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

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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.