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.

项目概要/摘要 遗传性视网膜变性的基因替代疗法改善了动物模型的视觉功能， 这为治愈人类失明奠定了势头。最佳治疗是恢复正常视觉功能， 然而，当前的临床试验面临着与恢复的可变性和持久性相关的挑战，因为 对视网膜回路对治疗的反应和任何潜在的反应缺乏严格的机制理解 阻碍全面康复。为了恢复视力，必须了解幸存的视网膜神经元如何改变 视力恢复治疗中的突触连接以及如何利用视网膜可塑性来改善 视觉功能。我们的长期目标是阐明使视网膜建立 基因治疗后的功能连接。拟议工作的目标是确定潜在的 使用色盲小鼠模型在细胞和电路分辨率方面的功能恢复机制， 它可以恢复基因治疗后锥体介导功能的选择性丧失。在目标 1 中，我们将确定 基因治疗后 ON 和 OFF 通路的空间和时间处理的恢复。我们将测量 特定神经节细胞类型的时空感受野。在目标 2 中，我们将确定以下贡献： 突触重塑和递质释放对视锥双极细胞结构和功能的稳态 基因治疗后。实现稳健和持续的治疗需要了解基因治疗的原理 恢复一级和二级突触的重新布线和神经递质释放。成像和 电生理学将使我们能够确定外视网膜和内视网膜的布线模式，以及视锥细胞和视网膜如何 双极细胞释放速率可能会适应输入的变化以达到稳态。该方法具有创新性 寻找在视网膜可塑性研究基因影响的背景下恢复视力的新视角 在视网膜回路的单细胞水平上对连接模式和功能特性进行治疗。结果 对于（1）揭示视网膜可塑性是否有利于恢复视觉功能具有重要意义，（2） 确定允许剩余视网膜神经元重新建立功能连接的机制 新获救的视锥细胞，以及（3）提供光感受器后功能最大化所必需的知识 恢复。