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

通过视网膜功能体内细胞成像加速光感受器替代疗法的补充

• 批准号: 10861568
• 负责人: Juliette Elizabeth McGregor
• 金额: $ 16.58万
• 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/10861568
• 关键词: Ablation; Acceleration; Anatomy; Animal Model; Area; Blindness; Calcium; California; Cell physiology; Cells; Clinical Trials; Collaborations; Cone; Custom; Data; Development; Eye; Functional Imaging; Funding; Future; Histology; Human; Hyperactivity; Image; Imaging Techniques; Individual; Location; Mediating; Modeling; Optics; Patients; Photoreceptors; Physiology; Preclinical Testing; Primates; Replacement Therapy; Research; Resolution; Retina; Retinal Degeneration; Retinal Ganglion Cells; Rodent; Side; Signal Transduction; Societies; System; Technology; Therapeutic Intervention; Time; Transplantation; Tretinoin; Universities; Vision; Visual System; Wisconsin; adaptive optics; biodegradable scaffold; blind; cellular imaging; density; fovea centralis; functional restoration; human pluripotent stem cell; imaging approach; improved; in vivo; in vivo imaging; nonhuman primate; novel; novel therapeutic intervention; pre-clinical; preclinical evaluation; preservation; regeneration potential; regenerative therapy; retinal imaging; sight restoration; success; synaptogenesis; therapy development; usability; virtual

To restore high quality, usable vision in patients, it is important to develop regenerative therapies in an animal model that shares key features of the human visual system. The non-human primate has a virtually identical retinal anatomy and physiology to the human and, uniquely amongst mammalian models, shares a fovea, the retinal area specialized for high acuity vision. Whilst the non-human primate is the gold standard animal model for research on human vision, its utility for pre-clinical testing has been limited due to both the absence of models of 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 primate 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 the development of human pluripotent stem cell (hPSC) derived photoreceptor replacement therapy, we will evaluate survival and functional integration of transplanted photoreceptor precursors in primate fovea 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 primate histology, we will examine the impact of the loss of photoreceptor signalling on primate inner retina. We will explore whether deafferented cone bipolar cells can remodel and functionally integrate with donor photoreceptors and whether retinal hyperactivity develops in primate 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 primate 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 primate photoreceptor ablation model and deploy it with photoreceptor replacement therapies to advance the field toward clinical trials.

为了恢复患者的高质量可用视力，重要的是在动物中开发再生疗法 这是一个共享人类视觉系统关键特征的模型。非人类灵长类动物有一个几乎相同的 视网膜解剖学和生理学与人类相似，并且在哺乳动物模型中是唯一的，共享一个中央凹， 专门用于高视力的视网膜区域。而非人类灵长类动物是黄金标准动物 模型的研究人类视觉，其实用性的临床前测试已受到限制，由于缺乏 视力丧失的模型和证明恢复功能的困难。在此前的AGI资助下， 罗切斯特大学的高级视网膜成像联盟最近克服了这些挑战 创建一个利用自适应光学技术的临床前测试平台，以：1.）创建局部区域 的感光器消融在灵长类动物的轴向限制，和2.）光学读出恢复视网膜 通过在活体眼睛中进行细胞级钙成像来观察神经节细胞功能。该系统 开发用于满足光感受器替代疗法的需要，所述光感受器替代疗法需要光感受器损失， 保留了宿主的视网膜回路此外，高分辨率的体内成像方法非常适合于预处理。 再生疗法的临床评估，其中恢复连接的时间表未知， 功能整合发生在细胞尺度上。在本提案中，我们将使用我们的平台生成预- 这些临床数据将为未来的患者光感受器替代疗法的临床试验提供信息。功能 移植的光感受器与宿主视网膜的整合需要高密度递送高浓度的 优质供体光感受器和具有突触发生能力的宿主视网膜。我们组建了一个 可以探索和优化这种互动的双方。在与一个团队的持续合作中 在威斯康星州大学，由临床医生和人类发育专家大卫·甘姆领导， 多能干细胞（hPSC）衍生的光感受器替代疗法，我们将评估存活率， 移植到视网膜下的灵长类中心凹中的光感受器前体的功能整合 作为聚集体间隔开或随后掺入定制的生物可降解支架中。在与一个 加州大学伯克利分校的一个研究小组，由视网膜重塑专家Teresa Puthussery领导， 退化模型和灵长类动物组织学，我们将研究光感受器信号丢失的影响， 在灵长类动物的内层视网膜上我们将探讨是否去传入锥体双极细胞可以重塑和功能 与供体光感受器整合以及视网膜活动过度是否在灵长类动物中发展，就像在啮齿类动物中一样。 在恢复视力方面取得有意义的进展， 年，我们将研究这些现象是如何随着时间的推移在灵长类动物的中央凹中发展的， 宿主的再生潜力可以通过治疗性干预如视黄酸阻断剂来改善。 这些研究将使我们能够充分表征我们的灵长类动物感光器消融模型，并将其部署在 光感受器替代疗法，以推进该领域的临床试验。