Restoration of photopic vision by cell transplantation

通过细胞移植恢复明视觉

• 批准号: 246716412
• 负责人: Professor Dr. Marius Ader
• 金额: --
• 依托单位: Zentrum für Regenerative Therapien Dresden - CRTD
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/246716412?language=en
• 关键词: Restoration; photopic; vision; cell; transplantation

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.

在工业化国家，致残的主要原因是视网膜的主要感光细胞--光感受器退化造成的视力障碍和失明。杆状感光器在暗光条件下有助于视觉(暗视)，而视锥感光细胞只在白天条件下活跃(明视)。特别是在老年性黄斑变性(AMD)或视锥视杆细胞营养不良中，视锥细胞感光细胞的丧失会导致日光聚焦视力受损和颜色辨别能力下降。通过细胞移植替代丢失的光感受器是一种很有前途的治疗选择。事实上，最近的临床前研究表明，未成熟的杆状光感受器在移植到成年非神经源性小鼠视网膜后具有正确整合的潜力，并形成完全成熟和功能齐全的光感受器。然而，目前大多数研究都集中在视杆感受器作为供体细胞，这是因为可以从视杆细胞主导的小鼠视网膜获得足够的供体材料，这使得视锥细胞移植的研究还不够深入。因此，我们建议在临床前的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力的可能性。为了破译成功的视锥细胞移植的细胞和分子需求，我们将利用视锥细胞特异的报告小鼠，并将建立替代来源的视锥样光感受器用于移植研究。神经性视网膜亮氨酸拉链(NRL)缺陷小鼠的视网膜以缺少杆状感光器为特征，仅由视锥和视锥样光感受器组成。因此，可以从NRL缺乏的视网膜中分离出足够数量的视锥样光感受器，以便系统地评估它们在移植到成年小鼠视网膜后的迁移、整合和成熟。此外，我们将研究视锥细胞和视锥细胞样光感受器在以视锥细胞光感受器丧失为特征的色盲小鼠模型的神经元回路中的功能整合。由于明视视觉对人类的重要性，拟议中的评估视锥细胞介导的光检测恢复的原则验证研究将是为临床应用基于细胞的方法治疗最新的不可治愈的视网膜疾病铺平道路的必要前提。

项目成果

Stem Cell-Derived Photoreceptor Transplants Differentially Integrate Into Mouse Models of Cone-Rod Dystrophy.

• DOI: 10.1167/iovs.16-19087
• 发表时间: 2016-06
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: T. Santos-Ferreira;Manuela Völkner;O. Borsch;Jochen Haas;P. Cimalla;P. Vasudevan;P. Carmeliet;D. Cor

Daylight Vision Repair by Cell Transplantation

• DOI: 10.1002/stem.1824
• 发表时间: 2015-01-01
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Santos-Ferreira, Tiago;Postel, Kai;Ader, Marius
• 通讯作者: Ader, Marius