title: Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia.
abstract: Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-κ-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients.
authors.affiliation: Department of Pediatrics, New York University School of Medicine, New York, New York 10016, USA. felicia.axelrod@nyumc.org
authors.forename: Felicia B
authors.initials: FB
authors.lastname: Axelrod
authors.forename: Leonard
authors.initials: L
authors.lastname: Liebes
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Gold-Von Simson
authors.forename: Sandra
authors.initials: S
authors.lastname: Mendoza
authors.forename: James
authors.initials: J
authors.lastname: Mull
authors.forename: Maire
authors.initials: M
authors.lastname: Leyne
authors.forename: Lucy
authors.initials: L
authors.lastname: Norcliffe-Kaufmann
authors.forename: Horacio
authors.initials: H
authors.lastname: Kaufmann
authors.forename: Susan A
authors.initials: SA
authors.lastname: Slaugenhaupt
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004402:Dysautonomia, Familial / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007701:Kinetin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009518:New York; D012326:RNA Splicing / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D012333:RNA, Messenger; D035602:Transcriptional Elongation Factors; D007701:Kinetin