The contribution of plasticity to the recovery of retinal function following gene therapy

可塑性对基因治疗后视网膜功能恢复的贡献

• 批准号: 10591954
• 负责人: Joo Yeun Lee
• 金额: $ 10.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591954
• 关键词: Affect; Animal Model; Blindness; Cells; Clinical Trials; Cone; Dendrites; Dependovirus; Development; Electrophysiology (science); Equilibrium; Excitatory Synapse; Exhibits; Face; Functional disorder; Goals; Homeostasis; Human; Image; Individual; Inhibitory Synapse; Knowledge; Location; Measures; Mediating; Modeling; Mus; Neurons; Pathway interactions; Pattern; Phase; Photoreceptors; Physiological; Presynaptic Terminals; Property; Public Health; Reaction; Recovery; Recovery of Function; Research; Resolution; Retina; Retinal Diseases; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; Vertebrate Photoreceptors; Vision; Visual Acuity; Withdrawal; Work; achromatopsia; cell type; cyclic-nucleotide gated ion channels; experimental study; falls; functional restoration; ganglion cell; gene replacement therapy; gene therapy; horizontal cell; improved; inherited retinal degeneration; innovation; insight; mouse model; neuronal survival; neurotransmission; neurotransmitter release; optimal treatments; receptive field; response; retinal neuron; retinal rods; sight restoration; spatiotemporal; tool; voltage

PROJECT SUMMARY/ABSTRACT Gene replacement therapy for inherited retinal degenerations has improved visual function in animal models, which has built momentum to curing blindness in humans. Optimal therapy is the return of normal visual function, however, current clinical trials face challenges associated with variability and durability of recovery due to the lack of rigorous mechanistic understanding of the retinal circuit's reaction to the therapies and any potential hinderance to full recovery. To restore vision, it is essential to understand how surviving retinal neurons modify synaptic connections upon vision restoration treatment and how retinal plasticity can be leveraged to improve visual function. Our long-term goal is to elucidate fundamental mechanisms that enable the retina to establish functional connections following gene therapy. The objectives of the proposed work are to determine underlying mechanisms of functional recovery at cellular and circuit resolution using a mouse model of achromatopsia, which restores selective loss of cone-mediated function after gene therapy. In Aim 1, we will determine the recovery of spatial and temporal processing in ON and OFF pathways after gene therapy. We will measure spatio-temporal receptive fields of specific ganglion cell types. In Aim 2, we will determine the contribution of synaptic remodeling and transmitter release homeostasis to the structure and function of cone bipolar cells following gene therapy. Achieving robust and sustained therapies require understanding of how gene therapy restores rewiring and neurotransmitter release from first- and second-order synapses. Imaging and electrophysiology will allow us to determine the wiring patterns of outer and inner retina, and how cones and bipolar cell release rates potentially adapt to changes in inputs to reach homeostasis. The approach is innovative for a new perspective on restoring vision in the context of the retinal plasticity investigating the effects of gene therapy on connectivity patterns and functional properties at the single-cell level of the retinal circuit. The results will be significant for (1) revealing whether retinal plasticity is constructive toward restoring visual function, (2) determining mechanisms that allow the remaining retinal neurons to re-establish functional connections with newly rescued cones, and (3) providing knowledge essential for maximizing function after photoreceptor recovery.

PROJECT SUMMARY/ABSTRACT Gene replacement therapy for inherited retinal degenerations has improved visual function in animal models, which has built momentum to curing blindness in humans. Optimal therapy is the return of normal visual function, however, current clinical trials face challenges associated with variability and durability of recovery due to the lack of rigorous mechanistic understanding of the retinal circuit's reaction to the therapies and any potential hinderance to full recovery. To restore vision, it is essential to understand how surviving retinal neurons modify synaptic connections upon vision restoration treatment and how retinal plasticity can be leveraged to improve visual function. Our long-term goal is to elucidate fundamental mechanisms that enable the retina to establish functional connections following gene therapy. The objectives of the proposed work are to determine underlying mechanisms of functional recovery at cellular and circuit resolution using a mouse model of achromatopsia, which restores selective loss of cone-mediated function after gene therapy. In Aim 1, we will determine the recovery of spatial and temporal processing in ON and OFF pathways after gene therapy. We will measure spatio-temporal receptive fields of specific ganglion cell types. In Aim 2, we will determine the contribution of synaptic remodeling and transmitter release homeostasis to the structure and function of cone bipolar cells following gene therapy. Achieving robust and sustained therapies require understanding of how gene therapy restores rewiring and neurotransmitter release from first- and second-order synapses. Imaging and electrophysiology will allow us to determine the wiring patterns of outer and inner retina, and how cones and bipolar cell release rates potentially adapt to changes in inputs to reach homeostasis. The approach is innovative for a new perspective on restoring vision in the context of the retinal plasticity investigating the effects of gene therapy on connectivity patterns and functional properties at the single-cell level of the retinal circuit. The results will be significant for (1) revealing whether retinal plasticity is constructive toward restoring visual function, (2) determining mechanisms that allow the remaining retinal neurons to re-establish functional connections with newly rescued cones, and (3) providing knowledge essential for maximizing function after photoreceptor recovery.