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

全色盲的特征在于视网膜中所有视锥细胞类型的功能障碍。与许多形式的遗传性视网膜疾病一样，单一基因（主要是CNGA 3或CNGB 3）的突变足以引起疾病。由于光感受器位于视觉的最开始，因此功能丧失对视觉通路的所有下游部分都具有严重后果。在这里，我们着手评估功能障碍的视锥细胞对不同层次的视觉所造成的影响，以指定的病理生理学和神经可塑性的相互作用，在一个比较的approach.We将研究AC在人类患者和小鼠模型，这使我们能够ex-plore的AC表型的基因替代治疗后的部分或全部逆转的潜力的影响。该提议得益于以下事实：色盲（AC）中的治愈性基因疗法是最先进的，如我们最近在相应的小鼠模型中成功恢复视力所强调的[cnga 3-/-]（Michalakis等人，2010年）。因此，它很可能在未来为人类应用而建立。虽然这项主要工作集中在遗传缺陷的纠正上，但我们在这里研究的是感光细胞水平上的治疗性恢复对整个视觉系统的影响。具体而言，我们的研究问题涉及（i）AC中的原生视觉系统的状态，（ii）相关脑区的可塑性和重组，（iii）视觉系统状态和可塑性对年龄和个体基因型等修饰因素的依赖性，以及（iv）神经可塑性与视觉功能和小鼠模型视觉功能恢复的相关性。这些调查将在很大程度上平行进行，在人和小鼠（后者提供了未处理和治疗状态的比较）与结合的行为和生理技术，包括先进的成像（主要是MRI/fMRI）和非侵入性的电生理学。在更普遍的观点，这项研究在AC将有助于评估的影响，修改因素和可塑性的治疗成功的视觉系统疾病。其结果有望有助于优化即将到来的视网膜基因治疗干预措施，以促进人类AC的个体化基因治疗。具体而言，这包括选择用于检测和随访治疗成功的生物标志物，以及在即将进行的试验中建立患者选择的诊断和一般标准。此外，AC的比较，详细的调查，预计将产生根本的见解，在哺乳动物视觉系统的病理生理学和可塑性的相互作用。

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.