As a PhD candidate, you will study drug repositioning in patients with mitochondrial DNA-associated Leigh syndrome (MILS). MILS is a currently untreatable brain disease affecting 1/100,000 new-borns.
Mitochondria are known as the powerhouses of the cell, and their dysfunction is demonstrated in a wide variety of, often lethal, human pathologies including cancer, diabetes and aging-related neurodegeneration. For MILS, drug discovery is particularly challenging. The limited access to patient neural tissue and the impossibility to engineer mtDNA hinder the development of the cellular and animal models needed for treatment discovery.
This research project is part of the European EJP-RD consortium "CureMILS", consisting of researchers from Austria, Finland, Germany, Italy, Luxemburg, the Netherlands and Poland. CureMILS aims to develop therapies MILS and will employ neural cells generated from MILS patients via cellular reprogramming to carry out analysis of repurposable drugs, thereby allowing the identification of therapeutic strategies. Our proof-of-concept study demonstrated that this approach is feasible and relevant.
After screening 150 FDA-approved compounds, we identified phosphodiesterase 5 inhibitors (PDE5i) as a potential therapy for MILS. Compassionate use of PDE5i is now proving to be beneficial in a MILS patient. We propose to extend this approach using the largest available library of repurposable compounds (8,000). We will validate hit compounds by combining mitochondrial profiling with multi-omics analysis using reprogramming-derived neural models (neural progenitors, neurons, and brain organoids) from different MILS patients. 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, we will establish a paradigmatic working pipeline for reprogramming-driven drug discovery of rare neurological disorders.
At Radboudumc, research will focus on validation and mechanistic analyses of hit compounds in MILS neuronal cells. This entails elucidation of mitochondrial and functional effects of PDE5i and a selection of newly discovered compounds in NPCs and MILS neurons.
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