Seattle Children’s Researchers Identify Drug That Could Suppress Intractable Epilepsy

Study shows successful treatment of epilepsy in mouse models within one hour of using drug to target genetic pathway known to cause the condition


Scientists at Seattle Children’s Research Institute have found a way to rapidly suppress epilepsy in mouse models by manipulating a known genetic pathway using a cancer drug currently in human clinical trials for the treatment of brain and breast cancer.

The findings, reported in the journal eLIFE, open a new class of drugs to study for the treatment of intractable epilepsy, a severe form of epilepsy that does not respond to drugs. About 460,000 children have epilepsy in the United States, and about 20 percent of them have intractable epilepsy.

“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 Dr. Kathleen Millen, a researcher at the institute’s Center for Integrative Brain Research and lead study author. “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.”

This study builds on work by Dr. William Dobyns and Dr. Ghayda Mirzaa, Seattle Children’s researchers who discovered that intractable epilepsy can be caused by mutations in a particular gene, PIK3CA. In normal human cells, this gene is highly regulated and is important to cell signaling, proliferation, growth and survival. When the gene is dysregulated, it can lead to cancer and other conditions such as intractable epilepsy.

Mutations in the PIK3CA gene cause brain malformation and some forms of intractable epilepsy in children. Millen’s lab developed mouse models with the same PIK3CA mutations to recapitulate the brain abnormalities and intractable epilepsy found in humans. The team then used a drug called BKM120 to stop the epilepsy successfully and rapidly in the mouse models. The drug works by reducing activity of the PIK3CA gene.

“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,” Millen said. “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. This opens up new families of drugs to study for the treatment of intractable epilepsy.”

Millen and her lab will now study this class of drugs in more detail with the hope that they may be used in future clinical trials for patients with intractable epilepsy.

“We are making rapid progress toward understanding the causes of the most challenging forms of epilepsy in children and finding treatments that really work,” said Dobyns, who discovered the gene studied in the paper and evaluates children as part of the large epilepsy team at Seattle Children’s Hospital. “We have the right tools, like gene sequencing technologies, cutting-edge brain imaging and animal models, but we need a larger team to expedite our work and implement clinical trials. Philanthropic support could help tremendously with that.”

The epilepsy studies were conducted in collaboration with Dr. Franck Kalume, also a researcher at the institute’s Center for Integrative Brain Research. Dr. Achira Roy and Jonathan Skibo worked on the study as members of Millen’s lab. In addition, the Dana Farber Cancer Institute, St. Jude’s Children’s Research Hospital and The University of Texas MD Anderson Cancer Center were collaborating institutions.

The work was funded by National Institutes of Health, National Cancer Institute, Citizens United for Research in Epilepsy and seed funds from the Seattle Children’s Hydrocephalus Research Guild.

About Seattle Children’s

Seattle Children’s mission is to provide hope, care and cures to help every child live the healthiest and most fulfilling life possible. Together, Seattle Children’s Hospital, Research Institute and Foundation deliver superior patient care, identify new discoveries and treatments through pediatric research, and raise funds to create better futures for patients.

Ranked as one of the top five children’s hospitals in the country by U.S. News & World Report, Seattle Children’s serves as the pediatric and adolescent academic medical center for Washington, Alaska, Montana and Idaho – the largest region of any children’s hospital in the country. As one of the nation's top five pediatric research centers, Seattle Children’s Research Institute is internationally recognized for its work in neurosciences, immunology, cancer, infectious disease, injury prevention and much more. Seattle Children’s Hospital and Research Foundation works with the Seattle Children’s Guild Association, the largest all-volunteer fundraising network for any hospital in the country, to gather community support and raise funds for uncompensated care and research.

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