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Abstract #106561 Published in IGR 23-3
Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors
Nishijima E; Honda S; Kitamura Y; Namekata K; Kimura A; Guo X; Azuchi Y; Harada C; Murakami A; Matsuda A; Nakano T; Parada LF; Harada TMolecular Therapy 2023; 31: 810-824
Activation of neurotrophic factor signaling is a promising therapy 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 tropomyosin 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 virus (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 optic 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 neurotrauma and neurodegenerative disorders, including glaucoma.
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan; Department of Ophthalmology, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan.
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