The STXBP1 team of FGA obtained funding from the 2019 Million Dollar Bike Ride event, organized by the Orphan Disease Center in the US, for a high throughput screen to identify new therapeutic interventions for STXBP1 patients.
STXBP1 Syndrome is characterized by (severe) developmental delay and intellectual disability, often accompanied by epileptic seizures and neurological and neuropsychiatric symptoms, such as motor impairments and autistic or hyperactivity features. STXBP1 mutations are among the most frequently observed epilepsy and ID-associated mutations. Currently, treatment options for patients with STXBP1 Syndrome do not extend beyond seizure control.
To identify new leads for therapeutic intervention, co-applicants Annemiek van Berkel, Hanna Lammertse and Matthijs Verhage (PI) of FGA-CNCR and Dr. Lukas Neukomm from Lausanne University, Switserland, proposed a three-stage screening platform. First, a high-throughput compound screen will be performed using fruitflies expressing STXBP1/rop mutations. In a secondary screen, optogenetic stimulation will be applied which elicits a grooming behaviour that is lost in STXBP1/rop mutant fruitflies. Finally, promising compounds identified through the primary and secondary screens will be validated in a panel of human, patient-derived neurons derived from induced pluripotent stem cells. A range of cellular/molecular assays and microscopy techniques will be applied to characterize the effect of STXBP1 Syndrome mutation and the effect of identified compounds. Combination of these approaches optimally combines the scale-ability of the fruitfly model with the possibility to maximally approach the patient situation using a patient-own cellular model, which takes into account the genetic background of STXBP1 Syndrome patients.
The grant is made possible by the Millon Dollar Bike Ride, a fundraising event where 750 cyclists and volunteers ride together to raise money for rare disease research. Thanks to the successful team of Lulu’s crew, over 138.000 dollar was raised for STXBP1 research. CNCR is very grateful to everyone who participated in the event and we are excited to work on this high-throughput screen.