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

• Applicant: Professor Dr. Andreas Schuppert, since 12/2022
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Bioinformatics and Theoretical Biology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460781697

Schinzel-Giedion Syndrome (SGS) is a rare disease usually leading to death in the first decade of life. SGS is caused by mutations in a gene called SETBP1, where mutations increase the stability of the SETBP1 protein allowing it to continue carrying out its function when it should otherwise be degraded. While SGS is a multi-system disorder, a major burden on affected children and their families are the seizures that do not respond to any known medication and that occur frequently.In collaboration with the SGS Foundation which is run by and for families of people with SGS, we have developed stem cell models derived from six children with SGS and their healthy parents, as well as four mouse models of SGS. We have re-purposed an internationally approved drug currently used to treat Multiple Sclerosis (MS) and which is being investigated in other non-MS clinical trials related to brain health. We have discovered that this drug can reverse molecular signatures of SGS in human brain-like cells related to its fundamental molecular function, meaning the drug targets the underlying cause of disease.The purpose of this proposal is to perform preclinical proof-of-principle studies to assess this drug in human and mouse models of SGS, and to understand its mechanism of action to create a viable treatment for children with SGS to reduce seizures. These studies include investigating: 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, including brain electrical activity; 4) the transcriptional effects of the drug in different types of human brain cells and mouse SGS models with the idea of understanding downstream and potential off-target effects on all human genes; and 5) machine learning approaches using data across all research modalities to aid in determining the validity of the drug as a future treatment for SGS children.

• DFG Programme: Research Grants
• International Connection: Canada, Italy, Sweden
• Cooperation Partners: Professor Carl Ernst, Ph.D.; Professor Andrew G. Ewing, Ph.D.; Thi Ngoc Nhu Phan, Ph.D.; Professor Rocco Giovanni Piazza, Ph.D.; Alessandro Sessa, Ph.D.
• Ehemaliger Antragsteller: Patrick Keeler, Ph.D., until 12/2022