Brain immune pathway may offer new treatment target for Dravet syndrome

Inhibiting a specific immune signaling pathway in the brain may reduce inflammation and seizure susceptibility, making it a potential new treatment target for Dravet syndrome, according to a study in mice.

The study led by Li Gan, PhD, a professor at Weill Cornell Medical College in New York, found that the cGAS–STING signaling pathway, which can become activated during seizures, leads to widespread inflammation in the brain. That inflammation, in turn, can make the brain even more susceptible to seizures.

“Inflammation may help drive and sustain the disease. This finding links seizures to the brain’s immune system in a way that had not been fully appreciated before,” Gan, who also directs the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell, said in a Weill Cornell Medicine news story.

The study, “cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy,” was published in Nature Neuroscience.

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Immune signaling may help drive Dravet seizures

Dravet syndrome is a severe form of infantile-onset epilepsy characterized by repeated seizures, or sudden bursts of electrical activity in the brain, that begin in the first year of life. About one-third of patients with epilepsy do not respond well to anti-seizure medications, so new treatment options are needed.

Gan’s team found that in children and adults with drug-resistant epilepsy, cGAS–STING signaling was activated in microglia, the brain’s immune cells. cGAS is a protein that detects double-stranded DNA when it appears outside its usual location in a cell. “Rather than … only involving abnormal electrical signaling, the disease may also involve a self-sustaining immune response triggered by DNA released from stressed neurons [nerve cells],” Gan said.

Because cGAS detects DNA outside its normal location, researchers examined neurons from patients and found increased levels of 53BP1, a protein that marks damaged DNA. They also found increased STING in microglia. STING, which is activated downstream of cGAS, triggers the production of type I interferons, signaling proteins that can promote inflammation.

To further investigate the pathway, the team turned to a mouse model of Dravet. In these mice, the cGAS–STING signaling pathway was activated primarily in the hippocampus, a brain region important for memory and often involved in epilepsy. Microglia in the hippocampus contained abnormal amounts of double-stranded DNA outside the nucleus, where DNA is normally stored.

To test whether overactive neurons were the source of signals activating this pathway, the team grew mouse neurons and microglia in the lab. They made neurons overactive using pentylenetetrazole (PTZ), a chemical that disrupts inhibitory signaling through GABA-A receptors. The overactive neurons released substances that activated cGAS–STING in microglia.

When the Cgas gene was removed from microglia, this activation disappeared. Direct exposure to PTZ also did not activate cGAS–STING signaling in microglia, supporting the idea that signals released by overactive neurons, rather than PTZ itself, activated the pathway. “Our findings suggest that DNA released from hyperexcitable neurons can activate cGAS–STING in microglia,” the team wrote.

Male mice lacking the Cgas gene had less severe seizures after treatment with PTZ or kainic acid compared with male mice carrying the gene. Female mice showed a trend toward less severe seizures after the first PTZ challenge and after kainic acid, and took longer to develop tonic-clonic seizures after a second PTZ challenge. Kainic acid is another chemical commonly used to trigger seizures in research. Mice in which Cgas was removed only from microglia also had less severe seizures after PTZ treatment.

cGAS inhibitor reduces seizure susceptibility in mice

Gan’s team also tested TDI-6570, which inhibits cGAS and can cross the blood-brain barrier, a selective barrier that regulates the movement of substances from the bloodstream into the brain. Young model mice received TDI-6570 or a control treatment daily. TDI-6570 reduced early mortality, increased the temperature needed to trigger a seizure, and reduced levels of CCL5, a signaling protein produced in response to type I interferon signaling.

Detailed genetic analysis showed that reducing or inhibiting cGAS reversed many abnormal gene-expression changes in microglia. Genetic reduction of cGAS restored 696 of 1,276 altered genes toward normal, with affected pathways involving inflammation, immune signaling, and phagocytosis, the process by which cells remove debris. Astrocytes, which support neurons, also showed reduced inflammatory changes.

Lowering cGAS did not restore Nav1.1 protein levels in the Dravet mouse model, but it did restore the expression of many genes involved in neuronal communication. These included Bdnf, which helps support neuron survival; Homer1, which helps regulate communication between neurons; and Mef2c, which controls genes involved in brain development and synaptic function.

Because the findings are preclinical, “we could identify biomarkers in the cerebrospinal fluid [the liquid that protects the brain and the spinal cord] or in the plasma [the clear liquid part of the blood] that can select patients with seizures who would be suitable for this kind of intervention,” Gan said. “Future studies will be needed to determine whether cGAS inhibitors could benefit a wider population of patients.”