Early clinical testing suggests a drug identified by researchers at Vanderbilt University Medical Center may relieve severe forms of childhood epilepsy caused by genetic mutations that affect GABA, the body’s major inhibitory neurotransmitter.
Preliminary results of a clinical trial of 4-phenylbutyrate (PBA) “show a significant reduction in seizure activity among participants,” according to a recent paper published by the journal Clinical Pharmacology & Therapeutics.
“Some children who failed multiple anti-seizure drugs have become seizure free,” said Jing-Qiong (Katty) Kang, MD, PhD, associate professor of Neurology and Pharmacology at Vanderbilt, whose work provided the scientific basis for the clinical trial.
Kang, the recipient of a major research grant from the National Institutes of Health, is quick to acknowledge the support she has received from two nonprofit patient advocacy organizations, SLC6A1 Connect and Cure GABA-A, established by the mothers of children with severe forms of genetic epilepsy.
The organizations held scientific symposia for families preceding the American Epilepsy Society annual meeting Dec. 5-6 in Los Angeles. Kang, who recently presented her work at the Pediatric Neurosurgery Translational Research Roundtable at Harvard Medical School, spoke at both meetings.
Monica Joanna Elnekaveh founded Cure GABA-A after her daughter Eleanor was diagnosed with a severe form of genetic epilepsy. Now a leading patient advocacy group, the nonprofit has informed parents of children with rare genetic epilepsies around the world about the research advances coming from VUMC.
“When our family first received the diagnosis, we were at a loss with no place to turn,” Elnekaveh said. “Now, we’ve created an active and thriving foundation so that other families have hope and a place to go for guidance.”
“We’re just moms, fighting for our children’s lives,” added Amber Freed, founder of SLC6A1 Connect, which is named for the genetic defect responsible for her son Maxwell’s seizure disorder. “Dr. Kang is a hero for our community.”
Freed is corresponding author of the paper published in Clinical Pharmacology & Therapeutics. Besides Kang, co-authors include Jacob Tiller, a premedical student at Brown University who serves as chief scientific officer for SLC6A1 Connect. First author Melissa DeLeeuw is a graduate student in the Kang lab.
While it is unusual for lay people to co-author scientific publications, this paper highlights the pivotal role of patient-led initiatives in supporting research and therapeutic innovations. “Hero moms like Monica and Amber are the driver for helping translate our findings from bench to patient care,” Kang said.
Kang’s quest to understand and treat rare genetic epilepsies in children began in 2003, when she joined the laboratory of Robert Macdonald, MD, PhD, then chair of Neurology at VUMC, as a postdoctoral fellow.
Macdonald had investigated the GABA-A — gamma-aminobutyric acid type A — receptor for more than 25 years. Mutations in this ion channel protein, which regulates the flow of electrically charged ions across the surfaces of nerve cells, can result in “hyperexcitable” brain signals and seizures.
Inspired by Macdonald’s encouragement and bolstered by financial contributions from nonprofit organizations including Cure GABA-A, Kang and her colleagues systematically studied the effect of genetic variations on the function and trafficking of the GABA-A receptor and GABA transporter 1 (GAT1). The proteins play key roles in GABA signaling.
Defective proteins encoded by epilepsy-associated genes are truncated (incomplete) and misfolded into nonfunctional three-dimensional shapes. Accumulation of these mutants in the cell can block assembly and trafficking (transport) of normal proteins.
In cystic fibrosis, for example, defective trafficking of a chloride channel protein leads to the production of unusually thick mucus and chronic respiratory infections. In models of cystic fibrosis, PBA, which originally was approved to treat urea cycle disorders, restored trafficking of the normal protein.
Kang had identified the same pathological mechanisms in epilepsy mutations and wondered if the drug also could be useful in treating certain types of childhood epilepsy.
Over the next decade, she and her colleagues developed preclinical (animal) models of SLC6A1variants, which served as tools for understanding disease pathophysiology and for drug discovery.
Results of their studies in mouse models, which were published in the journals Brain Communications in 2022 and Epilepsia in January 2024, demonstrated for the first time that PBA can mitigate seizures.
In the current clinical trial, 70% of children with SLC6A1 mutations who were treated with PBA had a 90% reduction in seizure activity, Kang said. Based on anecdotal feedback, PBA also is showing promise in treating epilepsies resulting from mutations in the GABA-A receptor.
Led by Zachary Grinspan, MD, MS, director of the Pediatric Epilepsy Program at New York’s Weill Cornell Medical Center, the clinical trial also is being conducted at Children’s Hospital Colorado in Aurora and the University of Texas Southwestern Medical Center.
Meanwhile, the Kang lab is pursuing other strategies, including enhancing the expression of functional GAT1 proteins and GABA-A receptor subunits, improving the functionality of mutant proteins, and using small molecules to restore normal gene function.
“We have made huge strides in the past year,” Kang said. “The impact of our findings on patient care is immediate and profound.”
