Inhibition of nonsense mediated mRNA decay by drugs that prevent hypusination of eukaryotic initiation factor 5A

A method for inhibiting nonsense-mediated messenger RNA (mRNA) decay (NMD) in a mammalian subject having a Nonsense-Associated Disease (NAD) comprising:

• 1) identifying the mammalian subject as having a Nonsense-Associated Disease (NAD), the Nonsense-Associated Disease comprising a genetic disorder wherein a gene in the mammalian subject has a premature stop codon which results in a loss of protein function and a reduction in mRNA levels;
• 2) administering to the mammalian subject having the Nonsense-Associated Disease (NAD) an effective amount of composition comprising an iron chelator which inhibits the activity of deoxyhypusine hydroxylase (DOHH), said iron chelator comprising a compound selected from the group consisting of formula (I), (III), and (IV)
• wherein
• R1 is (C1-C6) alkyl;
• R2 is (C1-C10) straight or branched alkyl, (C3-C6)cycloalkyl or phenoxy(C1-C3)alkyl,
• where the phenoxy group is substituted by a substituted or unsubstituted phenoxy;
• and
• R3 is hydrogen or a cation moiety to form a pharmacologically acceptable salt;
• wherein R1, R2, R3, and R4 each individually represent a hydrogen, an alkyl, alkenyl, or alkoxy group containing 1 to about 8 carbon atoms, an aryl, arylaklyl, or cycloalkyl group containing about 5 to 12 carbon atoms, or a peptide or peptidomimetic moiety containing 10 to about 30 carbon atoms,
• wherein inhibiting the activity of deoxyhypusine hydroxylase (DOHH) results in suppressing hypusination of eIF5A protein, and suppressing hypusination of eIF5A protein results in inhibiting nonsense-mediated messenger RNA (mRNA) decay (NMD), and
• 3) administering to the mammalian subject a composition comprising a nonsense suppressor,
• whereby degradation of NMD-susceptible mRNA is decreased and translation termination at a misplaced nonsense codon is reduced.