Achromatopsia: Exploring nature and plasticity of vision in the absence of functional cones

色盲的特征是视网膜中所有类型的视锥感光细胞功能障碍。就像在许多形式的遗传性视网膜疾病中一样，单个基因的突变，主要是CNGA3或CNGB3，足以导致疾病。由于光感受器处于视觉的最开始阶段，功能丧失会对视觉通路的所有下游部分造成严重后果。在这里，我们开始评估视锥细胞功能障碍对不同视觉水平的影响，以比较的方法明确病理生理学和神经可塑性的相互作用。我们将在人类患者和小鼠模型中研究AC的影响，这使我们能够探索基因替代治疗后AC表型部分或完全逆转的可能性。该提案得益于这样一个事实，即色盲(AC)的治疗性基因疗法是最先进的，我们最近在各自的小鼠模型上成功地恢复了视力[cnga3-/-](Michalakis等人，2010年)。因此，它很可能在未来为人类应用而建立。虽然这项初步工作的重点是纠正遗传缺陷，但我们在这里调查的是光感受器水平的治疗性修复对整个视觉系统的影响。具体地说，我们的研究问题涉及(I)AC中自然视觉系统的状态，(Ii)所涉及的脑区的可塑性和重组，(Iii)视觉系统状态和可塑性对诸如年龄和个体基因类型等修改因素的依赖性，以及(Iv)神经可塑性与小鼠模型中视觉功能和视觉功能恢复的相关性。这些研究将在很大程度上在人和小鼠身上并行进行(后者提供未治疗和治疗状态的比较)，结合行为和生理技术，包括先进的成像(主要是MRI/fMRI)和非侵入性电生理学。从更广泛的角度来看，这项AC研究将有助于评估视觉系统疾病的修饰因素和可塑性对治疗成功的影响。其结果有望有助于未来视网膜基因治疗干预措施的优化，以促进人类AC的个体化基因治疗。具体地说，这包括选择用于检测和跟踪治疗成功的生物标记物，以及在即将进行的试验中为患者选择建立诊断和一般标准。此外，对AC的比较、详细的研究有望对哺乳动物视觉系统中病理生理学和可塑性的相互作用产生基本的见解。

Achromatopsia is characterized by a dysfunction of all cone photoreceptor types in the retina. As in many forms of inherited retinal disorders, mutations of a single gene, predominantly CNGA3 or CNGB3, are sufficient to cause the disease. Since photoreceptors stand at the very beginning of vision, a functional loss has severe consequences for all downstream parts of the visual pathways. Here, we set out to assess the effects caused by dysfunctional cones on different levels of vision to specify the interplay of pathophysiology and neural plasticity in a comparative approach.We will study the effects of AC in human patients and in a mouse model, which allows us to ex-plore the potential for a partial or full reversal of the AC phenotype following gene replacement therapy. The proposal profits from the fact that curative gene therapy in achromatopsia (AC) is most advanced as highlighted by our recent successful restoration of vision in a respective mouse model [cnga3-/-] (Michalakis, et al., 2010). It is therefore likely to be established in the future for human applications. While this primary work focused on the correction of the genetic defect, we are here investigating the implications of a therapeutic restoration at the photoreceptor level on the visual system in its entirety. Specifically, our research questions concern (i) the state of the native visual system in AC, (ii) the plasticity and reorganisation of the brain regions involved, (iii) the de-pendence of visual system state and plasticity on modifying factors like age and individual geno-type, and (iv) the relevance of neural plasticity for visual function and for restoration of visual func-tion in the mouse model. These investigations will be conducted largely in parallel in man and mouse (the latter offering the comparison of untreated & treated states) with combined behavioural and physiological techniques, comprising advanced imaging (mainly MRI/fMRI) and non-invasive electrophysiology.In a more general view, this study in AC will help to estimate the impact of modifying factors and plasticity on treatment success in visual system disorders. Its outcome is expected to aid the opti-misation of upcoming retinal gene therapeutic interventions in order to facilitate individualized gene therapy of human AC. Specifically, this includes the choice of biomarkers for detection and follow-up of therapeutic success, and the establishment of diagnostic and general criteria for patient se-lection in upcoming trials. Furthermore, the comparative, detailed investigation of AC is expected to produce fundamental insights into the interplay of pathophysiology and plasticity in the mammalian visual system.