Unraveling 4-Phenylbutyrate's Therapeutic Role in SLC6A1 Disorders: Pharmacochaperoning Over HDAC Inhibition.

objectiveVariants in SLC6A1, encoding the GABA transporter 1 (GAT-1), cause epilepsy, autism spectrum disorder, and developmental delay via loss of GABA uptake, impaired trafficking, and ER retention. We previously found that 4-Phenylbutyrate (PBA), an FDA-approved drug, restores GABA uptake and reduces seizures in SLC6A1-related disorders, prompting a phase I clinical trial (NCT04937062) primarily designed to evaluate safety and tolerability of Ravicti (PBA). However, its exact mechanism, pharmacochaperoning or histone deacetylase (HDAC) inhibition, remains unclear. This study compares PBA with pharmacochaperones and HDAC inhibitors to determine how it restores GAT-1 function in the cell and mouse models.

methodsWe evaluated the function for 32 SLC6A1 variants and two representative mouse models at baseline and various treatment options using

resultsPBA restored GABA uptake and GAT-1 surface expression across all variants, and TUDCA mimicked the effects of PBA. HDAC inhibitors exhibited modest rescue in vitro but failed to restore GAT-1 function or mitigate seizures in the knockin mice.

interpretationPBA acts as a pharmacochaperone, not an HDAC inhibitor, to restore GAT-1 function and reduce seizure burden in the diseased mice, supporting pharmacochaperoning as the major mechanism for rescuing SLC6A1-related disorders.