Restoring vision in mouse models of retinal degeneration using human rod opsin.

使用人杆视蛋白恢复视网膜变性小鼠模型的视力。

• 批准号: MR/N012992/1
• 负责人: Robert Lucas
• 金额: $ 67.09万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN012992%2F1
• 关键词: Restoring; vision; mouse; models; retinal

Degeneration of the retina is a common cause of blindness. In many cases, this degeneration is predominantly a feature of the rod and cone photoreceptors, leaving the channel of communication between the eye and brain (the optic nerve) intact. In patients with such conditions then, the retina is still present but lacks the ability to respond to light. If one could restore photosensitivity to the retina of these people, one could hope to recreate vision. This indeed has been achieved in some patients using electronic prostheses. This places the emphasis on identifying the best possible way of regenerating visual responses in the degenerate retina. There are a number of exciting technologies in development to achieve this goal. It is likely that each will have strengths and limitations and that different patient groups benefit from different approaches. We are therefore at a stage at which we need to explore a variety of strategies for restoring photosensitivity to the degenerate retina in pre-clinical studies. We recently, trialled a very simple approach to this problem - introducing the protein that makes human rods photoreceptive (rod opsin) to surviving neurones in the retina of a mouse model of blindness. We found that rod opsin could make these neurones photoreceptive, and that the treated mice were able to recognise patterns and natural movies presented with standard computer monitors. If similar results were achieved in human patients with similar conditions, we could hope to allow patients currently completely blind to recognise some objects and use vision for spatial navigation in ordinary indoor lighting. As the intervention involves introducing a native human protein into the part of the body it is ordinarily expressed using methods already in clinical use, safety and ethical barriers to trialling in humans are minimised. However, before moving to patients we need a better appreciation of how this new therapy could work. Here we propose a series of experiments in mice that will tell us how safe and effective this potentially exciting new therapy could be.

视网膜退化是失明的常见原因。在许多情况下，这种退化主要是杆状和锥状光感受器的特征，使眼睛和大脑之间的通信通道（视神经）保持完整。在患有这种疾病的患者中，视网膜仍然存在，但缺乏对光的反应能力。如果能恢复这些人视网膜的光敏性，就有希望恢复视力。在一些使用电子义肢的病人身上确实做到了这一点。这将重点放在识别退化视网膜中再生视觉反应的最佳可能方式上。有许多令人兴奋的技术正在开发中，以实现这一目标。很可能每种方法都有其优点和局限性，不同的患者群体受益于不同的方法。因此，我们正处于一个需要在临床前研究中探索各种恢复退化视网膜光敏性的策略的阶段。我们最近尝试了一种非常简单的方法来解决这个问题——将使人类视杆细胞具有感光能力的蛋白质（视杆蛋白）引入失明小鼠视网膜中存活的神经元中。我们发现杆状视蛋白可以使这些神经元具有光感受性，并且接受治疗的小鼠能够识别在标准计算机显示器上呈现的模式和自然电影。如果在人类患者身上也能取得类似的结果，我们有望让目前完全失明的患者在普通的室内照明下识别一些物体，并利用视觉进行空间导航。由于这种干预涉及将一种天然的人类蛋白质引入人体的一部分，这种蛋白质通常是用已经在临床使用的方法表达的，因此在人体中进行试验的安全和伦理障碍被降到最低。然而，在转移到患者身上之前，我们需要更好地了解这种新疗法是如何起作用的。在这里，我们提出了一系列的小鼠实验，这些实验将告诉我们这种潜在的令人兴奋的新疗法是多么安全有效。

项目成果

Photoreceptive retinal ganglion cells control the information rate of the optic nerve.

• DOI: 10.1073/pnas.1810701115
• 发表时间: 2018-12-11
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Milosavljevic N;Storchi R;Eleftheriou CG;Colins A;Petersen RS;Lucas RJ
• 通讯作者: Lucas RJ

Using a bistable animal opsin for switchable and scalable optogenetic inhibition of neurons.

• DOI: 10.15252/embr.202051866
• 发表时间: 2021-05-05
• 期刊: EMBO reports
• 影响因子: 7.7
• 作者: Rodgers J;Bano-Otalora B;Belle MDC;Paul S;Hughes R;Wright P;McDowell R;Milosavljevic N;Orlowska-Feuer P;Martial FP;Wynne J;Ballister ER;Storchi R;Allen AE;Brown T;Lucas RJ
• 通讯作者: Lucas RJ

Chemogenetic Activation of Melanopsin Retinal Ganglion Cells Induces Signatures of Arousal and/or Anxiety in Mice.

• DOI: 10.1016/j.cub.2016.06.057
• 发表时间: 2016-09-12
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Milosavljevic, Nina;Cehajic-Kapetanovic, Jasmina;Procyk, Christopher A.;Lucas, Robert J.
• 通讯作者: Lucas, Robert J.

A High-Dimensional Quantification of Mouse Defensive Behaviors Reveals Enhanced Diversity and Stimulus Specificity.

• DOI: 10.1016/j.cub.2020.09.007
• 发表时间: 2020-12-07
• 期刊: Current biology : CB
• 作者: Storchi R;Milosavljevic N;Allen AE;Zippo AG;Agnihotri A;Cootes TF;Lucas RJ
• 通讯作者: Lucas RJ

Meclofenamic acid improves the signal to noise ratio for visual responses produced by ectopic expression of human rod opsin.

甲氯芬那酸可改善人视杆细胞视蛋白异位表达所产生的视觉反应的信噪比。

• 发表时间: 2017
• 期刊: Molecular vision
• 影响因子: 2.2
• 作者: Eleftheriou CG