Accelerating photoreceptor replacement therapy with in-vivo cellular imaging of retinal function

通过视网膜功能的体内细胞成像加速光感受器替代疗法

• 批准号: 10329081
• 负责人: Juliette Elizabeth McGregor
• 金额: $ 123.32万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10329081
• 关键词: 3-Dimensional; Ablation; Adult; Anatomy; Area; Automobile Driving; Behavior; Blindness; Calcium; California; Cell Therapy; Cell physiology; Cells; Clinical Data; Clinical Trials; Collaborations; Cone; Custom; Development; Evaluation; Eye; Family suidae; Fluorescence; Functional Imaging; Funding; Future; Generations; Histology; Human; Hyperactivity; Image; Imaging Techniques; Immune system; Immunoelectron Microscopy; Implant; Individual; Intervention; Lasers; Light; Location; Mediating; Methods; Modeling; Noise; Operative Surgical Procedures; Ophthalmoscopy; Optics; Patients; Photophobia; Photoreceptors; Physiologic pulse; Physiology; Population; Preclinical Testing; Primates; Replacement Therapy; Resolution; Retina; Retinal Degeneration; Retinal Ganglion Cells; Rodent; Scanning; Side; Signal Transduction; Societies; Speed; Structure; Synapses; System; Technology; Testing; Therapeutic Intervention; Time; Transplantation; Tretinoin; Universities; Variant; Vision; Visual system structure; Wisconsin; adaptive optics; base; blind; calcium indicator; cellular imaging; density; fovea centralis; functional restoration; fundus imaging; human pluripotent stem cell; imaging approach; imaging system; improved; in vivo; in vivo calcium imaging; in vivo evaluation; in vivo imaging; novel; novel therapeutic intervention; pre-clinical; preclinical evaluation; preservation; prevent; regeneration potential; regenerative therapy; response; retinal imaging; scaffold; sight restoration; stem cells; success; synaptogenesis; therapy development; virtual

Abstract To restore high quality, usable vision in patients, it is important to develop regenerative therapies in models that share key features of the human visual system, particularly a fovea, the retinal area specialized for high acuity vision. Pre-clinical testing has been challenging due to both the absence of models of foveal vision loss and the difficulty of demonstrating restored function. Under previous AGI funding, the Advanced Retinal Imaging Alliance at the University of Rochester has recently overcome these challenges to create a pre-clinical testing platform leveraging adaptive optics technology to: 1.) Create localized regions of photoreceptor ablation in the fovea that are axially confined, and 2.) Optically read out restored retinal ganglion cell function by performing cellular scale calcium imaging in the living eye. This system was developed to meet the needs of photoreceptor replacement therapy, which requires photoreceptor loss with preserved host retinal circuitry. Furthermore, a high-resolution in vivo imaging approach is well suited for pre-clinical evaluation of regenerative therapies where the timescales of restored connectivity are unknown and functional integration occurs on the cellular scale. In this proposal, we will use our platform to generate pre-clinical data that will inform future clinical trials of photoreceptor replacement therapy in patients. Functional integration of transplanted photoreceptors with the host retina requires both high-density delivery of high-quality donor photoreceptors and a host retina with the capacity for synaptogenesis. We have assembled a consortium that can explore and optimize both sides of this interaction. In continued collaboration with a team at the University of Wisconsin led by David Gamm, a clinician and expert in photoreceptor replacement therapy, we will evaluate survival and functional integration of transplanted photoreceptor precursors delivered to the sub-retinal space as aggregates or following incorporation into custom biodegradable scaffolds. In collaboration with a team at University of California, Berkeley led by Teresa Puthussery, an expert in retinal remodelling in retinal degeneration models and retinal histology, we will examine the impact of the loss of photoreceptor signalling on inner retina. We will explore whether deafferented cone bipolar cells can remodel and functionally integrate with donor photoreceptors and whether retinal hyperactivity develops in the fovea as it does in rodent. To make meaningful progress toward restoring vision in patients who have lived with vision loss for many years, we will examine how these phenomena develop in the fovea over time and whether the regenerative potential of the host can be improved by therapeutic interventions such as retinoic acid blockers. These studies will allow us to fully characterize our novel photoreceptor ablation model and deploy it with photoreceptor replacement therapies to advance the field toward clinical trials.

摘要 为了恢复患者高质量、可用的视力，重要的是开发具有人类视觉系统关键特征的再生疗法，特别是黄斑中心凹，这是专门用于高视力视力的视网膜区域。由于黄斑中心凹视力丧失模型的缺乏和证明功能恢复的困难，临床前测试一直是具有挑战性的。在之前的AGI资助下，罗切斯特大学的先进视网膜成像联盟最近克服了这些挑战，创建了一个利用自适应光学技术的临床前测试平台，以：1.在中心凹创建轴向受限的局部光感受器消融区域，以及2.)通过对活体眼睛进行细胞尺度的钙成像，光学读出恢复的视网膜神经节细胞功能。该系统是为了满足光感受器替代疗法的需要而开发的，光感受器替代疗法需要在保留宿主视网膜电路的情况下失去光感受器。此外，高分辨率体内成像方法非常适合于再生疗法的临床前评估，其中恢复连接的时间尺度未知，功能整合发生在细胞尺度上。在这项提案中，我们将使用我们的平台来生成临床前数据，这些数据将为未来在患者中进行光感受器替代疗法的临床试验提供信息。移植的光感受器与宿主视网膜的功能整合需要高密度的高质量供体光感受器和具有突触发生能力的宿主视网膜。我们已经组建了一个财团，可以探索和优化这种互动的双方。在与威斯康星大学由光感受器替代疗法临床医生和专家David Gamm领导的团队的持续合作下，我们将评估移植的光感受器前体作为聚集体输送到视网膜下间隙或整合到定制的可生物降解支架后的存活率和功能整合。与加州大学伯克利分校的一个团队合作，由视网膜变性模型和视网膜组织学中的视网膜重塑专家Teresa Puthussery领导的一个团队，我们将研究光感受器信号的丧失对视网膜内部的影响。我们将探索去传入的视锥双极细胞是否能重塑供体光感受器并在功能上与供体光感受器整合，以及是否像啮齿动物那样在中心凹发展视网膜过度活动。为了在视力丧失患者的视力恢复方面取得有意义的进展，我们将研究这些现象是如何随着时间的推移在中心凹发展的，以及是否可以通过维甲酸阻滞剂等治疗干预措施改善宿主的再生潜力。这些研究将使我们能够充分描述我们的新型光感受器消融模型，并将其与光感受器替代疗法结合起来，将该领域推向临床试验。