TREAT-SGS : Development and preclinical testing in human cell models and transgenic mice of a novel treatment for Schinzel-Giedion Syndrome

Schinzel-Giedion Syndrome (SGS) is a rare disease usually leading to death in the first decade of life. SGS is caused by increased stability of the SETBP1 protein and there is no treatment. While the disease is multi-system, a major burden on affected children and their families are the intractable seizures that occur frequently in any given day. In collaboration with the SGS Foundation we have developed stem cell models derived from four children and their healthy parents, and we have made four mouse models of SGS. We have re-purposed an internationally approved drug currently used to treat multiple sclerosis that can reverse molecular signatures of SGS. The purpose of this proposal is to perform preclinical proof-of-principle studies to assess this drug and investigate its mechanism of intervention to create a viable treatment for SGS. These studies include: 1) protein and lipid turnover in single cells from mouse and human before and after drug treatment; 2) changes in synaptic vesicle release to understand if this is rescued by drug treatment, which is especially relevant for seizure control; 3) drug effects on mouse brain structure and behaviour, as well as bioavailability of the drug in mouse SGS models; 4) the effects of the drug in developing human brain cells, tracking how single cells differentiate; and 5) machine learning approaches using all data across all research objectives to aid in determining the validity of the drug as a future treatment for SGS children.