Anti-tnf compounds

Abstract

TNFα antisense oligonucleotides are provided herein. Methods of treating TNFα diseases or disorders using the TNFα antisense oligonucleotides and related products are provided.

What is claimed is: 
     
         1 . A compound comprising the structure depicted in  FIG. 7  or salts thereof. 
     
     
         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 . 
     
     
         6 . The compound of any one of  claims 1 - 5 , wherein the compound further comprises a molecular species at one of the ends. 
     
     
         7 . The compound of any one of  claims 1 - 5 , wherein the compound further comprises a molecular species at both ends. 
     
     
         8 . The compound of any one of  claims 6 - 7 , 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 any one of  claims 6 - 7 , 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 any one of  claims 6 - 9 , 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 any one of  claims 6 - 9 , 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 13 , wherein the carrier is a lipid based carrier. 
     
     
         16 . The oligonucleotide of  claim 13 , wherein the carrier is a nanoparticle. 
     
     
         17 . The oligonucleotide of any one of  claims 13 - 16 , wherein the oligonucleotide further comprises a molecular species at the 3′ or 5′ end. 
     
     
         18 . The oligonucleotide of any one of  claims 13 - 16 , wherein the oligonucleotide further comprises a molecular species at both the 3′ and 5′ ends. 
     
     
         19 . The oligonucleotide of any one of  claims 17 - 18 , 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 any one of  claims 17 - 18 , 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 any one of  claims 17 - 18 , 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 any one of  claims 17 - 20 , 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  or  25 , wherein 6 nucleotides have a phosphorothioate modification. 
     
     
         27 . The oligonucleotide of  claim 24  or  25 , wherein 7 nucleotides have a phosphorothioate modification. 
     
     
         28 . The oligonucleotide of  claim 24  or  25 , wherein 8 nucleotides have a phosphorothioate modification. 
     
     
         29 . The oligonucleotide of any one of  claims 24 - 28 , wherein the phosphorothioate modified nucleotides are in a central region of the oligonucleotide. 
     
     
         30 . The oligonucleotide of  claim 29 , 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. 
     
     
         31 . The oligonucleotide of any one of  claims 24 - 30 , wherein each nucleotide has either a 2′O methyl modification or phosphorothioate internucleotide linkage. 
     
     
         32 . The oligonucleotide of  claims 24 , wherein only one nucleotide has both a 2′O methyl modification and a phosphorothioate internucleotide linkage. 
     
     
         33 . The oligonucleotide of  claim 24 , wherein only one nucleotide has a 2′-modified nucleotide. 
     
     
         34 . The oligonucleotide of  claim 33 , wherein the 2′-modification is selected from the group of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl(2′-O-DMAEOE), and 2′-O-N-methylacetamido (2′-O-NMA). 
     
     
         35 . 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.   
     
     
         36 . The nanostructure of  claim 35 , wherein the antisense oligonucleotide is 18 nucleotides in length. 
     
     
         37 . The nanostructure of  claim 35  or  36 , wherein the antisense oligonucleotide has phosphodiester internucleotide linkages. 
     
     
         38 . The nanostructure of  claim 37 , wherein less than all of the internucleotide linkages are phosphodiester. 
     
     
         39 . The nanostructure of  claim 35  or  36 , wherein the antisense oligonucleotide has phosphorothioate internucleotide linkages. 
     
     
         40 . The nanostructure of  claim 39 , wherein less than all of the internucleotide linkages are phosphorothioate. 
     
     
         41 . The nanostructure of any one of  claims 35 - 40 , wherein the antisense oligonucleotide has 2′O methyl modifications. 
     
     
         42 . The nanostructure of  claim 41 , wherein less than all of the nucleotides include a 2′O methyl modification. 
     
     
         43 . The nanostructure of  claim 36 , wherein the antisense oligonucleotide has 17 internucleotide linkages and wherein the 6 central internucleotide linkages are phosphorothioate. 
     
     
         44 . The nanostructure of  claim 43 , wherein the first 6 internucleotide linkages at the 5′ end of the oligonucleotide are phosphodiester internucleotide linkages. 
     
     
         45 . The nanostructure of  claim 44 , wherein the first 6 nucleotides at the 5′ end of the oligonucleotide are 2′O methyl modified nucleotides. 
     
     
         46 . The nanostructure of  claim 44  or  45 , wherein the last 5 nucleotides at the 3′ end of the oligonucleotide are 2′O methyl modified nucleotides. 
     
     
         47 . The nanostructure of  claim 36 , wherein the antisense oligonucleotide is selected from the group consisting of T-G-G-G-A-G-T-A-G-A-T-G-A-G-G-T-A-C (SEQ ID NO. 4), mUmGmGmGmAmGmUmAmGmAmUmGmAmGmGmUmAmC (SEQ ID NO. 10, Oligo 3742), T*G*G*G*A*G*T*A*G*A*T*G*A*G*G*T*A*C (SEQ ID NO. 9, Oligo 3500), mUmGmGmGmAmGT*A*G*A*T*G*mAmGmGmUmAmC (SEQ ID NO. 16, Oligo 3534), and mU*mG*mG*mG*mA*mG*T*A*G*A*T*G*mA*mG*mG*mU*mA*mC (SEQ ID NO. 18, Oligo 3509) wherein—refers to a phosphodiester bond, * refers to a phosphorothioate bond, and m refers to a O methyl. 
     
     
         48 . The nanostructure of any one of  claims 35 - 47 , wherein the antisense oligonucleotide is linked to the exterior of the core. 
     
     
         49 . The nanostructure of any one of  claims 35 - 47 , wherein the nanostructure includes 2-1,000 copies of the antisense oligonucleotide. 
     
     
         50 . The nanostructure of any one of  claims 35 - 48 , wherein the nanostructure includes at least one oligonucleotide structurally distinct from the antisense oligonucleotide. 
     
     
         51 . The nanostructure of any one of  claims 35 - 50 , wherein the antisense oligonucleotide has its 5′-terminus exposed to the outside surface of the nanostructure. 
     
     
         52 . The nanostructure of any one of  claims 35 - 50 , wherein the antisense oligonucleotide has its 3′-terminus exposed to the outside surface of the nanostructure. 
     
     
         53 . The nanostructure of any one of  claims 35 - 50 , wherein the antisense oligonucleotide is positioned laterally on the surface of the nanostructure. 
     
     
         54 . The nanostructure of any one of  claims 35 - 53 , wherein the antisense oligonucleotide is indirectly linked to the core through a linker. 
     
     
         55 . The nanostructure of any one of  claims 35 - 54 , wherein the antisense oligonucleotide is indirectly linked to the core through more than one linker. 
     
     
         56 . The nanostructure of any one of  claims 35 - 55 , wherein the core is a solid or hollow core. 
     
     
         57 . The nanostructure of any one of  claims 35 - 55 , wherein the core is inert, paramagnetic or superparamagnetic. 
     
     
         58 . The nanostructure of any one of  claims 35 - 55 , wherein the core is a solid core. 
     
     
         59 . The nanostructure of  claim 58 , wherein the solid core is comprised of noble metals, including gold and silver, transition metals including iron and cobalt, metal oxides including silica, polymers or combinations thereof. 
     
     
         60 . The nanostructure of  claim 58 , wherein the core is a polymeric core and wherein the polymeric core is comprised of amphiphilic block copolymers, hydrophobic polymers including polystyrene, poly(lactic acid), poly(lactic co-glycolic acid), poly(glycolic acid), poly(caprolactone) and other biocompatible polymers. 
     
     
         61 . The nanostructure of any one of  claims 35 - 55 , wherein the core is a liposomal core. 
     
     
         62 . A composition comprising the compound of any one of  claims 1 - 12 , the oligonucleotide of any one of  claims 13 - 34  or the nanostructure of any one of  claims 35 - 61 , further comprising a therapeutic agent for treating a TNF disorder associated with the nanostructure. 
     
     
         63 . The composition of  claim 62 , wherein the therapeutic agent is linked to the oligonucleotide. 
     
     
         64 . A method for treating a TNF disorder, comprising:
 administering to a subject having a TNF disorder a composition comprising the compound of any one of  claims 1 - 12 , the oligonucleotide of any one of  claims 13 - 34  or the nanostructure of any one of  claims 35 - 61  in an effective amount to treat the TNF disorder.   
     
     
         65 . The method of  claim 64 , wherein the TNF disorder is selected from the group consisting of an autoimmune disease, an infectious disease, transplant rejection or graft-versus-host disease, malignancy, a pulmonary disorder, an intestinal disorder, a cardiac disorder, sepsis, a spondyloarthropathy, a metabolic disorder, anemia, pain, a hepatic disorder, a skin disorder, a nail disorder, rheumatoid arthritis, psoriasis, psoriasis in combination with psoriatic arthritis, ulcerative colitis, Crohn's disease, vasculitis, Behcet's disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disorder (COPD), idiopathic pulmonary fibrosis (IPF), restenosis, diabetes, anemia, pain, a Crohn's disease-related disorder, juvenile rheumatoid arthritis (JRA), a hepatitis C virus infection, psoriatic arthritis, and chronic plaque psoriasis. 
     
     
         66 . The method of  claim 65 , wherein the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis, and nephritic syndrome. 
     
     
         67 . A method for reducing TNF levels in vivo, comprising:
 administering to a subject a composition comprising the compound of any one of  claims 1 - 12 , the oligonucleotide of any one of  claims 13 - 34  or the nanostructure of any one of  claims 35 - 61  in an effective amount to reduce TNF levels in vivo.   
     
     
         68 . 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. 
     
     
         69 . The stable self-assembling nanostructure of  claim 68 , wherein the oligonucleotide is at concentrations above 5 μM in DNase and RNase free water or other suitable solvents. 
     
     
         70 . The stable self-assembling nanostructure of  claim 68 , wherein the antisense oligonucleotide is 18 nucleotides in length. 
     
     
         71 . The stable self-assembling nanostructure of  claim 68 , wherein the antisense oligonucleotide has phosphodiester internucleotide linkages. 
     
     
         72 . The stable self-assembling nanostructure of  claim 68 , wherein less than all of the internucleotide linkages are phosphodiester.