Early clinical testing suggests that 4-phenylbutyrate (PBA), a drug identified by researchers at Vanderbilt University Medical Center, may alleviate severe forms of childhood epilepsy caused by genetic mutations affecting GABA, the body’s major inhibitory neurotransmitter. Preliminary results from a clinical trial of PBA indicate a significant reduction in seizure activity among participants, according to a paper published in Clinical Pharmacology & Therapeutics.
Clinical Trial Results
Jing-Qiong (Katty) Kang, MD, PhD, associate professor of Neurology and Pharmacology at Vanderbilt, whose work provided the scientific basis for the clinical trial, stated that some children who had not responded to multiple anti-seizure drugs have become seizure-free. In the clinical trial, 70% of children with SLC6A1 mutations treated with PBA experienced a 90% reduction in seizure activity. Anecdotal evidence suggests PBA also shows promise in treating epilepsies resulting from mutations in the GABA-A receptor.
The clinical trial, led by Zachary Grinspan, MD, MS, director of the Pediatric Epilepsy Program at New York’s Weill Cornell Medical Center, is also being conducted at Children’s Hospital Colorado in Aurora and the University of Texas Southwestern Medical Center.
GABA and Genetic Epilepsy
Mutations in the GABA-A receptor, an ion channel protein regulating the flow of electrically charged ions across nerve cell surfaces, can result in hyperexcitable brain signals and seizures. Defective proteins encoded by epilepsy-associated genes are often truncated and misfolded, leading to nonfunctional three-dimensional shapes. The accumulation of these mutants can block the assembly and transport of normal proteins.
PBA and its Mechanism
Inspired by the use of PBA in treating cystic fibrosis, where it restores trafficking of a chloride channel protein, Kang hypothesized that PBA could be useful in treating certain types of childhood epilepsy. Over the next decade, she and her colleagues developed preclinical models of SLC6A1 variants to understand disease pathophysiology and for drug discovery.
Support from Patient Advocacy
Kang acknowledged the support she has received from nonprofit patient advocacy organizations, SLC6A1 Connect and Cure GABA-A, founded by mothers of children with severe forms of genetic epilepsy. These organizations have played a pivotal role in supporting research and therapeutic innovations. Amber Freed, founder of SLC6A1 Connect, is a corresponding author of the paper published in Clinical Pharmacology & Therapeutics, highlighting the crucial role of patient-led initiatives.
Future Directions
Meanwhile, the Kang lab is exploring 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. Kang stated that they have made huge strides in the past year and that the impact of their findings on patient care is immediate and profound.
