transgene. Using gene therapy in the eyes, it was shown that iTrkB expression enhances neuroprotection and stimulates axon regeneration in mouse models of glaucoma and optic nerve injury. The system could potentially be applied to other trophic factor signaling pathways and advance the field of gene therapy for neuro-trauma and neurodegenerative disorders, including glaucoma.