Drug stops intractable epilepsy in mice

Investigators have suppressed intractable epilepsy in mice by targeting a known genetic pathway and using a drug currently in human clinical trials for brain and breast cancer, according to a study published online December 3, 2015 in eLIFE.

This discovery opens up a new class of drugs for the potential treatment of a large number of children. Currently, about 460,000 children in the United States have epilepsy, about 20% of whom have the intractable form.

“Intractable epilepsy is devastating because there’s no way to control seizures in those patients, and some of them will undergo surgery to remove the brain tissue that causes the epilepsy,” said lead study author Kathleen Millen, PhD, a Principal Investigator at the Center for Integrative Brain Research at Seattle Children’s Hospital Research Institute, Seattle, WA.

Surgery has been comparatively successful so far in combating seizures in children with intractable epilepsy, but a drug-based therapy is certainly preferable, the study authors wrote.

To that end, Dr. Millen explained, “We were able to stop seizures in mouse models within one hour of treatment using a drug that targets a genetic pathway linked to intractable epilepsy."

In this study, she and colleagues from the Dana Farber Cancer Institute in Boston, MA, St. Jude Children’s Research Hospital in Memphis, TN, and the University Texas MD Anderson Cancer Center in Houston, TX, built on prior research that showed that intractable epilepsy can be caused by mutations in the PIK3CA gene. Mutations of PIK3CA have also been linked to cancer and a wide range of brain and body overgrowth disorders.

The researchers developed mice with PIK3CA mutations that had the same brain abnormalities and intractable epilepsy found in humans. The team then gave the mice an orally administered drug called BKM120, which is being investigated in clinical trials for its ability inhibit cancer along the PI3K pathway. The drug successfully stopped epileptic seizures in the mice within one hour.

“When we turned down the over-activity of the gene with this drug, we were able to quickly stop the epilepsy in mice despite brain abnormalities,” Dr. Millen said.

The researchers realized that, in addition to this acute treatment, PIK3CA-related epilepsy is independent of cortical and cellular dysplasia—a major and paradigm-shifting finding. “We now know that the gene remains active in a fully formed brain and have proven that the genetic pathway can be targeted after embryonic brain development. The structural abnormalities themselves don’t have to be reversed to suppress epilepsy,” Dr. Millen said. “This opens up new families of drugs to study for the treatment of intractable epilepsy.”

The researchers will now further study this class of drugs with the goal of using them in future clinical trials for these patients.