Forschungsstipendien

Ein spezieller Fokus liegt dabei auf Forschungsvorhaben mit dem Potenzial ein breites Spektrum an mitochondrialen Erkrankungen zu adressieren und in dem spezifischen Projekt diese Methode an Mutationen im mitochondrialen Komplex V zu untersuchen.

Forschungsstipendien werden jährlich vergeben.

2022 Stipendium: 50.000 € wurden Prof. Dr. Alessandro Prigione, Abteilung für Allgemeine Pädiatrie, Neonatologie und Kinderkardiologie, Medizinische Fakultät, Heinrich-Heine-Universität Düsseldorf, gewährt. In dem geförderten Projekt geht es um einen neuartigen und personalisierten Ansatz, um Medikamente zu identifizieren, die bereits für andere Indikationen zugelassene wurden und das Potenzial haben auch Patienten mit mitochondrialen Erkrankungen helfen zu können:

A drug repositioning platform for MT-ATP6 mutations based on genetic screenings in patient-derived neurons and brain organoids

Projektzusammenfassung:

Leigh syndrome (LS) is a severe brain disease in children. The disease particularly affects dopaminergic neurons in the midbrain and basal ganglia, leading to psychomotor regression. LS is caused by genetic mutations disrupting the process of energy production in the mitochondria. A recurrent cause is represented by mutations in the mitochondrial DNA (mtDNA) gene, which encodes for a protein component of the complex V of the mitochondrial respiratory chain. LS is currently incurable and the mechanisms underlying the neuronal pathology are not known. The lack of treatments and mechanistic understanding are partly due to the paucity of pre-clinical model systems of LS. This is particularly the case of mtDNA mutations because of critical challenges associated with mtDNA engineering. We previously demonstrated that mutations can be used as a model system for LS. Neural cells differentiated from these patient-derived iPSCs can be employed to carry out compound screenings to identify potential treatments. The use of already approved compounds can further enhance the translational potential of such studies, as the identified hit drugs do not need to be further validated and can be immediately suggested for clinical use through a process called drug repositioning. In this project, we aim to extend our previous findings using dopaminergic neurons differentiated from various patientderived iPSCs carrying different mutations in the gene. We will employ a genetic screening based on genes that are known to be modulated by defined FDA-approved drugs (the so called “druggable genome”). This screening could lead on one hand to identify potential responsible drivers of the pathology in LS dopaminergic neurons, and on the other to uncover already approved drugs that can be repositioned for patients carrying pathogenic MT-ATP6 mutations. Lastly, we will validate the use of these drugs using three-dimensional brain organoids, which can more faithfully recapitulate features of the developing human brain. In fact, we and others have shown that brain organoids can be effectively used to investigate the disease mechanisms of LS. Overall, our platform based on dopaminergic neurons and brain organoids may lead to uncover genetic modifiers of LS and to identify potential innovative treatments that may be readily repositioned for children carrying pathogenic MT-ATP6 mutations.