Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disorder. The most prevalent causative mutation is a T --> C transition in a donor splice site of the IKBKAP transcript, resulting in aberrant splicing and a truncated protein. The mutations position and leaky nature suggested that its impact might be moderated by altering the level of splice-regulating proteins. The reported ability of (-)-epigallocatechin gallate (EGCG), a polyphenol, to down-regulate the expression of hnRNP A2/B1, a trans-activating factor that encourages the use of intron-distal 5' splice sites, prompted an evaluation of its effect on the IKBKAP transcript in FD-derived cells. EGCG reduces the level of hnRNP A2/B1 and increases the amounts of the wild-type IKBKAP-encoded transcript and functional protein. Combined treatment of cells with EGCG and tocotrienol, which upregulates IKBKAP transcription. results in a synergistic production of the functional gene product. These findings suggest the possible use of EGCG as a therapeutic modality for individuals with FD. (C) 2003 Elsevier Inc. All rights reserved.