Anti-TNF compounds
TNFα antisense oligonucleotides are provided herein. Methods of treating TNFα diseases or disorders using the TNFα antisense oligonucleotides and related products are provided.
1. A compound comprising the structure depicted in FIG. 7 , SEQ ID NO. 16, or salts thereof, of 18-19 nucleotides in length wherein the compound includes at least one phosphorothioate modification.
2. The compound of claim 1 , wherein the compound is 18 nucleotides in length.
3. The compound of claim 1 , formulated in a composition with a carrier.
4. The compound of claim 1 , wherein the compound is a sodium salt.
5. The compound of claim 1 , wherein the compound is the structure depicted in FIG. 8 , SEQ ID NO.16.
6. The compound of claim 1 , wherein the compound further comprises a molecular species at one of the ends.
7. The compound of claim 1 , wherein the compound further comprises a molecular species at both ends.
8. The compound of claim 6 , wherein the molecular species is selected from the group consisting of a spacer, a lipid, a sterol, cholesterol, stearyl, C16 alkyl chain, bile acids, cholic acid, taurocholic acid, deoxycholate, oleyl litocholic acid, oleoyl cholenic acid, glycolipids, phospholipids, sphingolipids, isoprenoids, such as steroids, vitamins, such as vitamin E, saturated fatty acids, unsaturated fatty acids, fatty acid esters, such as triglycerides, pyrenes, porphyrines, Texaphyrine, adamantane, acridines, biotin, coumarin, fluorescein, rhodamine, Texas-Red, digoxygenin, dimethoxytrityl, t-butyldimethylsilyl, t-butyldiphenylsilyl, cyanine dyes (e.g. Cy3 or Cy5), Hoechst 33258 dye, psoralen, and ibuprofen.
9. The compound of claim 6 , wherein the molecular species is a selected from the group consisting of a lipophilic moiety; a folic acid radical; a steroid radical; a carbohydrate radical; a vitamin A radical; a vitamin E radical; or a vitamin K radical.
10. The compound of claim 6 , wherein the molecular species is connected directly to the compound through a linkage selected from the group consisting of phosphodiester, phosphorothioate, methylphosphonate, and amide linkages.
11. The compound of claim 6 , wherein the molecular species is connected indirectly to the compound through a linker.
12. The compound of claim 11 , wherein the linker is a non-nucleotidic linker selected from the group consisting of abasic residues (dSpacer), oligoethyleneglycol, such as triethyleneglycol (spacer 9) or hexaethylenegylcol (spacer 18), and alkane-diol, such as butanediol.
13. An oligonucleotide comprising mUmGmGmGmAmGT*A*G*A*T*G*mAmGmGmUmAmC (SEQ ID NO. 16), wherein the oligonucleotide is 18 nucleotides in length, wherein m is a 2′O methyl, and wherein * is a phosphorothioate modification.
14. The oligonucleotide of claim 13 , wherein the oligonucleotide is formulated in a composition with a carrier.
15. The oligonucleotide of claim 14 , wherein the carrier is a lipid based carrier.
16. The oligonucleotide of claim 14 , wherein the carrier is a nanoparticle.
17. The oligonucleotide of claim 13 , wherein the oligonucleotide further comprises a molecular species at the 3′ or 5′ end.
18. The oligonucleotide of claim 13 , wherein the oligonucleotide further comprises a molecular species at both the 3′ and 5′ ends.
19. The oligonucleotide of claim 17 , wherein the molecular species is selected from the group consisting of a spacer, a lipid, a sterol, cholesterol, stearyl, C16 alkyl chain, bile acids, cholic acid, taurocholic acid, deoxycholate, oleyl litocholic acid, oleoyl cholenic acid, glycolipids, phospholipids, sphingolipids, isoprenoids, such as steroids, vitamins, such as vitamin E, saturated fatty acids, unsaturated fatty acids, fatty acid esters, such as triglycerides, pyrenes, porphyrines, Texaphyrine, adamantane, acridines, biotin, coumarin, fluorescein, rhodamine, Texas-Red, digoxygenin, dimethoxytrityl, t-butyldimethylsilyl, t-butyldiphenylsilyl, cyanine dyes (e.g. Cy3 or Cy5), Hoechst 33258 dye, psoralen, and ibuprofen.
20. The oligonucleotide of claim 17 , wherein the molecular species is a selected from the group consisting of a lipophilic moiety; a folic acid radical; a steroid radical; a carbohydrate radical; a vitamin A radical; a vitamin E radical; or a vitamin K radical.
21. The oligonucleotide of claim 17 , wherein the molecular species is connected directly to the compound through a linkage selected from the group consisting of phosphodiester, phosphorothioate, methylphosphonate, and amide linkages.
22. The oligonucleotide of claim 17 , wherein the molecular species is connected indirectly to the compound through a linker.
23. The oligonucleotide of claim 22 , wherein the linker is a non-nucleotidic linker selected from the group consisting of abasic residues (dSpacer), oligoethyleneglycol, such as triethyleneglycol (spacer 9) or hexaethylenegylcol (spacer 18), and alkane-diol, such as butanediol.
24. An oligonucleotide comprising 5′ TGGGAGTAGATGAGGTAC 3′ (SEQ ID NO. 4), wherein the oligonucleotide is 18-19 nucleotides in length, wherein 4-6 nucleotides at the 5′ end and 4-6 nucleotides at the 3′ end of the oligonucleotide include a 2′O methyl, and wherein 4-10 nucleotides have a phosphorothioate modification.
25. The oligonucleotide of claim 24 , wherein the 6 nucleotides at the 5′ end and 6 nucleotides at the 3′ end of the oligonucleotide include a 2′O methyl.
26. The oligonucleotide of claim 24 , wherein 6, 7, or 8 nucleotides have a phosphorothioate modification, and wherein the phosphorothioate modified nucleotides are in a central region of the oligonucleotide.
27. A stable self-assembling nanostructure, comprising
an antisense oligonucleotide of 18-19 nucleotides in length comprising TGGGAGTAGATGAGGTAC (SEQ ID NO. 4), wherein the antisense oligonucleotide is associated with a core.
28. The nanostructure of claim 27 , wherein the antisense oligonucleotide is indirectly linked to the core through a linker.
29. The nanostructure of claim 27 , wherein the antisense oligonucleotide is indirectly linked to the core through more than one linker.
30. The nanostructure of claim 27 , wherein the core is a hollow core.
31. A stable self-assembling nanostructure, comprising an antisense oligonucleotide of 18-19 nucleotides in length comprising TGGGAGTAGATGAGGTAC (SEQ ID NO. 4), wherein a hydrophobic group at the 3′ or 5′ terminus self-associates to form the core of the nanostructure in water or other suitable solvents.
32. The nanostructure of claim 30 , wherein the hollow core is a liposome.
33. The oligonucleotide of claim 24 , wherein the internucleotide linkage associated with the seventh, eighth, ninth, tenth, eleventh, and twelfth nucleotide from the 5′ end of the oligonucleotide is phosphorothioate modified.
34. The oligonucleotide of claim 24 , wherein each nucleotide has either a 2′O methyl modification or phosphorothioate internucleotide linkage.
35. The nanostructure of claim 27 , wherein the antisense oligonucleotide is 18 nucleotides in length.
36. The nanostructure of claim 27 , wherein the antisense oligonucleotide has 2′O methyl modifications.
37. The nanostructure of claim 27 , wherein the antisense oligonucleotide has 17 internucleotide linkages and wherein the 6 central internucleotide linkages are phosphorothioate.
38. The nanostructure of claim 27 , wherein the antisense oligonucleotide is linked to the exterior of the core.
39. The nanostructure of claim 27 , wherein the nanostructure includes 2-1,000 copies of the antisense oligonucleotide.
40. The nanostructure of claim 27 , wherein the antisense oligonucleotide is positioned laterally on the surface of the nanostructure.
41. The nanostructure of claim 27 , wherein the core is a liposomal core.
42. The stable self-assembling nanostructure of claim 31 , wherein the oligonucleotide is at concentrations above 5 μM in DNase and RNase free water or other suitable solvents.