Dr. Fröhlich and Prof. Rappold at the Institute of Human Genetics in Heidelberg, Germany have discovered that murine Foxp1 haploinsufficiency leads to mitochondrial dysfunction in the striatum and altered expression of striatum-specific phosphodiesterase 10A (PDE10a), an enzyme that plays a crucial role in the regulation of basal ganglia circuits. Specific inhibition of PDE10a with MP-10 significantly improved the existing behavioral deficits in these animals. Working with organoids has significant implications for a safe and humane testing of new drugs, particularly when organoids are grown from a patient's own cells. In the planned project, iPSC lines derived from FOXP1 patient and control cells will be used and differentiated into striatal organoids to investigate whether mitochondrial dysfunction and PDE10A dysregulation can also be found in human cells. In addition, it will be analyzed how the administration of MP-10 affects gene expression and signaling pathways in striatal medium spiny neurons and whether the drug improves mitochondrial function.

To address gaps in the understanding of FOXP1 syndrome's neurodevelopmental profile, this study will implement scalable and objective assessments of motor function, language, cognition, and autism symptoms in children ages 1-20. The study design includes both in-person and remote testing, allowing for broad participation. By identifying key developmental patterns and refining assessment tools, this project will lay critical groundwork for future clinical trials aimed at evaluating potential treatments for FOXP1 syndrome.