Drug Repurposing Fast-Tracks Treatments for Epilepsy
When CURE Epilepsy initially funded Dr. Katty (Jing-Qiong) Kang of Vanderbilt University back in 2007, it was to study a piece of basic science: GABA-A receptor mutations. No one could have predicted that this work would generate new questions about how a misfolded protein affects the brain — or that it would lead to discovering that an FDA-approved urea cycle disorder drug, phenylbutyrate, can provide seizure relief to some children with rare genetic epilepsies.
That’s the thing about science—serendipity and following curiosity can lead to incredible outcomes. In Dr. Kang’s case, she brought interesting data about phenylbutyrate and SLC6A1 epilepsy to her colleague Dr. Zach Grinspan of Weill Cornell, who had his own chance encounter with a colleague studying the same drug for a different rare epilepsy related to STXBP1 gene mutations. This led the pair to collaborate on drug repurposing across rare genetic epilepsies, knowing that testing an existing drug could shorten the time needed to bring a treatment to the community.
And time was of the essence for one Texas mother. In 2018 Amber Freed’s son, Max, had been diagnosed with a rare condition caused by a mutation in SLC6A1, a gene that makes a protein responsible for shuttling a chemical called GABA, the major inhibitory neurotransmitter, back into brain cells. When damaged by this mutation, the protein malfunctions, leading to a chemical imbalance in the brain. The condition begins as a developmental delay, but then progresses to movement difficulties, intellectual disability, and seizures.
“It’s like childhood dementia,” Freed says.
When considering the most promising science to fund, Freed and her advocacy group, SLC6A1 Connect, decided to pursue drug repurposing, an approach to find new uses for compounds that have already been approved for other conditions.
SLC6A1 Connect funded Dr. Kang to investigate the underlying pathology of SLC6A1 mutations. Drawing on her CURE Epilepsy-funded research on GABA-A receptors, Dr. Kang proposed testing phenylbutyrate as a possible therapy for SLC6A1 related epilepsy. She had observed similarities between mutant GABA-A receptors and the mutant SLC6A1 protein, suggesting that the drug might be able to rescue the mutant receptors and transporters.
By October 2020, Dr. Kang’s team first found that phenylbutyrate reduced seizures in a mouse model of SLC6A1 mutation [1] and got a clinical trial going by June 2021 — only three years after Max was diagnosed. Freed enrolled her son in the trial, and she credits the drug with allowing Max, now 8 years old, to talk and have some control over his seizures. Overall, preliminary results showed the drug helps stop seizures in children with SLC6A1 mutations, as well as in those with other types of genetic epilepsies [2].
