Discovery + Existing Drugs = New Hope

Current cancer therapies could inhibit intractable epileptic seizures caused by mutations in a gene that produces the mTOR protein.

Drs. Ghayda Mirzaa and William Dobyns of Seattle Children’s made a doubly important discovery when they unmasked a hidden link between epilepsy and genetic mutations in a molecular pathway: they found a root cause of a devastating disease and opened a door to stopping seizures with existing medications.

Mirzaa and Dobyns traced a group of brain disorders known as focal cortical dysplasia to mutations in a gene that produces the mTOR protein, which is essential in regulating cell growth and function. The mutations cause the mTOR signaling pathway to become overactive. The affected neurons grow unusually large and misshapen, leading to brain malformations, cognitive delays and epilepsy.

Mirzaa and Dobyns collaborated with the pharmaceutical company Novartis to find the mTOR–epilepsy link. Now, along with developmental biologist Dr. Kathleen Millen and several collaborators at Seattle Children’s and other institutions, they are in the laboratory to test and determine whether various mTOR inhibitors can treat focal cortical dysplasia and prevent potentially devastating complications like epilepsy.

Beyond symptomatic care

Focal cortical dysplasia is among the leading causes of intractable (resistant to therapy) epilepsy in the pediatric population. Increasingly frequent seizures – up to more than 50 a day – begin soon after a child is born and lead to developmental disabilities, frequent trips to the hospital and, in extreme cases, early death.

Epilepsy isn’t always invincible. Surgery can prevent seizures by removing the area of the brain where the seizures originate. But surgery is not always an option.

“You may not be able to find the area where the seizures begin, the area may be too large or there may be too many areas,” says Dobyns, a pediatric geneticist, neurologist and researcher.

Anti-seizure medications are helping some patients, but there are still many living with untreatable seizures.

The discovery of a link between epilepsy and the mTOR mutations – reported last year in JAMA Neurology – provides new hope for targeted treatments that move beyond current anti-seizure medications.

“With anti-seizure medications, all you’re doing is putting a Band-Aid over the symptom, which is the very last step in the disease,” Dobyns says. “Our goal is to target epilepsy at its starting point and give patients with mutations of mTOR or other genes that work with mTOR a new and effective treatment choice.”

Surgery would remain an option for patients whenever possible, Dobyns says, because surgery can eliminate seizures without requiring patients to take a drug for the rest of their life. However, targeted medications would fill a void for patients who can’t be operated on and who don’t respond to symptomatic therapies.

Hide and seek

Seattle Children’s has a tissue bank with brain tissue saved (with permission from patient families) from epilepsy surgeries over the years – a collaborative effort of Dr. Jeff Ojemann and other leading neurosurgeons at the hospital. Drs. Mirzaa, Dobyns and Ojemann used those samples to search for the genetic fingerprints of the dysplasia. They worked with a team at Novartis to shine a light on the shadowy mutations using state-of-the-art sequencing technology.

“The technology needs to be highly sensitive because mosaic mutations are extremely patchy in distribution,” Mirzaa says.

To observe how the mTOR mutations affect brain cells, Novartis introduced the mutations into rat neurons in culture. “Functional analysis demonstrated the same abnormalities in size and shape found in the neurons of children with focal cortical dysplasia and confirmed that the mTOR pathway activity was elevated,” says Mirzaa.

All of this creates hope for a new era in epilepsy care. “For the first time we may be able to provide targeted therapy rather than the standard medications that aren’t always successful,” Mirzaa says.

Published in the Academic Annual Report, March 2016.