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Novel Therapeutic Avenues for dynein-related Ciliopathies

Periodic Reporting for period 2 - TREATCilia (Novel Therapeutic Avenues for dynein-related Ciliopathies)

Reporting period: 2018-08-01 to 2020-01-31

Cilia are antenna like projections extending from the cell surface. Two main types can be distinguished: motile cilia essential for movement of fluids and non-motile cilia crucial for cell signalling pathways, enabling proper embryonic development and maintaining organ function. Motile cilia dysfunction can cause left-right body axis defects, heart defects as well as recurrent respirator infections and reduced fertility in humans. malfunction of non-motile cilia often results in complex developmental defects affecting the kidneys, eyes, brain, heart, liver and the skeleton. Over 100 genes have been found to be defective in ciliopathies, however a large number of cases is still genetically unexplained. As many as 1 in 1000 persons in Europe is affected by a cilia related genetic diseases, imposing huge health and socioeconomic challenges. There is currently no causative treatment option available.
TREATCilia aims to uncover underlying molecular pathophysiology in dynein based ciliopathies, from gene to mechanism and we hope to identify pharmacological therapeutics via a high-thoughput drugscreen utilising the flagellated geen algae chlamydomonas.
We are using Next Generation Sequencing (NGS) technologies, mainly Exome Sequencing to unravel the underlying genetic cause of human ciliary disorders. This has led to the identification of a number of novel disease causing genes and provided novel insight into ciliary protein organisation and functions. For example, we found that mutations in the outer dynein arm protein DNAH9 result in laterality defects associated with no or only very mild respiratory symptoms. As DNAH9 is only required for movement of parts of the cilium, cilia motility impairment is mild. Therefore, patients with DNAH9 protein dysfunction are difficult to diagnose and genetic diagnosis is required. Further, our results point stress that ciliary motility complexes such as dynein arms are organised in a compartementalised manner.
With regards to non-motile ciliopathies, we focus on reno-skeletal disorders such as Jeune Syndrom and Short-Rib-Polydactyly Syndrome. In addition to gene identification and genotype-phenotype studies, we have recreated several hypomorphic patient alleles using CRISPR/Cas technologies and we are investigating downstream effects using Transcriptomics and Proteomics approaches. Chlamoydomonas drugscreening is currently prepared.
Using cutting edge technologies such as CRISPR base editing approaches enables us to gain deeper insight into ciliary protein networks and dissect the molecular defects resulting from human patient mutations. Our longterm goal is to identify novel therapeutic approaches.