3D retina-RPE constructs for vision restoration in new retinal degeneration m

标题：3D视网膜-RPE构建新的大鼠视网膜变性模型的视力恢复 在晚期退行性疾病患者中，视网膜色素上皮(RPE)和 光感受器丢失。如果新的细胞可以恢复丢失细胞的功能，退化的视网膜可能 进行修复，恢复视力。我们的团队通过移植视网膜薄片来恢复视力 人胚胎干细胞(HESCs)来源的祖细胞和RPE细胞移植给丢失的受者 光感受器和视网膜色素上皮(RPE)细胞。新收获的板材的移植 视网膜祖细胞(通过一种独特的程序和仪器)已经显示出发育 具有正常形态的光感受器，与宿主的突触连接，并恢复失去的视觉 在几种视网膜变性模型和人类患者中的反应。这不能通过以下方式实现 将分离的细胞注入视网膜。尽管存在其他方法，但大多数方法仅限于 通过植入细胞的“护理”作用挽救受者的内源性视网膜细胞，一种方法 这并不能恢复丧失的功能。 新鲜的胎儿来源的神经母细胞组织供应有限。人类胚胎干细胞分化为 光感受器前体细胞和RPE细胞将为临床和研究创造无限的组织供应 使用。几个实验室最近开发了将多能干细胞分化为 视泡和视杯状结构，形成视网膜细胞类型，并有一定程度的板层。 我们希望使用这种方法来生产具有RPE的层叠视网膜祖细胞片材 移植。 我们的团队已经开发出1)一种从hESC中提取早期视网膜前体组织的方案和2)一种新的 免疫缺陷的视网膜变性啮齿动物模型。需要额外的临床前动物研究来 开发治疗上可行和可持续的干细胞衍生材料供应。 提出了一项为期三年的项目，以检验以下假设：(1)hESC来源的光感受器前体细胞， 与hESC来源的RPE膜一起移植到新的免疫缺陷的RD大鼠模型中，Will 开发成熟的光感受器标记，并与退化的宿主视网膜整合；(2)hESC来源 视网膜祖细胞可以恢复这种啮齿动物模型的视觉反应，其程度与移植 视动测试和电生理检查显示胎儿视网膜有RPE。 ESC来源的完整视网膜祖层与RPE联合移植治疗大鼠视网膜变性 为开发视网膜疗法提供了一个很好的模型来回答一个重要的问题。证明 Concept将为恢复和改善视网膜疾病患者的视力提供新的组织来源。

Title: 3D retina-RPE constructs for vision restoration in new rat retinal degeneration model In patients with advanced degenerative diseases, both retinal pigment epithelium (RPE) and photoreceptors are lost. If new cells can restore the function of the lost cells, a degenerating retina might be repaired and eyesight restored. Our team targets vision restoration by transplanting sheets of retinal progenitor and RPE cells derived from human embryonic stem cells (hESCs) to recipients that have lost photoreceptors and retinal pigment epithelium (RPE) cells. Transplants of freshly harvested sheets of retinal progenitor cells (delivered by a unique procedure and instrument) have shown to develop photoreceptors with normal morphology, synaptic connections with the host and to restore lost visual responses in several retinal degeneration models and in human patients. This cannot be achieved by injecting dissociated cells into the retina. Although other approaches exist, the majority are restricted to rescue of endogenous retinal cells of the recipient by a 'nursing' role of the implanted cells, an approach which does not restore lost function. The supply of fresh fetal-derived neuroblastic tissue is limited. Differentiation of hESCs into sheets of photoreceptor progenitors and RPE cells would create an unlimited tissue supply for clinical and research use. Several laboratories have recently developed procedures to differentiate pluripotent stem cells into optic vesicles and optic cup-like structures that develop retinal cell types with some degree of lamination. We want to use this approach for producing laminated retinal progenitor sheets with RPE for transplantation. Our team has developed 1) a protocol to derive early retinal progenitor tissue from hESC and 2) a new immunodeficient rodent model of retinal degeneration. Additional pre-clinical animal research is required to develop a therapeutically viable and sustainable supply of stem cell derived material. A three-year project is proposed to test the hypothesis that (1) hESC-derived photoreceptor progenitors, transplanted together with a hESC-derived RPE sheet to a new immunodeficient rat model of RD, will develop mature photoreceptor markers and integrate with the degenerating host retina; (2) hESC-derived retinal progenitors can restore visual responses in this rodent model to the same extent as transplants of fetal retina with RPE, as shown by optokinetic testing and electrophysiology. Transplantation of intact ESC-derived retinal progenitor layers with RPE in rats with retinal degeneration provides an excellent model to answer an important question for developing retinal therapies. Proof of concept will provide a new tissue source to restore and improve vision in patients with retinal diseases.