Genetic diseases affecting the retina can result in partial or complete loss of visual function. Leber’s Congenital Amaurosis (LCA) is a rare blinding disease, usually inherited in an autosomally recessive manner, with no cure. Retinal gene therapy has been shown to improve vision in LCA patients caused by mutations in the RPE65 gene (LCA2). However, little is known about how activity in central visual pathways is affected by the disease or by subsequent gene therapy. Functional MRI was used to assess retinal signal transmission in cortical and subcortical visual structures before and one year after retinal intervention. The fMRI paradigm consisted of 15-second blocks of flickering (8-Hz) black and white checkerboards interleaved with 15 seconds of blank (black) screen. Visual activation in the brain was assessed using the general linear model, with multiple comparisons corrected using the false discovery rate method. Response to visual stimulation through untreated eyes of LCA2 patients showed heightened fMRI responses in the superior colliculus (SC) and diminished activities in the lateral geniculate nucleus (LGN) compared to controls, indicating a shift in the patients’ visual processing towards the retinotectal pathway (RT). Following gene therapy, stimuli presented to the treated eye elicited significantly stronger fMRI responses in the LGN and primary visual cortex, indicating some reengagement of the geniculostriate pathway (GS) pathway. Across patients, the post-treatment LGN fMRI responses correlated significantly with performance on a clinical test measuring light sensitivity. Our results demonstrate that the low vision observed in LCA2 patients involves a shift in visual processing toward the retinotectal pathway, and that gene therapy partially reinstates visual transmission through the GS pathway. This selective boosting of retinal output through the GS pathway and its correlation to improved visual performance, following several years of degenerative retinal disease, is striking. However, while retinal gene therapy and other ocular interventions have given hope to RPE65 patients, it may take years before development of therapies tailored to treat the diseases in other low vision patients are available. Our demonstration of a shift toward the RT pathway in these patients may spur the development of new tools and rehabilitation strategies to help maximize the use of residual visual abilities and augment experience-dependent plasticity.

中文翻译：

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基因治疗前后受退行性视网膜疾病影响的中央视觉通路

影响视网膜的遗传疾病可能导致视觉功能部分或完全丧失。莱伯氏先天性黑蒙 (LCA) 是一种罕见的致盲性疾病，通常以常染色体隐性方式遗传，无法治愈。视网膜基因治疗已被证明可以改善由 RPE65 基因 (LCA2) 突变引起的 LCA 患者的视力。然而，人们对中枢视觉通路的活动如何受到疾病或后续基因治疗的影响知之甚少。功能性 MRI 用于评估视网膜干预前和术后一年皮质和皮质下视觉结构的视网膜信号传输。 fMRI 范例由 15 秒的闪烁 (8 Hz) 黑白棋盘块和 15 秒的空白（黑色）屏幕组成。使用一般线性模型评估大脑中的视觉激活，并使用错误发现率方法校正多重比较。与对照组相比，LCA2 患者未经治疗的眼睛对视觉刺激的反应显示上丘 (SC) 的 fMRI 反应增强，外侧膝状核 (LGN) 的活动减弱，表明患者的视觉处理向视网膜顶盖通路转变。转发）。基因治疗后，给予治疗眼的刺激在 LGN 和初级视觉皮层中引起明显更强的 fMRI 反应，表明膝纹通路 (GS) 通路有一定程度的重新参与。在患者中，治疗后 LGN fMRI 反应与测量光敏感性的临床测试表现显着相关。我们的结果表明，在 LCA2 患者中观察到的低视力涉及视觉处理向视网膜顶盖通路的转变，并且基因治疗部分恢复了通过 GS 通路的视觉传输。经过数年的退行性视网膜疾病后，通过 GS 通路选择性地提高视网膜输出及其与改善视觉表现的相关性是惊人的。然而，虽然视网膜基因治疗和其他眼部干预措施给 RPE65 患者带来了希望，但可能需要数年时间才能开发出专门治疗其他低视力患者疾病的疗法。我们对这些患者向 RT 途径的转变的证明可能会刺激新工具和康复策略的开发，以帮助最大限度地利用残余视觉能力并增强依赖于经验的可塑性。