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

项目摘要：视觉输入的变化对神经元电路的影响是复杂的，我们的大部分 有关视觉系统可塑性的知识来自动物研究。虽然这些研究已经开始 强调与视觉反应中视觉皮质可塑性有关的特定神经基础 损害、视力恢复和环境相互作用，类似的研究在人类中是不可能的 由于涉及的程序具有不道德的侵入性。能够接触到一群具有良好特征的 将参加LCA2的RPE65突变所致Leber先天性巨结肠(LCA2)受试者 3期临床试验提供了在视力恢复的盲人身上研究这一过程的独特机会。 通过基因治疗(GT)。我们希望在动物大脑皮质可塑性变化的报道中找到相似之处 LCA患者的反向眼睑缝合(恢复视力)和人类视网膜GT(恢复视力)的研究。 对这些受试者进行干预前后的无创脑成像将为我们提供机会 只研究视力恢复对人脑的影响和可塑性的潜在机制，但 也是为了将注意力集中在GT前LCA2患者使用的替代视觉通路上。一条这样的路径 似乎利用了固有的光敏性视网膜神经节细胞(IpRGC)，一个问题是 是GT后视网膜信号对大脑的相对改变。 据我们所知，这将是第一次将结构和功能相结合的纵向研究 神经影像技术在脑可塑性研究中的应用 活体中的人类，关注一大群出生时患有严重视力障碍的人 在恢复视力的干预前后进行测量。 LCA第三阶段临床试验将招募24名患者，其中8名随机分配用于 在收到GT的前一年。所有受试者将接受由亚毫米3D结构组成的成像 成像，以及一种提供微结构信息的强大的新扩散磁共振成像(DMRI)方法 反映树突萌发和髓鞘形成的程度。这些测试将提供对 视觉皮质对GT反应的变化。还将测量所有患者的初级和高级视觉功能 受试者使用一组功能磁共振成像(FMRI)范例。视觉功能将单独进行评估， 在第三阶段临床试验期间，数据将提供给这项研究。然后，视觉功能数据将 并与中枢神经系统影像和视功能数据进行相关分析。 该项目的完成将提供有关神经可塑性程度的重要时空数据 人类视觉系统及其在GT后增强视觉功能中所起的作用。这些数据 未来可能在评估基因疗法介导的逆转失明的研究中具有潜在的应用价值。

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.