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

3D 视网膜-RPE 结构用于新发视网膜变性患者的视力恢复

• 批准号: 8614522
• 负责人: HANS S KEIRSTEAD
• 金额: $ 38.57万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2014-04-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8614522
• 关键词: 3-Dimensional; Address; Animal Experimentation; Area; Basic Science; Blindness; Cells; Clinical; Clinical Research; Clinical Trials; Cone; Contrast Sensitivity; Data; Degenerative Disorder; Development; Electrophysiology (science); Funding; Future; Generations; Grant; Harvest; Human; Immunohistochemistry; Implant; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Methods; Modeling; Morphology; Nurse' s Role; Opsin; Optic vesicle; Patients; Photoreceptors; Pluripotent Stem Cells; Positioning Attribute; Procedures; Protocols documentation; Publications; Rattus; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Rhodopsin; Rodent Model; Source; Spinal cord injury; Stem cell transplant; Stem cells; Structure; Structure of retinal pigment epithelium; Synapses; Testing; Therapeutic Human Experimentation; Tissue Donors; Tissues; Translating; Transplantation; United States Food and Drug Administration; Vision; Visual; Visual Acuity; Work; base; blastocyst; cell type; dehydroretinal; experience; fetal; functional restoration; human embryonic stem cell; improved; induced pluripotent stem cell; instrument; light intensity; monolayer; nerve stem cell; oligodendrocyte precursor; optic cup; photoreceptor progenitor; pluripotency; pre-clinical; programs; public health relevance; recoverin protein; repaired; response; restoration; retinal progenitor cell; sham surgery; stem cell population; success; superior colliculus Corpora quadrigemina; transcription factor

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.

标题：用于新大鼠视网膜变性模型中视力恢复的3D视网膜-RPE构建体 在患有晚期退行性疾病的患者中，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失去的细胞的功能， 修复视力恢复我们的团队的目标是通过移植视网膜 将来自人胚胎干细胞（hESC）的祖细胞和RPE细胞移植到已经丧失了 光感受器和视网膜色素上皮（RPE）细胞。移植新鲜收获的床单 视网膜祖细胞（通过独特的程序和仪器输送）已经显示出可以发育成 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 将分离的细胞注射到视网膜中。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”作用拯救受体的内源性视网膜细胞， 它不能恢复失去的功能。 新鲜的胎儿来源的神经母细胞组织的供应是有限的。将hESC分化为细胞片层， 光感受器祖细胞和RPE细胞将为临床和研究提供无限的组织供应 使用.几个实验室最近已经开发出将多能干细胞分化为 视泡和视杯状结构，其发育具有一定程度层压的视网膜细胞类型。 我们想使用这种方法来生产具有RPE的层压视网膜祖细胞片， 移植 我们的团队已经开发了1）从hESC获得早期视网膜祖细胞组织的方案，2）一种新的 视网膜变性的免疫缺陷啮齿动物模型。需要进行额外的临床前动物研究， 开发治疗上可行且可持续的干细胞衍生材料供应。 提出了一个为期三年的项目来检验以下假设：（1）hESC衍生的感光细胞祖细胞， 与hESC衍生的RPE片一起移植到新的RD免疫缺陷大鼠模型， 发育成熟的感光细胞标记物并与退化的宿主视网膜整合;（2）hESC衍生的 视网膜祖细胞可以在这种啮齿动物模型中恢复视觉反应，其程度与移植的视网膜祖细胞相同 视网膜色素上皮的胎儿视网膜，如视动测试和电生理所示。 视网膜前体层与RPE联合移植治疗视网膜变性大鼠 提供了一个很好的模型来回答发展视网膜治疗的一个重要问题。证明 concept将为视网膜疾病患者提供一种新的组织来源，以恢复和改善视力。