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 isolated oligonucleotide comprising SEQ ID NO: 4 that inhibits the formation of a poly(A) signal in intron 9 of KCNH2, wherein the oligonucleotide is no more than 30 nucleotides in length and wherein the oligonucleotide comprises a modified nucleotide, a locked nucleotide, a G-clamp nucleotide, a nucleotide base analog, a 3′-terminal cap moiety, or a phosphate backbone modification.
2. The oligonucleotide of claim 1 comprising SEQ ID NO: 5.
3. The oligonucleotide of claim 2 consisting of a sequence of SEQ ID NO: 5.
4. The oligonucleotide of claim 1 comprising a morpholino nucleotide.
5. The oligonucleotide of claim 4 wherein all of the nucleic acids in the oligonucleotide are morpholino nucleotides.
6. A pharmaceutical composition comprising an effective amount of the oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.
7. A method of treating long-QT syndrome caused by mutations in the KCNH2 gene, the method comprising: administering to the subject the pharmaceutical composition of claim 6 , thereby treating the long-QT syndrome.