Rescue of STXBP1 encephalopathies with small molecules in mouse models in vivo
Awardee: Jacqueline Burré
Institution: Weill Medical College of Cornell University
Grant Amount: $80,070
Funding Period: February 1, 2022 - January 31, 2023
Summary:
Mutations in STXBP1 lead to nerve cell dysfunction in the brain due to a reduction in functional STXBP1 amount. We had previously identified three small molecules (4-phenylbutyrate and two novel compounds) that restore nerve cell function in cultured mouse nerve cells and in live worm disease models. Yet, if and to what extent these small molecules revert the dysfunction in a brain remains unknown. Plus, it remains unclear if there is a critical period for when treatment needs to start, necessitating studies in a mouse model. We have established a mouse line with half of STXBP1 amount and are in the process of generating two additional mouse lines with missense mutations in STXBP1. We will use these mouse models of STXBP1 disorder to test the effect of our three small molecules in living animals. We will measure changes in seizure frequency, learning and memory, anxiety, hyperactivity and general movement, in addition to brain structure and development. To reveal if there is a critical period for when treatment needs to be started, we will determine the efficiency of the three small molecules in reversing the identified dysfunction when given to mice in utero, to newborn mice or to adolescent mice. Our study is significant because it further dissects the disease mechanism in a living animal, and because of its translational importance. Importantly, our studies will go hand-in-hand with the on-going 4-phenylbutyrate clinical trial at Weill Cornell Medicine, to achieve the most effect with the least amount of drug.