A brain organoid-based computational framework for drug repurposing to treat patients with mitochondrial diseases

• Applicant: Professor Alessandro Prigione, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558189146

Complex I is the first and largest component of the mitochondrial respiratory chain responsible for cellular energy production. Its deficiency is the most frequent cause of mitochondrial dysfunction in humans, and it has been associated with common conditions including diabetes and Parkinson´s disease. In particular, disruption of complex I is the most common cause of Leigh syndrome, a severe and incurable primary mitochondrial disease affecting children. Leigh syndrome is characterized by psychomotor regression and degeneration of neuronal cells, which greatly rely on mitochondrial energy, and particularly those in basal ganglia structures, such as the striatum. Among nuclear genes causative of Leigh syndrome, a particularly relevant one is the complex I gene NDUFS4, given that mice with a homozygous deletion of Ndufs4 represent the main animal model of Leigh syndrome. The advent of cellular reprogramming enabled the development of additional disease models of Leigh syndrome through patient-derived induced pluripotent stem cells (iPSCs) differentiated into neurons or three dimensional brain organoids. The applicant Prigione previously demonstrated the use of this approach in the context of genes causative of Leigh syndrome that are located in complex IV and V. These investigations allowed to conduct compound screening to identify potential treatment strategies. However, performing such screenings is expensive and time consuming. Therefore, there is a high need for developing innovative approaches that could allow the discovery of therapeutics of rare incurable diseases like Leigh syndrome using alternative in silico computational routes. In this proposal, we aim to establish a novel strategy for identifying repurposable drugs to treat complex I defects. To reach this goal, we will develop a machine-learning methodology to drug identification using patient-specific iPSCs carrying NDUFS4 mutations differentiated into region-specific brain organoids for cortical and striatal structures in order to capture the features of the disease. We anticipate that our pipeline may represent an innovative approach to accelerate the drug discovery process that could be later on applied to other incurable neurological diseases with high medical needs.

• DFG Programme: Research Grants
• International Connection: Luxembourg
• Partner Organisation: Fonds National de la Recherche
• Cooperation Partner: Professor Dr. Antonio Del Sol, Ph.D.