Kinetin in familial dysautonomia carriers: implications for a new therapeutic strategy targeting mRNA splicing.
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.
Gold-von Simson
Gabrielle
G
Department of Pediatrics, New York University School of Medicine, New York, New York 10016, USA. gold01@med.nyu.edu
Goldberg
Judith D
JD
Rolnitzky
Linda M
LM
Mull
James
J
Leyne
Maire
M
Voustianiouk
Andrei
A
Slaugenhaupt
Susan A
SA
Axelrod
Felicia B
FB
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
D002352:Carrier Proteins; C114720:Elp1 protein, human; D012333:RNA, Messenger; D035602:Transcriptional Elongation Factors; D007701:Kinetin