Improving functional connectivity following transplantation of cone photoreceptors

改善视锥光感受器移植后的功能连接

• 批准号: MR/T002735/2
• 负责人: Robin Ali
• 金额: $ 244万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT002735%2F2
• 关键词: Improving; functional; connectivity; following; transplantation

Hereditary retinal disease and age-related macular degeneration (AMD) are major causes of irreversible blindness in the UK. Inherited retinal dystrophies affect 1 in 2,500, usually during childhood or early adulthood, while AMD affects 1:3 over the age of 75. The number of number of people in the UK affected by sight loss is set to double, to 4 million, by 2050 and sight loss is estimated to cost the UK economy £28bn a year, directly and indirectly. At present, we lack effective treatments for these conditions and there is an urgent requirement to develop new therapies. Both conditions involve the loss of the light sensitive cone and rod photoreceptor cells in the retina. Photoreceptor replacement aims to restore vision by the transplantation of healthy cells, ideally derived from a renewable source. Once transplanted these cells must form new connections (synapses) with their target cells, called bipolar cells, within the host retina. Restoring functional connectivity following transplantation is an ambitious goal for CNS repair. Nonetheless, the macula, which is crucial for high acuity daylight vision occupies a small area and relatively few functional photoreceptor cells may be required to achieve useful vision, so even low efficiency cone photoreceptor transplantation may result in clinical benefit. Stem cell biology has seen extraordinary progress in the past decade and we, and others, now have the ability to generate of large numbers of transplantable photoreceptors from a variety of stem cell sources. While there are some reported indications of new connections being formed between transplanted photoreceptors and host bipolar cells, achieving robust functional synaptic connectivity remains a significant challenge, particularly in advanced retinal disease, where the retina can undergo many, often inhibitory, changes. We have new and exciting data that demonstrates the feasibility of rescuing visual function (mouse models of) advanced retinal disease by transplantation of human stem cell-derived photoreceptors. Most importantly, this rescue does indeed appear to be mediated by the formation of new synaptic connections between the donor and host neurons. In this project, we will establish the full extent of synaptic connections following transplantation of stem cell-derived cone photoreceptors that can be achieved used current methods. We then seek to develop new methods to further improve functional connectivity in order to restore daylight vision in animal models of advanced degenerative retinal disease. We will conduct the following investigations to achieve this goal. We will (i) perform experiments to establish the extent of functional connectivity between transplanted cells and the host eye using current reported protocols, (ii) identify important interactions that may limit the number of new functional connections made after transplantation and develop strategies to improve connectivity and restore vision. Together, these experiments using both murine and human embryonic stem cell-derived donor cells and rodent models of advanced retinal disease will provide the framework for us to move to developing similar approaches to treat human disease.

遗传性视网膜疾病和老年性黄斑变性(AMD)是英国不可逆转失明的主要原因。遗传性视网膜营养不良通常在儿童或成年早期影响1/2500，而AMD影响75岁以上的1/3。到2050年，英国受失明影响的人数将翻一番，达到400万人，据估计，失明每年直接或间接地给英国经济造成280亿英镑的损失。目前，我们缺乏针对这些疾病的有效治疗方法，迫切需要开发新的治疗方法。这两种情况都涉及视网膜中感光锥体和视杆感光细胞的丧失。光感受器置换的目的是通过移植健康的细胞来恢复视力，理想的情况是来自可再生的来源。一旦移植，这些细胞必须与宿主视网膜内的目标细胞形成新的连接(突触)，称为双极细胞。移植后恢复功能连接是中枢神经系统修复的一个雄心勃勃的目标。尽管如此，对于高视力日光视觉至关重要的黄斑所占的面积很小，而且可能需要相对较少的功能性光感受器细胞来实现有用的视力，因此即使是低效率的视锥感光细胞移植也可能产生临床益处。干细胞生物学在过去十年中取得了非凡的进步，我们和其他人现在有能力从各种干细胞来源产生大量可移植的光感受器。虽然有一些报道表明，移植的光感受器和宿主双极细胞之间正在形成新的连接，但实现强大的功能性突触连接仍然是一个巨大的挑战，特别是在晚期视网膜疾病中，视网膜可能会经历许多通常是抑制性的变化。我们有新的和令人兴奋的数据，证明了通过移植人类干细胞衍生的光感受器来挽救晚期视网膜疾病的视觉功能(小鼠模型)的可行性。最重要的是，这种救援似乎确实是通过在供体神经元和宿主神经元之间形成新的突触连接来实现的。在这个项目中，我们将在干细胞来源的视锥感受器移植后建立全面的突触连接，这是使用现有方法可以实现的。然后，我们寻求开发新的方法来进一步改善功能连接，以便在晚期退行性视网膜疾病的动物模型中恢复日光视力。为了实现这一目标，我们将进行以下调查。我们将(I)进行实验，以确定移植细胞和宿主眼之间的功能连接程度，(Ii)确定可能限制移植后新的功能连接数量的重要相互作用，并制定改善连接和恢复视力的策略。总之，这些使用小鼠和人类胚胎干细胞来源的捐赠者细胞和晚期视网膜疾病啮齿动物模型的实验将为我们提供框架，以开发类似的方法来治疗人类疾病。

项目成果

Extracellular vesicles in the retina - putative roles in physiology and disease.

• DOI: 10.3389/fnmol.2022.1042469
• 发表时间: 2022
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Kalargyrou, Aikaterini A.;Guilfoyle, Siobhan E.;Smith, Alexander J.;Ali, Robin R.;Pearson, Rachael A.
• 通讯作者: Pearson, Rachael A.

Tracking neuronal motility in live murine retinal explants.

• DOI: 10.1016/j.xpro.2021.101008
• 发表时间: 2021-12-17
• 期刊: STAR protocols
• 作者: Aghaizu ND;Warre-Cornish KM;Robinson MR;Ali RR;Pearson RA
• 通讯作者: Pearson RA

Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors.

• DOI: 10.1016/j.celrep.2021.109022
• 发表时间: 2021-04-20
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Ribeiro J;Procyk CA;West EL;O'Hara-Wright M;Martins MF;Khorasani MM;Hare A;Basche M;Fernando M;Goh D;Jumbo N;Rizzi M;Powell K;Tariq M;Michaelides M;Bainbridge JWB;Smith AJ;Pearson RA;Gonzalez-Cordero A;Ali RR
• 通讯作者: Ali RR

A comprehensive atlas of Aggrecan, Versican, Neurocan and Phosphacan expression across time in wildtype retina and in retinal degeneration.

• DOI: 10.1038/s41598-022-11204-w
• 发表时间: 2022-05-04
• 期刊: Scientific reports
• 影响因子: 4.6