Restoration of photopic vision by cell transplantation

工业化国家残疾的主要原因是视网膜主要感光细胞-光感受器-退化造成的视力障碍和失明。而杆状光感受器 虽然锥状光感受器在昏暗的光线条件下有助于视觉（暗视觉），但锥状光感受器仅在日光条件下活跃（明视觉）。具体地，如在年龄相关性黄斑变性（AMD）或视锥-视杆营养不良中的视锥光感受器的损失导致受损的聚焦日光视觉和颜色辨别。通过细胞移植替代丢失的光感受器代表了一种有希望的治疗选择。事实上，最近的临床前研究表明，未成熟的视杆细胞光感受器具有在移植到成年非神经原性小鼠视网膜中后正确整合并形成完全成熟和功能性光感受器的潜力。然而，目前大多数研究都集中在视杆细胞作为供体细胞，因为从视杆细胞占主导地位的小鼠视网膜中可以获得足够的供体材料，使得视锥细胞的移植没有得到很好的研究。因此，我们建议在临床前视锥细胞功能丧失的小鼠模型中研究视锥细胞光感受器恢复明视视觉的可能性。为了破译成功的视锥细胞移植的细胞和分子要求，我们将利用视锥细胞特异性报告小鼠，并将建立一个替代来源的视锥细胞样光感受器的移植研究。神经视网膜亮氨酸拉链（Nrl）缺陷小鼠的视网膜的特征在于不存在视杆光感受器，而是仅由视锥和视锥样光感受器组成。因此，可以从Nrl缺陷型视网膜分离足够量的视锥样光感受器，从而允许系统地评估它们在移植到成年小鼠视网膜中后的迁移、整合和成熟。此外，我们将调查锥和锥样光感受器的功能整合到色盲的小鼠模型的神经元回路，其特征在于锥光感受器的损失。由于明视觉对人类的重要性，拟议的原理验证研究评估恢复锥介导的光检测将是一个必要的先决条件，铺平道路的临床应用的细胞为基础的方法治疗最新的不可治愈的视网膜疾病。

The prime reason for disability in industrialized countries is vision impairment and blindness caused by degeneration of the main light sensing cells of the retina - the photoreceptors. Whereas rod photoreceptors contribute to vision in dim light conditions (scotopic vision), cone photoreceptors are only active in day-light conditions (photopic vision). Specifically the loss of cone photoreceptors as in age related macular degeneration (AMD) or cone-rod dystrophies leads to impaired focused day-light vision and color discrimination. Replacement of lost photoreceptors by cell transplantation represents a promising treatment option. Indeed, recent pre-clinical studies demonstrated that immature rod photoreceptors have the potential to correctly integrate following transplantation into the adult, non-neurogenic mouse retina and form fully mature and functional photoreceptors. However, currently most studies focused on rod photoreceptors as donor cells due to the accessibility of sufficient donor material from the rod-dominated mouse retina, leaving transplantation of cones not well studied. Therefore we propose to investigate the probability of cone photoreceptors for the restoration of photopic vision in pre-clinical mouse models of cone function loss. To decipher the cellular and molecular requirements for successful cone transplantation we will take advantage of cone-specific reporter mice and will establish an alternative source of cone-like photoreceptors for transplantation studies. The retinas of neural retina leucine zipper (Nrl) deficient mice are characterized by the absence of rod photoreceptors and instead consist solely of cone and cone-like photoreceptors. Therefore, sufficient amounts of cone-like photoreceptors can be isolated from Nrl-deficient retinas allowing to systematically evaluate their migration, integration and maturation following transplantation into the adult mouse retina. Furthermore, we will investigate the functional integration of cone and cone-like photoreceptors into the neuronal circuitry of mouse models of achromatopsia that are characterized by loss of cone photoreceptors. Due to the importance of photopic vision for humans, the proposed proof-of-principle study assessing the restoration of cone-mediated light detection will be an essential prerequisite to pave the way towards the clinical application of cell-based methods for the treatment of up to date incurable retinal diseases.