2026 Grant Recipient – Christopher Makinson

Preclinical therapeutic development using an ARHGEF9 mouse model of LGS

Columbia University

Highlights:

• Mutations in ARHGEF9 is causal for developmental and epileptic encephalopathy (DEE).
• Mouse model of ARHGEF9-DEE exhibit several types of spontaneous seizures including generalized tonic-clonic seizures and spike-wave discharge (SWD) seizures.
• A subset of SWD events were accompanied by movement including jerks which has also been observed in patients with LGS, highlighting the potential for this mouse model in LGS research.
• Evaluate the validity and efficacy of mRNA-based gene therapy strategies in ARHGEF9 mutant mice in reducing seizure burden.

Results: Grant in Progress

Results will be shared when the grant is completed.

Lay Abstract:

ARHGEF9 is a gene associated with a severe neurodevelopmental condition called developmental and epileptic encephalopathy (DEE). In order to understand how mutations in ARGHGEF9 cause the symptoms of DEE, including intellectual disability and seizure, we generated a mouse model of ARHGEF9-DEE by introducing the patient-identified mutation G55A into the corresponding position of the mouse genome. We found that these animals exhibit multiple types of spontaneous seizures.

These animals exhibit several types of spontaneous seizures including generalized tonic-clonic seizures and spike-wave discharge (SWD) seizures. Interestingly, a subset of SWD events were accompanied by movement including jerks which has been observed in patients with Lennox-Gastaut Syndrome and ARHGEF9-DEE

Further analysis showed that certain neurons within the cortex and hippocampus develop aggregations that contain important synaptic proteins, effectively blocking these proteins from reaching the parts of the cell where they are needed. As a result, signaling between neurons is severely affected. Here we will use this animal model to design and test gene therapy strategies that involve reducing the mutant Arhgef9 protein. We will test the effects of Arhgef9 knockdown on protein aggregation at the cellular level and on seizure generation.

Updated 05/06/26 (KK)