EGFR nucleic acids and uses thereof
Disclosed herein are molecules and pharmaceutical compositions that mediate RNA interference against EGFR. Also described herein include methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that mediate RNA interference against EGFR.
1. A polynucleic acid molecule that mediates RNA interference against EGFR, comprising a sense strand and an antisense strand that hybridizes to an EGFR target sequence selected from SEQ ID NOs: 1-376, wherein:
the polynucleic acid molecule comprises the sense strand comprising i) two consecutive 2′-O-methyl modified nucleotides at the 5′-end and ii) eight consecutive repeats of A-B, wherein A is a 2′-fluoro modified nucleotide and B is a 2′-O-Me modified nucleotide, and iii) at least one phosphorothioate internucleotide linkage;
the polynucleic acid molecule comprises from about 90% to about 100% modification; and
the polynucleic acid molecule is from about 10 to about 50 nucleotides in length.
2. The polynucleic acid molecule of claim 1 , wherein the antisense strand comprises two consecutive 2′-fluoro modified nucleotides at the 5′-end.
3. The polynucleic acid molecule of claim 1 , wherein the sense strand comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA).
4. The polynucleic acid molecule of claim 1 , wherein the sense strand further comprises at least one inverted abasic moiety.
5. The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule further comprises a phosphorodithioate linkage on the antisense strand.
6. The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule is from about 10 to about 30 nucleotides in length.
7. The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule is at least 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length.
8. The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule comprises about 100% modification.
9. The polynucleic acid molecule of claim 1 , wherein the sense strand and the antisense strand are RNA molecules.
10. The polynucleic acid molecule of claim 1 , wherein the sense strand comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 377-1892.
11. The polynucleic acid molecule of claim 1 , wherein the antisense strand comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 377-1892.
12. A pharmaceutical composition comprising:
a) the polynucleic acid molecule of claim 1 ; and
b) a pharmaceutically acceptable excipient.
13. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition is formulated as a nanoparticle formulation.
14. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition is formulated for parenteral, oral, intranasal, buccal, rectal, or transdermal administration.
15. A method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a composition comprising the polynucleic acid molecule of claim 1 .
16. The method of claim 15 , wherein the disease or disorder is a cancer.
17. The method of claim 16 , wherein the cancer comprises a EGFR-associated cancer.
18. The method of claim 16 , wherein the cancer comprises bladder cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma multiforme, head and neck cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, or thyroid cancer.
19. The method of claim 16 , wherein the cancer comprises acute myeloid leukemia, CLL, DLBCL, or multiple myeloma.
20. A method of inhibiting the expression of EGFR gene in a primary cell of a patient, comprising administering the polynucleic acid molecule of claim 1 to the primary cell.
21. The method of claim 20 , wherein the method is an in vivo method.
22. The method of claim 20 , wherein the patient is a human.
23. The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule comprises two inverted abasic moieties.
24. The polynucleic acid molecule of claim 2 , wherein the antisense strand comprises eight consecutive repeats of B-A.
25. The polynucleic acid molecule of claim 24 , wherein the eight repeats of B-A are adjacent to the two consecutive 2′-fluoro modified nucleotides.
26. The polynucleic acid molecule of claim 1 , wherein the sense strand comprises 5′-B-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-dTdT-3′.
27. The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule has improved stability relative to an equivalent polynucleic acid molecule without the modification of at least three phosphorothioate internucleotide linkages.
28. The polynucleic acid molecule of claim 1 , wherein the sense strand comprises a sequence selected from SEQ ID NOs: 377-1892.
29. The polynucleic acid molecule of claim 1 , wherein the antisense strand comprises a sequence selected from SEQ ID NOs: 377-1892.
30. The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule comprises about 100% modification, and wherein at least 45% of the modification is 2′-O-methyl.