Among incurable inherited metabolic diseases, mitochondrial diseases represent a major therapeutic challenge, as they can be caused by mutations in oxidative phosphorylation genes that are encoded by either the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). This fact hampers the generation of effective model systems, given the challenges of mtDNA engineering. One of the most severe forms of mitochondrial disease is Leigh syndrome (LS), a devastating neurological disease with no cure leading to early death in children. In this talk, I will present our ongoing efforts in advancing the understanding and therapies for LS using induced pluripotent stem cells (iPSCs) and brain organoids. I will show examples of innovative interventions for LS identified through deep learning screening or neuronal high-content screening. A repurposable drug that we discovered has received the designation of Orphan Drug Designation (ODD) from the European Medicines Agency (EMA) for the treatment of LS, and for this a clinical trial is now under development. Through collaborations with clinical scientists, we hope to translate our findings in the lab into concrete therapies for incurable pediatric mitochondrial diseases with highly unmet medical needs.

Learning Objectives:

1. Recognize the challenges of mitochondrial disorders

2. Discuss the potential of pluripotent stem cells and brain organoids

3. Outline potential repurposable drugs for the mitochondrial disease Leigh syndrome