title: Kinetin in familial dysautonomia carriers: implications for a new therapeutic strategy targeting mRNA splicing.
abstract: Familial dysautonomia (FD) is caused by an intronic splice mutation in the IkappaB kinase-associated protein gene (IKBKAP) that leads to partial skipping of exon 20 and tissue-specific reduction of IkappaB kinase-associated protein/elongator protein 1 (IKAP/ELP-1 protein). Kinetin increases IKBKAP mRNA and protein expression in FD cell lines. To determine whether oral kinetin alters IKBKAP splicing in vivo, we administered kinetin to 29 healthy carriers of the major FD mutation for 8 d. Adverse effects, kinetin, and IKBKAP mRNA levels were monitored. In the highest dosing cohorts (23.5 mg/kg/d), the target plasma kinetin level was achieved in 91% of subjects at 2 h. After 8 d, IKBKAP mRNA expression in leukocytes increased as kinetin levels increased. There is a linear association between log plasma kinetin level and corresponding log change from baseline in IKBKAP mRNA expression that allows estimation of IKBKAP mRNA levels because of kinetin ingestion. Adverse effects were transient and mild. This is the first report of in vivo IKBKAP splicing modification and strongly suggests kinetin's therapeutic potential in FD and perhaps in other splicing disorders. Furthermore, our findings support our hypothesis that treatments, which target a particular splicing mutation, can be successfully developed.
authors.affiliation: Department of Pediatrics, New York University School of Medicine, New York, New York 10016, USA. gold01@med.nyu.edu
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Gold-von Simson
authors.forename: Judith D
authors.initials: JD
authors.lastname: Goldberg
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rolnitzky
authors.forename: James
authors.initials: J
authors.lastname: Mull
authors.forename: Maire
authors.initials: M
authors.lastname: Leyne
authors.forename: Andrei
authors.initials: A
authors.lastname: Voustianiouk
authors.forename: Susan A
authors.initials: SA
authors.lastname: Slaugenhaupt
authors.forename: Felicia B
authors.initials: FB
authors.lastname: Axelrod
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004402:Dysautonomia, Familial / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006579:Heterozygote; D006801:Humans; D007701:Kinetin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D012333:RNA, Messenger; D035602:Transcriptional Elongation Factors; D007701:Kinetin