Plasticity of the human visual system studied in response to retinal gene therapy

研究视网膜基因治疗对人类视觉系统可塑性的影响

• 批准号: 9028222
• 负责人: Manzar Ashtari
• 金额: $ 59.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028222
• 关键词: Animal Model; Animals; Anisotropy; Axon; Blindness; Brain; Brain imaging; Clinical Data; Clinical Trials; Complex; Contralateral; Data; Dendrites; Diffusion Magnetic Resonance Imaging; Enrollment; Environment; Exhibits; Eye; Fiber; Functional Magnetic Resonance Imaging; Future; Human; Image; Individual; Intervention; Ipsilateral; Knowledge; Lateral Geniculate Body; Leber' s amaurosis; Longitudinal Studies; Measurement; Measures; Mediating; Medicine; Methods; Modeling; Motion; Mutation; Myelin; Neurites; Neuronal Plasticity; Neurons; Pathway interactions; Patients; Pattern; Phase; Phase III Clinical Trials; Photoreceptors; Play; Procedures; Process; Pulvinar structure; RPE65 protein; Randomized; Rehabilitation therapy; Reporting; Residual state; Resolution; Retina; Retinal; Retinal Degeneration; Retinal Ganglion Cells; Role; Science; Signal Transduction; Stimulus; Structure; Surgical sutures; Synapses; System; Techniques; Testing; Time; Vision; Visual; Visual Cortex; Visual Pathways; Visual impairment; Visual system structure; area striata; base; blind; density; early onset; experience; extrastriate visual cortex; gene therapy; in vivo; indexing; melanopsin; millimeter; myelination; neuroimaging; neuronal circuitry; relating to nervous system; response; restoration; retinotectal; superior colliculus Corpora quadrigemina; visual information

Project Summary: The impact of changes in visual input on neuronal circuitry is complex and much of our knowledge of plasticity in the visual system comes from animal studies. While these studies have started to highlight the specific neural underpinnings responsible for visual cortex plasticity in response to visual impairment, restored vision and environment interactions, similar studies have not been possible in humans due to the unethical invasiveness of the procedures involved. Having access to a group of well-characterized subjects with Leber’s Congenital Amaurosis due to RPE65 mutations (LCA2) who will participate in an LCA2 Phase 3 clinical trial provides the unique opportunity to study this process in blind humans who gain vision through gene therapy (GT). We hope to draw parallels between cortical plasticity changes reported in animal studies with reverse eye-lid suture (regaining sight) and human retinal GT in LCA patients (gaining sight). Noninvasive brain imaging before and after intervention in these subjects will provide us the opportunity to not only study the effects of regaining vision on the human brain and the underlying mechanisms of plasticity, but also to bring focus on alternate visual pathways used by the LCA2 patients before GT. One such pathway appears to utilize intrinsically photosensitive Retinal Ganglion Cells (ipRGC) and one question is whether there is a relative change in retinal signaling to the brain after GT. To our knowledge this will be the first longitudinal study to combine structural and functional neuroimaging techniques to examine and gain a deeper understanding of the process of brain plasticity in humans in vivo, focusing on a large group of individuals born with severe visual impairment with measurements before and after an intervention that restores vision. The Phase 3 LCA clinical trial will enroll 24 patients, including 8 randomly assigned to be followed for one year before receiving GT. All subjects will undergo imaging consisting of sub-millimeter 3D structural imaging, and a powerful new method of diffusion MRI (dMRI) that provides microstructural information reflecting degree of dendritic sprouting and myelination. These tests will provide detailed assessment of the changes of the visual cortex in response to GT. Primary and higher visual functions will also be measured in all subjects using a battery of functional MRI (fMRI) paradigms. Visual function will be assessed separately, during the Phase 3 clinical trial and data will be made available to this study. The visual function data will then be correlated with the CNS imaging and visual function data. Completion of this project will provide important temporal-spatial data on the degree of neuroplasticity of the human visual system and the role it plays in enhancement of visual function following GT. These data may have future potential application to studies evaluating gene therapy-mediated reversal of blindness.

项目摘要：视觉输入变化对神经元电路的影响很复杂，我们的大部分 视觉系统中可塑性的知识来自动物研究。这些研究开始 突出显示负责视觉皮层可视性的特定神经基础 损害，恢复视力和环境相互作用，人类不可能进行类似的研究 由于涉及的程序的不道德侵入性。可以访问一组符合特征的 由RPE65突变（LCA2）引起的Leber先天性弹药的受试者将参加LCA2 第三阶段临床试验提供了在获得视力的盲人中研究这一过程的独特机会 通过基因疗法（GT）。我们希望在动物报道的皮质可塑性变化之间提取相似之处 LCA患者（获得视力）的反向眼睛缝合线（恢复视力）和人类残留GT的研究。 干预这些主题之前和之后的无创脑成像将为我们提供不可能的机会 仅研究恢复视力对人脑和可塑性的潜在机制的影响，但是 还要重点关注LCA2患者在GT之前使用的替代视觉途径。这样的道路 似乎利用本质上光敏性的视网膜神经节细胞（IPRGC），一个问题是是否在那里 是GT后对大脑的残留信号的相对变化。 据我们所知，这将是第一项结合结构和功能的纵向研究 神经影像学技术，以检查并更深入地了解大脑可塑性的过程 人类在体内，专注于一大批患有严重视觉障碍的人 干预前后恢复视力的测量。 第三阶段LCA临床试验将招募24名患者，其中包括8例随机分配的患者 收到GT前一年。所有受试者都将经过由亚毫米3D结构组成的成像 成像，以及提供微观结构信息的强大扩散MRI（DMRI）的新方法 反映树突发芽和髓鞘的程度。这些测试将对 响应GT的视觉皮层的变化。主要和更高的视觉功能也将在所有人中衡量 使用功能性MRI（fMRI）范式的受试者。视觉功能将分别评估， 在第三阶段临床试验中，将提供该研究的数据。然后，视觉功能数据将 与CNS成像和视觉功能数据相关。 该项目的完成将提供有关神经可塑性程度的重要临时空间数据 人类视觉系统及其在GT后增强视觉功能方面所扮演的作用。这些数据 在评估基因治疗介导的失明逆转的研究中可能会有未来的潜在应用。