Modulation of KCNH2 isoform expression by oligonucleotides as a therapeutic approach for long QT syndrome
Oligonucleotides with activity in preventing poly(A) adenylation at intron 9 of the KCNH2 gene, as well as pharmaceutical compositions comprising the oligonucleotides and methods of using the oligonucleotides to treat long QT syndrome in a subject are disclosed. The oligonucleotides include antisense sequences corresponding to sites termed DSE-1 and DSE-2 in intron 9.
1. An oligonucleotide no more than 30 nucleotides in length, comprising SEQ ID NO: 3 and at least one of a modified nucleotide, locked nucleotide, G-clamp nucleotide, nucleotide base analog, 3′-terminal cap moiety, or phosphate backbone modification, provided that the oligonucleotide inhibits formation of a poly(A) signal in intron 9 of KCNH2.
2. The oligonucleotide of claim 1 comprising SEQ ID NO: 4.
3. The oligonucleotide of claim 1 comprising SEQ ID NO: 5.
4. The oligonucleotide of claim 1 consisting of a sequence of SEQ ID NO: 5.
5. The oligonucleotide of claim 1 comprising a morpholino nucleotide.
6. The oligonucleotide of claim 5 wherein all of the nucleic acids in the oligonucleotide are morpholino nucleotides.
7. A pharmaceutical composition comprising an effective amount of the oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.
8. The oligonucleotide of claim 1 comprising a modified nucleotide.
9. The oligonucleotide of claim 1 comprising a locked nucleotide.
10. The oligonucleotide of claim 1 comprising a G-clamp nucleotide.
11. The oligonucleotide of claim 1 comprising a nucleotide base analog.
12. The oligonucleotide of claim 1 comprising a 3′-terminal cap moiety.
13. The oligonucleotide of claim 1 comprising a phosphate backbone modification.