Oligonucleotide analogues targeting human LMNA
Provided are LMNA-targeted antisense oligonucleotides for reducing expression of one or more aberrantly spliced LMNA mRNA isoforms that encode progerin.
1. An antisense oligonucleotide for use in modulating aberrant splicing of a human LMNA pre-mRNA, wherein the antisense oligonucleotide is an oligomer selected from a peptide nucleic acid (PNA) antisense oligonucleotide, a locked nucleic acid (LNA) antisense oligonucleotide, a 2′-O-methyl phosphorothioate antisense oligonucleotide, or a 2′-methoxyethyl antisense oligonucleotide, the antisense oligonucleotide has up to 40 nucleobases; and the antisense oligonucleotide comprises a targeting sequence comprising any one of SEQ ID NOs:3-8, 10-18, and 20-34.
2. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is a PNA antisense oligonucleotide.
3. The antisense oligonucleotide of claim 2 , wherein the targeting sequence comprises any one of SEQ ID NOs:3-7, 11, and 14-16.
4. The antisense oligonucleotide of claim 2 , wherein the targeting sequence consists essentially of SEQ ID NO:4.
5. The antisense oligonucleotide of claim 2 , wherein the targeting sequence consists essentially of SEQ ID NO:11.
6. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is a LNA antisense oligonucleotide.
7. The antisense oligonucleotide of claim 6 , wherein the targeting sequence comprises any one of SEQ ID NOs:3-7, 11, and 14-16.
8. The antisense oligonucleotide of claim 6 , wherein the targeting sequence consists essentially of SEQ ID NO:4.
9. The antisense oligonucleotide of claim 6 , wherein the targeting sequence consists essentially of SEQ ID NO:11.
10. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is a 2′-O-methyl phosphorothioate antisense oligonucleotide.
11. The antisense oligonucleotide of claim 10 , wherein the targeting sequence comprises any one of SEQ ID NOs:3-7, 11, and 14-16.
12. The antisense oligonucleotide of claim 10 , wherein the targeting sequence consists essentially of SEQ ID NO: 4.
13. The antisense oligonucleotide of claim 10 , wherein the targeting sequence consists essentially of SEQ ID NO:11.
14. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is a 2′-methoxyethyl antisense oligonucleotide.
15. The antisense oligonucleotide of claim 14 , wherein the targeting sequence comprises any one of SEQ ID NOs:3-7, 11, and 14-16.
16. The antisense oligonucleotide of claim 14 , wherein the targeting sequence consists essentially of SEQ ID NO:4.
17. The antisense oligonucleotide of claim 14 , wherein the targeting sequence consists essentially of SEQ ID NO:11.