Translational potential of Sema4D as a novel antiepileptic therapy

Approximately one-third of patients diagnosed with epilepsy , ~1M people in the U.S. alone, suffer from pharmacoresistant epilepsy (also called drug resistant epilepsy or DRE) and live with chronic intractable seizures. This is a life-threatening condition that impacts nearly every aspect of daily life; for example, affected individuals frequently cannot drive, affecting work and social opportunities. Patients must live with the constant threat of life-changing outcomes including permanent damage to brain areas and even death. For patients with DRE, the only treatment choice is invasive treatments such as resective brain surgery, region ablation or deep brain stimulation (DBS). Even when feasible, surgical intervention carries significant risks of damage to neighboring regions with consequent long-term cognitive deficits.

Seizure generation (or ictogenesis) in the brain is characterized by the pathophysiological appearance of hyperexcitability. A simple theory holds that seizures arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. The efficacy of most anti-epileptic drugs (AEDs) can be explained on the basis of this model. For example, many AEDs either limit neuronal excitability directly (voltage-gated Na⁺ channel blockers such as phenytoin or T-type Ca²⁺ channels blockers like ethosuximide) or potentiate inhibition via an action on the GABA_A receptor subtype (benzodiazepenes such as diazepam).

Our idea is to deliver Sema4D to the brain thereby instructing neurons to assemble more inhibitory synapses on a rapid time scale and suppress seizures. To this end, we demonstrated that Sema4D-Fc treatment (i.e. infusion of purified mouse Sema4D ECD conjugated to the Fc region of mouse IgG2A into hippocampus) drives GABAergic synapse density and increases resistance to seizures in vivo, using two mouse models of epilepsy (Acker et al., 2018).

Interestingly, infusion of Sema4D-Fc into a discrete region (CA1) of the hippocampus suppresses seizures (Acker et al., 2018) despite the fact that the seizure may have originated outside of hippocampus, suggesting that this treatment could be generalizable to multiple seizure disorders. In support this hypothesis, seizures are frequently associated with hippocampal hyperactivity and a variety of hippocampal defects including granule cell ectopic migration, mossy fiber sprouting, and sclerosis (Thom, 2014). It has been proposed that global seizures can be suppressed by cutting off seizure propagation from the foci at strategic choke points (Paz and Huguenard, 2015); in fact, all major regions in the hippocampal tri-synaptic circuit may be involved in promoting seizures. The hypothesis that enhancing inhibition in the hippocampus may suppress seizure activity was directly tested in studies using optogenetics (Choy et al., 2017; Krook-Magnuson et al., 2013), DREADDs (Katzel et al., 2014), and transplantation of interneuron progenitor cells (Hunt et al., 2013) to enhance interneuron activity, suppress excitatory neuron activity, or increase interneuron density in specific hippocampal sub-regions in epileptic mice.

Therefore, a major current and future research area in the lab focuses on exploring the translational potential of Sema4D as an anti-seizure therapy. Based on our findings described above, we were issued US Patent US10626163B2 entitled "Methods of Modulating GABAergic Inhibitory Synapse Formation and Function Using Sema4D." This patent protects our intellectual property around the novel idea of delivering Sema4D polypeptides to the nervous system in order to rapidly increase inhibitory tone and suppress seizures.