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

项目概述：视觉输入的变化对神经元回路的影响是复杂的，我们的大部分研究都是关于视觉输入对神经元回路的影响。 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 强调负责视觉皮层可塑性的特定神经基础， 损伤，恢复视力和环境相互作用，类似的研究在人类中是不可能的。 因为这是不道德的侵入性手术有机会接触到一组特征鲜明的 因RPE 65突变（LCA 2）而患有Leber先天性黑蒙的受试者，将参加LCA 2 3期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 基因治疗（GT）我们希望在动物大脑皮层可塑性变化的研究中， 在LCA患者中使用反向眼睑缝合（恢复视力）和人视网膜GT（恢复视力）的研究。 在这些受试者的干预前后进行无创脑成像将为我们提供机会， 只研究恢复视力对人类大脑的影响以及可塑性的潜在机制， 还将重点放在LCA2患者在GT之前使用的替代视觉通路上。 似乎利用了固有光敏视网膜神经节细胞（ipRGC），一个问题是是否存在 是GT后视网膜信号到大脑的相对变化。 据我们所知，这将是第一个纵向研究，联合收割机的结构和功能相结合， 神经成像技术，以检查和获得更深入的了解大脑可塑性的过程， 人类在体内，重点是一个大群体的人出生时有严重的视力障碍， 测量之前和之后的干预，恢复视力。 3期LCA临床试验将入组24例患者，其中8例随机分配接受随访， 所有受试者将接受亚毫米3D结构成像， 成像，以及一种强大的新方法，扩散磁共振成像（dMRI），提供微观结构信息 反映树突出芽和髓鞘形成的程度。这些测试将提供详细的评估， 视觉皮层对GT的反应变化。初级和高级视觉功能也将在所有 受试者使用电池的功能性磁共振成像（fMRI）范例。将单独评估视觉功能， 在III期临床试验期间，将向本研究提供数据。然后，视觉功能数据将 与中枢神经系统成像和视觉功能数据相关。 本研究的完成将为神经可塑性的研究提供重要的时空数据 的人类视觉系统和它在增强视觉功能后GT的作用。这些数据 可能有未来的潜在应用研究评估基因治疗介导的逆转失明。

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.