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Retinal Ganglion Cell Replacement in Optic Neuropathies

视神经病变中的视网膜神经节细胞替代

基本信息

批准号：
10239017
负责人：
David J. Calkins
金额：
$ 135.75万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239017
关键词：
ATOH7 gene Animals Autopsy Axon Axonal Transport Biological Assay Blindness Brain Cell Death Cell Nucleus Cell Transplantation Cells Clustered Regularly Interspaced Short Palindromic Repeats Data Diagnosis Distal Dose Electrophysiology (science)Electroretinography Evoked Potentials Fluorescence Gene Expression Glaucoma Goals Growth Histologic Histology Human Image Implant In Vitro Injections Injury Institution Label Laboratories Light Measures Mediating Membrane Microspheres Modality Modeling Molecular Monkeys Ophthalmoscopy Optic Nerve Optical Coherence Tomography Pathway interactions Patients Photons Photosensitivity Physiologic Intraocular Pressure Physiology Property Protocols documentation Research Resolution Retina Retinal Ganglion Cells Risk Factors Rodent Rodent Model Saimiri Scanning Shipping Ships Signal Transduction Structure Testing Translations Transplantation Visual system structure adaptive optics axonopathy cell replacement therapy cohort fluorophore fundus imaging human embryonic stem cell human embryonic stem cell line human stem cells in vivo innovation melanopsin migration neurite growth nonhuman primate notch protein optic nerve disorder portability progenitor programs regeneration potential sight restoration standard of care synaptogenesis therapeutic development transcription factor transcriptome translation to humans transplant model visual dysfunction

项目摘要

PROJECT SUMMARY Glaucoma is a leading causes of blindness and along with other optic neuropathies is characterized by the loss of retinal ganglion cells (RGCs). Increased intraocular pressure (IOP) management is the current standard of care for glaucoma patients, but fails to stop the irreversible loss of RGCs and progressive visual dysfunction. Vision restoration through RGC replacement therapy, one of the NEI’s Audacious Goals program, could be a potential solution, and considerable progress has been made in understanding the molecular signals that regulate RGC specification from human stem cells, as well as in RGC transplant and integration in rodents. However, when considering translation of laboratory advances to human testing, rodent models are limited by critical differences in retinal physiology, and proof-of-concept in non-human primates would greatly increase confidence and aid in therapeutic development before moving to human testing. Thus there is a considerable need for a tractable non-human primate model. Here we will establish a squirrel monkey-induced glaucoma model and the parameters to study human stem cell-derived RGC integration and potential vision restoration in a retina and visual system closer to those of human. Through this 5-year proposal we will achieve critical milestones, including validating the monkey glaucoma model, studying key structural and functional measures using innovative new modalities that should be portable between monkey and humans, and demonstrating the model’s ability to move across institutions. All of this will be accomplished in the setting of studying RGC transplant: differentiation, migration, local integration and synapse formation, growth down the optic nerve, and targeting to distal brain nuclei, with the goal of vision restoration.

项目摘要青光眼是失明的主要原因，并且沿着其他视神经病变的特征在于：视网膜神经节细胞（RGC）的丧失。眼内压（IOP）升高的管理是目前青光眼患者的标准护理，但未能阻止RGC的不可逆损失和进行性视力下降。功能障碍通过RGC替代疗法恢复视力，NEI的大胆目标计划之一，可能是一个潜在的解决方案，在理解分子生物学方面已经取得了相当大的进展。调节来自人类干细胞的RGC特化的信号，以及在RGC移植和整合中的信号。啮齿动物然而，当考虑将实验室进展转化为人类测试时，啮齿动物模型是受视网膜生理学关键差异的限制，在非人类灵长类动物中的概念验证将大大在进行人体试验之前增加信心并帮助治疗开发。因此有相当需要一个易处理的非人灵长类动物模型。在这里，我们将建立一个松鼠猴子诱导人干细胞源性视网膜神经节细胞整合和潜在视力的青光眼模型和参数研究视网膜和视觉系统的恢复更接近人类。通过这五年的计划，我们将实现关键的里程碑，包括验证猴子青光眼模型，研究关键的结构和使用创新的新模式进行功能性测量，这些模式应该在猴子和人类之间便携，并展示该模型在机构间的移动能力。所有这些都将在设置中完成研究RGC移植：分化，迁移，局部整合和突触的形成，向下生长视神经，靶向远端脑核团，目的是恢复视力。