CureMILS: A reprogramming-based strategy for drug repositioning in patients with mitochondrial DNA-associated Leigh syndrome

Mitochondrial DNA (mtDNA)-associated Leigh syndrome (MILS) is an untreatable brain disease affecting 1/100,000 newborns. MILS is typically caused by mtDNA mutations in the ATP-generating subunit MT-ATP6. Drug discovery is particularly challenging for MILS. 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. Our consortium will employ neural cells generated from MILS patients via cellular reprogramming to carry out large-scale screenings using 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.