Recently, Yale School of Medicine researchers set out to study the underlying mechanisms of severe forms of epilepsy resulting from two neurodevelopmental disorders called focal cortical dysplasia (FCDII) and tuberous sclerosis complex (TSC). Epilepsy in these disorders have stumped researchers for a long time because they can cause serious damage to the brain but do not respond to classical anti-epilepsy medication. This lack of knowledge about how and why these drug-resistant seizures develop has hampered any progress in developing new treatments.
However, scientists did know that both conditions result from mutated genes in the same molecular pathway (mTOR) that plays a big part in cell growth and maturation. Yale researchers hypothesized that replicating the mutation's effects would help them understand what was causing these debilitating diseases and uncover treatment options.
Angelique Bordey, PhD, professor of neurosurgery and cellular and molecular physiology at the Yale School of Medicine and lead-author Lawrence S. Hsieh, PhD, replicated the mutations in mice's brains while they were in the womb. After birth, the mice all had similar cortical malformations and seizures similar to those found in people with FCDII and TSC.
In their paper, published in Science Translational Medicine on November 18, 2020, Dr. Bordey and Dr. Hsieh reported their observations on the mutation's effects on the brain.
Using electrophysiological, immunohistochemical, and behavioral approaches, the authors found that the diseased neurons within the focal cortical malformation abnormally expressed a protein known as HCN4, an ion channel responsible for the rhythmic activity of cells including heart cells.
This channel may be the key to devastating seizures. When the researchers prevented the HCN4 channel from opening in the mice's brains, the seizures stopped. Dr. Bordey and Dr. Hsieh also validated their findings by identifying HCN4 in tissue samples of people with TSC and FCDII.
"Collectively, our findings identified a potential mechanism responsible for seizure generation in mTOR-dependent focal cortical malformations," she says. "They suggest that a targeted gene therapy option to prevent seizure initiation might effectively reduce seizures in people with TSC and FCDII."
Earlier this year, Dr. Bordey and her colleagues published a study in Science Translational Medicine that included many of the same co-authors, with Dr. Longbo Zhang, as the lead author. In this study, the authors compared brain samples from patients with FCDII to control patients who had brain surgery related to head trauma. They found that the samples from the patients with FCDII expressed significantly more of a protein called FLNA, while those from the head trauma patients did not.
Normalizing FLNA levels using a strategy called RNA interference decreased seizure activity by 83 percent. Furthermore, when the authors treated mice with a drug that targets FLNA, the treated mice experienced a decrease in seizure activity of 60-70 percent compared to control mice that received a placebo. The treatment also reduced seizures when injected in juvenile and adult mice after seizure onset.
"Taken together, these papers show we have at least two options to pursue as we explore the ability to block seizures," Dr. Bordey says. "That's important because one solution may work for some patients but not others." She estimates that Phase 1 trials of gene therapy in human subjects could begin as soon as 2023.