New genetic therapy approaches for inherited retinal diseases

遗传性视网膜疾病的新基因治疗方法

• 批准号: MR/V029762/1
• 负责人: Jasmina Cehajic-Kapetanovic
• 金额: $ 176.99万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV029762%2F1
• 关键词: New; genetic; therapy; approaches; inherited

Inherited retinal diseases, including retinitis pigmentosa and Leber congenital optic neuropathy (LHON) are the leading cause of untreatable blindness in the younger population in developed countries. They are caused by genetic mutations that lead to premature loss of cells in the retina that are important for vision. In retinitis pigmentosa, light detecting cells called photoreceptors are lost, but other retinal cells such as ganglion cells that transmit impulses to the brain remain intact. In LHON, mutations in mitochondrial genes affect the ganglion cells first, so the signal from the retina cannot be sent to the brain. Significant advances have been made in research to develop genetic treatments for these diseases, and we now have an approved gene therapy treatment, Luxturna, for one form of the disease caused by mutations in a specific gene. Gene therapy treatments aim to replace the mutated genes by healthy copies. However, for many patients, mutations are not known and for those who present late, where the photoreceptors have already been loss, gene replacement may not be possible. In these patients, optogenetic therapy is a very promising strategy where light sensitive proteins are expressed in surviving cells of the retina, including ganglion cells, to make them able to detect light and restore vision. However, efficient targeting of these cells with genetic therapies has not been achieved to date. Moreover, as the mitochondria in ganglion cells are affected in LHON, if we can deliver healthy genes to these cells, and in particular to the mitochondria, then there is potential to slow down ganglion cell degeneration and associated loss of vision. In this project we aim to develop a surgical procedure using a robot to more effectively deliver genetic therapies to retinal ganglion cells. The procedure will involve robot-assisted direct infusion into the optic nerve in an animal model, which is currently not possible to perform manually in patients. Having achieved this, we then aim to develop applications for this technique including optogenetic applications and for the treatment of optic neuropathies in future human clinical trials. Lastly, the project aims to explore the possibility of using an innovative gene editing technique called CRISPRa, to activate patients' own copies of genes and make them express light-detecting proteins in surviving retinal cells with potential to restore vision. The approaches have potential to lead to the treatment of a much broader range of blinding diseases. Optogenetic therapy could become a universal treatment and restore vision in any late stage retinal degeneration irrespective of genetic cause. Improved targeting of retinal ganglion cells could lead to potential treatments of LHON and other optic neuropathies including glaucoma, the most common cause of irreversible blindness worldwide. In addition, improved mitochondrial targeting may have implications for treatment of other inherited mitochondrial disease that lead to systemic diseases and involve organs other than the eye.

遗传性视网膜疾病，包括视网膜色素变性和Leber先天性视神经病变(LHON)，是发达国家年轻人无法治愈的失明的主要原因。它们是由基因突变引起的，这些突变导致视网膜中对视力重要的细胞过早丧失。在视网膜色素变性中，被称为光感受器的光检测细胞丢失，但其他视网膜细胞，如向大脑传递脉冲的神经节细胞保持完好。在LHON中，线粒体基因的突变首先影响神经节细胞，因此来自视网膜的信号无法发送到大脑。为这些疾病开发基因治疗方法的研究已经取得了重大进展，我们现在有一种被批准的基因治疗方法，Luxturna，用于治疗一种由特定基因突变引起的疾病。基因治疗的目标是用健康的拷贝来取代突变的基因。然而，对于许多患者来说，突变是未知的，对于那些出现较晚的患者来说，那里的光感受器已经丢失，基因替换可能是不可能的。在这些患者中，光遗传疗法是一种非常有希望的策略，在包括神经节细胞在内的视网膜存活细胞中表达光敏蛋白，使它们能够探测光线并恢复视力。然而，到目前为止，通过基因疗法有效地靶向这些细胞还没有实现。此外，由于神经节细胞中的线粒体在LHON中受到影响，如果我们能够将健康的基因输送到这些细胞，特别是线粒体，那么就有可能减缓神经节细胞的退化和相关的视力丧失。在这个项目中，我们的目标是开发一种使用机器人的外科手术程序，以更有效地向视网膜神经节细胞提供基因治疗。该程序将包括在动物模型中由机器人辅助直接向视神经输注，这目前不可能在患者身上手动进行。在实现这一目标之后，我们的目标是在未来的人类临床试验中开发这项技术的应用，包括光遗传学应用和视神经疾病的治疗。最后，该项目旨在探索使用一种名为CRISPRa的创新基因编辑技术的可能性，以激活患者自己的基因副本，并使他们在存活的视网膜细胞中表达光检测蛋白，具有恢复视力的潜力。这些方法有可能导致治疗范围更广的致盲疾病。光遗传疗法可以成为一种普遍的治疗方法，可以在任何晚期视网膜退化中恢复视力，而不考虑遗传原因。改善对视网膜神经节细胞的靶向可能导致LHON和其他视神经疾病的潜在治疗，包括青光眼，这是全球最常见的不可逆性失明原因。此外，改进的线粒体靶向可能对治疗其他遗传性线粒体疾病具有意义，这些遗传性线粒体疾病会导致全身疾病，并涉及眼睛以外的器官。

项目成果

Compound dominant-null heterozygosity in a family with RP1-related retinal dystrophy.

• DOI: 10.1016/j.ajoc.2022.101698
• 发表时间: 2022-12
• 期刊: American journal of ophthalmology case reports
• 作者: Buckley, Thomas M W;Cehajic-Kapetanovic, Jasmina;Shanks, Morag;Clouston, Penny;MacLaren, Robert E
• 通讯作者: MacLaren, Robert E

Characterizing Visual Fields in RPGR Related Retinitis Pigmentosa Using Octopus Static-Automated Perimetry.

• DOI: 10.1167/tvst.11.5.15
• 发表时间: 2022-05-02
• 期刊: TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
• 影响因子: 3
• 作者: Buckley, Thomas M. W.;Josan, Amandeep Singh;Taylor, Laura J.;Jolly, Jasleen K.;Cehajic-Kapetanovic, Jasmina;MacLaren, Robert E.
• 通讯作者: MacLaren, Robert E.

Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient.

• DOI: 10.3390/genes13112103
• 发表时间: 2022-11-12
• 期刊: Genes
• 影响因子: 3.5

First-in-Human Robot-Assisted Subretinal Drug Delivery Under Local Anesthesia

• DOI: 10.1016/j.ajo.2021.11.011
• 发表时间: 2022-01-15
• 期刊: AMERICAN JOURNAL OF OPHTHALMOLOGY
• 影响因子: 4.2
• 作者: Cehajic-Kapetanovic, Jasmina;Xue, Kanmin;MacLaren, Robert E.
• 通讯作者: MacLaren, Robert E.