Evaluating the Safety and Efficacy of ASO-Based Therapy in the Murine Model of Schinzel-Giedion Syndrome

Schinzel-Giedion Syndrome (SGS) is a very rare and severe genetic disorder caused by mutations in the SETBP1 gene. These mutations lead to an abnormal accumulation of the SETBP1 protein, which interferes with normal brain development and function. Children with SGS experience severe developmental delays, seizures, brain abnormalities, and shortened life expectancy. There is currently no cure, and treatments are limited to symptom management. Our project explores a promising new therapy using antisense oligonucleotides (ASOs) — small synthetic molecules designed to reduce the production of harmful proteins. We developed an ASO that effectively lowers SETBP1 levels in cells derived from SGS patients. In preliminary tests in mice genetically engineered to carry the human SETBP1 mutation, this treatment reduced protein levels and improved survival. We now aim to assess this ASO’s therapeutic potential more extensively. First, we will test whether it can restore normal function of neurons derived from SGS patients. Next, we will study how the ASO spreads in the brain, how long it lasts, and whether it causes side effects in mice. Finally, we will evaluate if it can reverse key features of SGS in the mouse model, such as seizures and brain malformations. This research could lay the foundation for the first treatment targeting the root cause of SGS. By demonstrating that reducing SETBP1 levels is safe and effective, we hope to move a step closer to a clinical therapy that could significantly improve the lives of children with this devastating condition.