Retina organoids as models for assessing pathomechanisms and effects of novel treatments in retinal disorders

干细胞在培养皿中生长的细胞组合（“类器官”）具有以前所未有的细节复制人体器官的细胞类型和形态的能力。这些体外系统的可及性及其高度的生理相关性有可能从根本上改变我们对器官发育和功能的理解。此外，它们现在使在人体外建立疾病模型和在人体组织上测试疗法成为可能。视网膜的类器官，眼睛中的感光组织，展示了人类视网膜的所有细胞类型和基因图谱。它们越来越多地被用于模拟视网膜疾病。它们最大的潜力在于探索在动物模型中没有充分复制的疾病，以及没有批准的治疗方法。这包括罕见的遗传疾病，如Usher综合征（USH）和Leber遗传性视神经病变（LHON），它们会导致视力障碍直至失明。在USH患者中，光感受器的功能通常从童年或青春期开始受损。LHON主要影响年轻人，由细胞中负责能量产生的线粒体DNA基因突变引起。在这里，视网膜神经节细胞主要受到影响，因为它们有最高的能量需求。我们的团队积极参与了伊地苯酮（2015年在欧盟获得批准）的临床研究和LHON的玻璃体内基因治疗研究，但仍有许多悬而未决的问题和其他治疗方法正在开发中。因此，复制USH和LHON特征的人视网膜体外模型将是进一步了解病理机制和作为新疗法测试环境的宝贵资产。既往关于视网膜类器官治疗USH的研究存在局限性，因为患者的遗传背景，除了已知的遗传缺陷外，也会影响疾病的进展，而且这种影响尚未被分离出来。对于LHON，到目前为止还没有发表过类器官模型。我们的团队将开发人类视网膜类器官作为USH和LHON的疾病模型。第二步，我们将使用我们的体外系统作为与项目伙伴合作开发的基因疗法的测试环境。人类视网膜类器官和我们在神经成像方面的专业知识的独特结合使我们能够与研究团队成员合作培养USH和LHON类器官，并表征它们的功能。我们在临床试验中建立LHON基因疗法的经验，以及与USH领域专家的合作，使我们能够在活体人类视网膜组织中测试新的基因疗法。最终，我们的模型将有助于更好地理解这两种疾病的病理机制。

Cell assemblies grown from stem cells in a Petri dish („organoids“) have the ability to replicate cell types and morphology of human organs in unprecedented detail. The accessibility of these in vitro systems and their high physiological relevance have the potential to fundamentally change our understanding of organ development and function. Furthermore, they now make it possible to model diseases outside the human body and test therapies on human tissue. Organoids of the retina, the light-sensitive tissue in the eye, exhibit all cell types and the genetic profile of the human retina. They are increasingly being used to model retinal diseases. Their strongest potential lies in the exploration of diseases that are not adequately replicated in animal models and for which no approved therapies exist. This includes rare genetic diseases such as Usher syndrome (USH) and Leber's hereditary optic neuropathy (LHON), which cause visual impairments up to blindness. In USH patients, the function of photoreceptors is often impaired from childhood or adolescence. LHON primarily affects young adults and is caused by mutations in genes of the mitochondrial DNA responsible for energy production in cells. Here, retinal ganglion cells are primarily affected, as they have the highest energy demands. Our team has been significantly involved in clinical studies on idebenone (approved in EU from 2015) and on intravitreal gene therapy study for LHON but there are many open questions and additional treatment approaches in development. In vitro models of human retina that replicate the characteristics of USH and LHON would therefore be an invaluable asset for further understanding of pathomechanisms and as a testing environment for novel therapies. Previous studies on retinal organoids for USH have limitations as the genetic background of the patient, in addition to the known genetic defect, also influences the disease progression, and this effect has not been isolated. For LHON, there is no organoid model published so far. Our team will develop human retinal organoids as disease models for USH and LHON. In a second step, we will use our in vitro systems as testing environments for gene therapies being developed in collaboration with our project partners. The unique combination of human retinal organoids and our expertise in neural imaging enables us to grow USH and LHON organoids and characterize their function in collaboration with research team members. Our experience in establishing LHON gene therapy in clinical trials and collaboration with experts in the field of USH enable us to test new gene therapies in living human retinal tissue. Ultimately, our models will contribute to a better understanding of pathomechanisms of both diseases.