A reprogramming-based strategy for drug repositioning

The research project aims at identifying drugs to treat a rare neurological disorder, designated Leigh syndrome (MILS in brief). This is an untreatable brain disease affecting 1/100,000 births and is caused by defects of the cellulars mitochondrial DNA. Mitochondria are essential organelles that provide energy to the cell and maintain their own genome. MILS is typically caused by mitochondrial DNA mutations of a gene called MT-ATP6, that encodes for a protein subunit that is necessary to generate ATP. ATP provides cellular energy to drive many biological processes, such as growth and proliferation, muscle contraction, nerve stimulus transmission etc. Drug discovery for MILS is particularly challenging. Given the limited access to patients neural tissue and the impossibility to engineer mtDNA, we thus far lack the cellular and animal models needed for the evaluation of treatments. Recent progress in stem cell biology allow cellular reprogramming of somatic cells into virtually any other cell type. Within a European-wide consortium, we will use state-of-the-art cellular reprogramming technologies to convert skin cells from MILS patients into neural cells, allowing the identification of molecular intervention strategies. We previously screened a small library of 150 compounds, that have been already approved by the Food and Drug Administration (FDA) and identified small molecules with phosphodiesterase 5 inhibitor (PDE5i) activity as a potential drug to treat MILS. Now, we extend this approach using the largest available library of repurposing compounds (approx. 8,000). We will validate top hit compounds by combining targeted mitochondrial profiling. Moreover, we will perform genome-wide analysis at all levels of cellulars functionalioty (multi-omics analysis) using reprogramming- derived neural models (neural progenitors, neurons, and brain organoids) carrying different MT-ATP6 mutations. By that our consortium will identify drugs suited for repositioning as interventions in MILS, laying the foundation for a multi-national clinical trial and a concrete path towards a cure for MILS. Moreover, this project will be instrumental to establish a paradigmatic working pipeline for reprogramming-driven drug discovery of other rare (neurological) disorders. Besides the coordinator Alessandro Prigione (University of Duesseldorf, Germany) and Frank Edenhofer (University of Innsbruck, Austria), six other European researchers from Netherlands, Poland, Italy, Finland and Luxemburg are taking part in this research project.

Our research group is continuously engaged in a variety of outreach activities aimed at communicating scientific findings to the general public. We regularly participate in public science events such as open-door days and research nights, accept offers for lectures at public institutions, and disseminate our results not only through peer-reviewed scientific journals but also via press releases, media publications, and interviews.