Abstract for laypersons

The eye is a complex organ with many different types of cells that all have specialized functions. Defects in any one of these cell-types result in various eye diseases, often leading to vision impairment and, ultimately, blindness. Most of these cell types have a specialized compartment called the primary cilium, that helps to control many aspects of that cells function. This is essential for development and function as it acts as “control center” for many different signaling pathways, most importantly the ‘WNT signaling pathway’. In this project we are focusing on a tissue consisting of ciliated cells called the retinal pigment epithelium (RPE). These cells are found at the back of the eye and are vital for visual function. Many patients with vision impairment have defects in RPE cells. Especially if the cilium is dysfunctional, the WNT signaling pathway is also disrupted and the RPE cells don’t develop and function leading to retinal degeneration. We plan to find ways to bypass the function of the cilium to help RPE cells develop and function better, even when the cilium is disrupted. Therefor we want to identify different substances that might control the WNT signaling pathway. We will be looking for new molecules from various natural compound libraries. We will be testing these on RPE cells grown in culture to see if we can improve their development and function. Potential candidates might be used as possible treatments for patients that have dysfunctional cilia in their RPE cells.

Scientific abstract

The vertebrate eye is a complex organ, consisting of multiple cell-types with many specialized functions. Defects in any one of these cell-types result in various eye diseases, often leading to vision impairment and, ultimately, blindness. A multitude of retinal diseases have genetic causes and are hereditary. Strikingly, at least 50 % of these encode genes associated with the primary cilium, a microtubule-based signaling organelle found on the surface of most vertebrate cells. The retinal pigment epithelium (RPE) is a ciliated monolayer epithelium that supports the retina and is essential for visual transduction. In the last years our lab has focused on the role of primary cilia in the RPE in coordinating development and function which is largely regulated via regulation of WNT signaling. We have also been able show that ciliary dysfunction in the RPE significantly contributes to retinal degeneration. Despite the high percentage of genes linked to retinal degeneration encoding ciliary associated proteins, the development of treatment options is currently limited with the few approaches being developed relying on gene replacement predominantly in photoreceptor cells. Considering our findings on the vital role of the cilium in the RPE contributing to disease pathogenesis, it is essential to also focus on this cell type. Our long-term goal is to identify cell-based therapies to counteract neuroretinal degeneration in patients with cilia related ocular disorders with a particular focus on the RPE. Since our published and preliminary data show WNT signaling defects during RPE maturation in ciliopathy models, and improved iPSC-RPE maturation upon pharmacological inhibition of WNT, our objective in this application is to identify novel, more specific WNT inhibitors, which will be tested in comparison to known WNT inhibitors on their ability to rescue impaired cilia deficiencies and improve maturation and function of iPSC-RPE. Our central hypothesis is that we can accelerate and improve RPE maturation not only in control but also in diseased states via pharmacological manipulation of ciliary mediated WNT signaling. As many of the currently known compounds are less specific, leading to off target side effects and toxicity, there is a critical need to identify RPE specific WNT inhibitors that could be used to design treatment strategies. Moreover, pharmacologically manipulation of (ciliary) WNT signaling provides us with insights into RPE related signaling pathways. Not only can this be off benefit to visual community optimizing iPSC-RPE differentiation and maturation, but it could also enable us to provide individual treatment strategies for example in the case of ciliary related retinal degeneration.