Chimeric oligomeric compounds and their use in gene modulation
First Claim
1. A composition comprising a first oligomer and a second oligomer, wherein:
- at least a portion of said first oligomer is capable of hybridizing with at least a portion of said second oligomer, at least a portion of said first oligomer is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of said first or said second oligomers is a chimeric oligomeric compound.
1 Assignment
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Accused Products
Abstract
Oligomer compositions comprising first and second oligomers are provided wherein at least a portion of the first oligomer is capable of hybridizing with at least a portion of the second oligomer, at least a portion of the first oligomer is complementary to and capble of hybridizing to a selected target nucleic acid, and at least one of the first or second oligomers includes at least one nucleotide comprising a chimeric organic composition. Oligomer/protein compositions are also provided comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein comprising at least a portion of an RNA-induced silencing complex (RISC), wherein at least one nucleotide comprising a chimeric organic composition.
110 Citations
124 Claims
-
1. A composition comprising a first oligomer and a second oligomer, wherein:
-
at least a portion of said first oligomer is capable of hybridizing with at least a portion of said second oligomer, at least a portion of said first oligomer is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of said first or said second oligomers is a chimeric oligomeric compound. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 116, 119, 122)
-
2. The composition of claim 1 wherein said first and said second oligomers are a complementary pair of siRNA oligomers.
-
3. The composition of claim 1 wherein said first and said second oligomers are an antisense/sense pair of oligomers.
-
4. The composition of claim 1 wherein each of said first and second oligomers has about 8 to about 80 nucleobases.
-
5. The composition of claim 1 wherein each of said first and second oligomers has about 10 to about 50 nucleobases.
-
6. The composition of claim 1 wherein each of said first and second oligomers has about 12 to about 30 nucleobases.
-
7. The composition of claim 1 wherein each of said first and second oligomers has about 12 to about 24 nucleobases.
-
8. The composition of claim 1 wherein each of said first and second oligomers has about 19 to about 23 nucleobases.
-
9. The composition of claim 1 wherein said first oligomer is an antisense oligomer.
-
10. The composition of claim 9 wherein said second oligomer is a sense oligomer.
-
11. The composition of claim 9 wherein said second oligomer has a plurality of ribose nucleotide units.
-
12. The composition of claim 1 wherein said first oligomer is a chimeric oligomeric compound.
-
13. The composition of claim 1 wherein said chimeric oligomeric compound is a gapmer, an inverted gapmer, a 3′
- -hemimer, a 5′
-hemimer or a blockmer.
- -hemimer, a 5′
-
14. The composition of claim 13 wherein the chimeric oligomeric compound comprises at least two of DNA, RNA, PNA segments, and mixtures thereof.
-
15. The composition of claim 13 wherein said chimeric oligomeric compound is a gapmer.
-
16. The composition of claim 15 wherein said gapmer comprises two terminal RNA segments having nucleotides of a first type and an internal RNA segment having nucleotides of a second type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
17. The composition of claim 16 wherein said terminal RNA segments comprise two or three nucleotides.
-
18. The composition of claim 16 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
-
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
O—
S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
-
19. The composition of claim 13 wherein said chimeric oligomeric compound is an inverted gapmer.
-
20. The composition of claim 19 wherein said inverted gapmer comprises two terminal RNA segments having nucleotides of a second type and an internal RNA segment having nucleotides of a first type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
21. The composition of claim 20 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
-
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
O—
S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
-
22. The composition of claim 13 wherein said chimeric oligomeric compound is 3′
- -hemimer.
-
23. The composition of claim 22 wherein said 3′
- -hemimer comprises a terminal RNA segment having nucleotides of a first type and a further RNA segment having nucleotides of a second type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
24. The composition of claim 23 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
-
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
O—
S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
-
25. The composition of claim 13 wherein said chimeric oligomeric compound is 5′
- -hemimer.
-
26. The composition of claim 25 wherein said 5′
- -hemimer comprises a terminal RNA segment having nucleotides of a first type and a further RNA segment having nucleotides of a second type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
27. The composition of claim 26 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
-
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
0-, S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to Calkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
-
28. The composition of claim 13 wherein the chimeric oligomeric compound comprises a blockmer.
-
29. The composition of claim 28 wherein said blockmer comprises an oligonucleotide having a block of at least two consecutive nucleotides of a first type located immediately adjacent at least one nucleotide of a second type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
30. The composition of claim 29 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
0-, S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
31. The composition of claim 30 wherein said nucleotides of said of said second type comprise 2′
- -OH nucleotides.
-
32. The composition of claim 29 further including a plurality of blocks of at least two consecutive nucleotides of a first type and wherein each of said blocks of nucleotides of said first type is separated from others of said blocks of nucleotides of said first type by a nucleotide of said second type.
-
33. The composition of claim 13 wherein said chimeric oligomer compound comprises a gapmer of the formula PNA-RNA-PNA.
-
34. The composition of claim 20 wherein said chimeric oligomeric compound comprises a 5′
- -hemimer the formula PNA-RNA or a 31-hemimer of the formula RNA-PNA.
-
35. The composition of claim 13 wherein said chimeric oligomeric compound comprises an inverted gapmer of the formula RNA-PNA-RNA.
-
36. The composition of claim 13 wherein the chimeric oligomeric compound is divided into at least two regions;
-
the first region comprising α
-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages;
α
-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages;
α
-nucleosides linked by non-phosphorous linkages;
4′
-thionucleosides linked by charged or neutral 3′
-5′
phosphorous linkages;
4′
-thionucleosides linked by charged or neutral 2′
-5′
phosphorous linkages;
4′
-thionucleosides linked by non-phosphorous linkages;
carbocyclic-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages;
carbocyclic-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages;
carbocyclic-nucleosides linked by non-phosphorous linkages;
β
-nucleosides linked by charged or neutral 3′
-5′
linkages;
β
-nucleosides linked by charged or neutral 2′
-5′
linkages;
or β
-nucleosides linked by non-phosphorous linkages; and
the second region consists of 2′
-ribo-α
-nucleosides linked by charged 3′
-5′
phosphorous linkages.
-
-
37. The composition of claim 13 wherein the chimeric oligomeric compound is divided into at least two regions;
-
the first region comprising α
-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, α
-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, α
-nucleosides linked by non-phosphorous linkages, 4′
-thionucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, 4′
-thionucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, 4′
-thionucleosides linked by non-phosphorous linkages, carbocyclic-nucleosides linked by charged or neutral phosphorous linkages, carbocyclic-nucleosides linked by non-phosphorous linkages, β
-nucleosides linked by charged or neutral 3′
-5′
linkages, β
-nucleosides linked by charged or neutral 2′
-5′
linkages, or β
-nucleosides linked by non-phosphorous linkages; and
the second region comprising nucleobases linked by non-phosphorous linkages or nucleobases that are attached to phosphate linkages via a non-sugar tethering moiety.
-
-
38. The composition of claim 13 wherein the chimeric oligomeric compound is divided into at least two regions;
-
the first region comprising nucleobases linked by non-phosphorous linkages and nucleobases that are attached to phosphate linkages via non-sugar tethering groups, and nucleosides selected from α
-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, α
-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, α
-nucleosides linked by non-phosphorous linkages, 4′
-thionucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, 4′
-thionucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, 4′
-thionucleosides linked by non-phosphorous linkages, carbocyclic-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, carbocyclic-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, carbocyclic-nucleosides linked by non-phosphorous linkages, β
-nucleosides linked by charged or neutral 3′
-5′
linkages;
β
-nucleosides linked by charged or neutral 2′
-5′
linkages, or β
-nucleosides linked by non-phosphorous linkages; and
the second region comprising 2′
-ribo-β
-nucleosides linked by charged 3′
-5′
phosphorous linkages wherein the 3′
-5′
phosphorous linkages.
-
-
39. The composition of claim 13 comprising at least two segments, wherein at least one segment comprises non-naturally occurring internucleoside linkages.
-
40. The composition of claim 1 wherein the chimeric oligomeric compound comprises an oligomer mimetic.
-
41. The composition of claim 16 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
42. The composition of claim 16 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and wherein said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and wherein said —
-
43. The composition of claim 16 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
44. The composition of claim 20 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
45. The composition of claim 20 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and wherein said —
O-alkyl is —
CH3.
- O-alkyl sugar substituent and wherein said —
-
46. The composition of claim 20 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
47. The composition of claim 23 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
48. The composition of claim 23 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and said —
-
49. The composition of claim 23 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
50. The composition of claim 26 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
51. The composition of claim 26 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and said —
-
52. The composition of claim 26 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
53. The composition of claim 29 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
54. The composition of claim 29 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and said —
-
55. The composition of claim 29 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
116. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier.
-
119. A method of modulating the expression of a target nucleic acid in a cell comprising contacting said cell with a composition of claim 1.
-
122. A method of treating or preventing a disease or disorder associated with a target nucleic acid comprising administering to an animal having or predisposed to said disease or disorder a therapeutically effective amount of a composition of claim 1.
-
2. The composition of claim 1 wherein said first and said second oligomers are a complementary pair of siRNA oligomers.
-
-
56. A composition comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein, said protein comprising at least a portion of a RNA-induced silencing complex (RISC), wherein said oligomer is a chimeric oligomeric compound.
- View Dependent Claims (57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 117, 120, 123)
-
57. The composition of claim 56 wherein said oligomer is an antisense oligomer.
-
58. The composition of claim 56 wherein said oligomer has about 8 to about 80 nucleobases.
-
59. The composition of claim 56 wherein said oligomer has about 10 to about 50 nucleobases.
-
60. The composition of claim 56 wherein said oligomer has about 12 to about 30 nucleobases.
-
61. The composition of claim 56 wherein said oligomer has about 12 to about 24 nucleobases.
-
62. The composition of claim 56 wherein said oligomer has 19 to 23 nucleobases.
-
63. The composition of claim 56 including a further oligomer, wherein said further oligomer is complementary to and hydrizable to said oligomer.
-
64. The composition of claim 63 wherein said further oligomer is a sense oligomer.
-
65. The composition of claim 63 wherein said further oligomer is an oligomer having a plurality of ribose nucleotide units.
-
66. The composition of claim 56 wherein said first oligomer is a chimeric oligomeric compound.
-
67. The composition of claim 56 wherein said chimeric oligomeric compound is a gapmer, an inverted gapmer, a 3′
- -hemimer, a 5′
-hemimer or a blockmer.
- -hemimer, a 5′
-
68. The composition of claim 67 wherein the chimeric oligomeric compound comprises at least two of DNA, RNA, PNA segments, and mixtures thereof.
-
69. The composition of claim 68 wherein said chimeric oligomeric compound is a gapmer.
-
70. The composition of claim 69 wherein said gapmer comprises two terminal RNA segments having nucleotides of a first type and an internal RNA segment having nucleotides of a second type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
71. The composition of claim 70 wherein said terminal RNA segments each have two or three nucleotides.
-
72. The composition of claim 70 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
-
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
O—
S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C2-0 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
-
73. The composition of claim 67 wherein said chimeric oligomeric compound is an inverted gapmer.
-
74. The composition of claim 73 wherein said inverted gapmer comprises two terminal RNA segments having nucleotides of a second type and an internal RNA segment having nucleotides of a first type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
75. The composition of claim 74 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
-
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
O—
S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
-
76. The composition of claim 67 wherein said chimeric oligomeric compound is 3′
- -hemimer.
-
77. The composition of claim 76 wherein said 3′
- -hemimer comprises a terminal RNA segment having nucleotides of a first type and a further RNA segment having nucleotides of a second type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
78. The composition of claim 77 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
-
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
O—
S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
-
79. The composition of claim 67 wherein said chimeric oligomeric compound is 5′
- -hemimer.
-
80. The composition of claim 79 wherein said 5′
- -hemimer comprises a terminal RNA segment having nucleotides of a first type and a further RNA segment having nucleotides of a second type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
81. The composition of claim 80 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
-
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
0-, S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
-
82. The composition of claim 67 wherein the chimeric oligomeric compound comprises a blockmer.
-
83. The composition of claim 82 wherein said blockmer comprises an oligonucleotide having a block of at least two consecutive nucleotides of a first type located immediately adjacent at least one nucleotide of a second type and where said nucleotides of said first type are different from said nucleotides of said second type.
-
84. The composition of claim 83 wherein each of said nucleotides of said first type independently including at least one sugar substituent;
said sugar substituent comprising halogen, amino, trifluoroalkyl, trifluoroalkoxy, azido, aminooxy, alkyl, alkenyl, alkynyl, O—
, S—
, or N(R*)-alkyl;
O—
, S—
, or N(R*)-alkenyl;
0-, S—
or N(R*)-alkynyl;
O—
, S—
or N-aryl, O—
, S—
, or N(R*)-aralkyl;
wherein said alkyl, alkenyl, alkynyl, aryl and aralkyl may be substituted or unsubstituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C5-C20 aryl or C6-C20 aralkyl; and
said substituted C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10alkynyl, C5-C20 aryl or C6-C20 aralkyl comprising substitution with alkoxy, thioalkoxy, phthalimido, halogen, amino, keto, carboxyl, nitro, nitroso, cyano, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, aminooxy, isocyanato, sulfoxide, sulfone, disulfide, silyl, heterocycle, carbocycle, an intercalator, a reporter group, a conjugate, a polyamine, a polyamide, a polyalkylene glycol, or a polyether of the formula (—
O-alkyl)m, where m is 1 to about 10; and
R* is hydrogen, or a protecting group.
-
85. The composition of claim 84 wherein said nucleotides of said of said second type comprise 2′
- -OH nucleotides.
-
86. The composition of claim 83 further including a plurality of blocks of at least two consecutive nucleotides of a first type and wherein each of said blocks of nucleotides of said first type is separated from others of said blocks of nucleotides of said first type by a nucleotide of said second type.
-
87. The composition of claim 67 wherein said chimeric oligomer compound comprises a gapmer of the formula PNA-RNA-PNA.
-
88. The composition of claim 74 wherein said chimeric oligomeric compound comprises a 5′
- -hemimer the formula PNA-RNA or a 3′
-hemimer of the formula RNA-PNA.
- -hemimer the formula PNA-RNA or a 3′
-
89. The composition of claim 67 wherein said chimeric oligomeric compound comprises an inverted gapmer of the formula RNA-PNA-RNA.
-
90. The composition of claim 67 wherein the chimeric oligomeric compound is divided into at least two regions;
-
the first region comprising α
-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages;
α
-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages;
α
-nucleosides linked by non-phosphorous linkages;
4′
-thionucleosides linked by charged or neutral 3′
-5′
phosphorous linkages;
4′
-thionucleosides linked by charged or neutral 2′
-5′
phosphorous linkages;
4′
-thionucleosides linked by non-phosphorous linkages;
carbocyclic-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages;
carbocyclic-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages;
carbocyclic-nucleosides linked by non-phosphorous linkages;
β
-nucleosides linked by charged or neutral 3′
-5′
linkages;
β
-nucleosides linked by charged or neutral 2′
-5′
linkages;
or β
-nucleosides linked by non-phosphorous linkages; and
the second region consists of 2′
-ribo-α
-nucleosides linked by charged 3′
-5′
phosphorous linkages.
-
-
91. The composition of claim 67 wherein the chimeric oligomeric compound is divided into at least two regions;
-
the first region comprising α
-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, α
-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, α
-nucleosides linked by non-phosphorous linkages, 4′
-thionucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, 4′
-thionucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, 4′
-thionucleosides linked by non-phosphorous linkages, carbocyclic-nucleosides linked by charged or neutral phosphorous linkages, carbocyclic-nucleosides linked by non-phosphorous linkages, β
-nucleosides linked by charged or neutral 3′
-5′
linkages, β
-nucleosides linked by charged or neutral 2′
-5′
linkages, or β
-nucleosides linked by non-phosphorous linkages; and
the second region comprising nucleobases linked by non-phosphorous linkages or nucleobases that are attached to phosphate linkages via a non-sugar tethering moiety.
-
-
92. The composition of claim 67 wherein the chimeric oligomeric compound is divided into at least two regions;
-
the first region comprising nucleobases linked by non-phosphorous linkages and nucleobases that are attached to phosphate linkages via non-sugar tethering groups, and nucleosides selected from α
-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, α
-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, α
-nucleosides linked by non-phosphorous linkages, 4′
-thionucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, 4′
-thionucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, 4′
-thionucleosides linked by non-phosphorous linkages, carbocyclic-nucleosides linked by charged or neutral 3′
-5′
phosphorous linkages, carbocyclic-nucleosides linked by charged or neutral 2′
-5′
phosphorous linkages, carbocyclic-nucleosides linked by non-phosphorous linkages, β
-nucleosides linked by charged or neutral 3′
-5′
linkages;
β
-nucleosides linked by charged or neutral 2′
-5′
linkages, or β
-nucleosides linked by non-phosphorous linkages; and
the second region comprising 2′
-ribo-α
-nucleosides linked by charged 3′
-5′
phosphorous linkages wherein the 3′
-5′
phosphorous linkages.
-
-
93. The composition of claim 67 comprising at least two segments, wherein at least one segment comprises non-naturally occurring internucleoside linkages.
-
94. The composition of claim 56 wherein the chimeric oligomeric compound comprises an oligomer mimetic.
-
95. The composition of claim 70 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
96. The composition of claim 70 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and wherein said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and wherein said —
-
97. The composition of claim 70 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
98. The composition of claim 74 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
99. The composition of claim 74 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and wherein said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and wherein said —
-
100. The composition of claim 74 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
101. The composition of claim 77 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
102. The composition of claim 77 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and said —
-
103. The composition of claim 77 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
104. The composition of claim 80 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
105. The composition of claim 80 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and said —
-
106. The composition of claim 80 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
107. The composition of claim 83 wherein said nucleotides of said first type comprise nucleotides having a 2′
- halogen sugar substituent and said halogen is F.
-
108. The composition of claim 83 said nucleotides of said first type comprise nucleotides having a 2′
- O-alkyl sugar substituent and said —
O-alkyl is —
O—
CH3.
- O-alkyl sugar substituent and said —
-
109. The composition of claim 83 said nucleotides of said first type comprise nucleotides having a 2′
- sugar substituent and where said 2′
sugar substituent is of the formula —
X—
Y, wherein;
X is O, S, NR**, or CR* wherein each R** is independently H or C1-6 alkyl; and
Y is substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C2-20 alkenyl, or substituted or unsubstituted C6-20 aryl.
- sugar substituent and where said 2′
-
117. A pharmaceutical composition comprising the composition of claim 56 and a pharmaceutically acceptable carrier.
-
120. A method of modulating the expression of a target nucleic acid in a cell comprising contacting said cell with a composition of claim 56.
-
123. A method of treating or preventing a disease or disorder associated with a target nucleic acid comprising administering to an animal having or predisposed to said disease or disorder a therapeutically effective amount of a composition of claim 56.
-
57. The composition of claim 56 wherein said oligomer is an antisense oligomer.
-
110. An oligomer having at least a first region and a second region, wherein
said first region of said oligomer is complementary to and capable of hybridizing with said second region of said oligomer, at least a portion of said oligomer is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of said first or said second oligomers is a chimeric oligomeric compound. - View Dependent Claims (111, 112, 113, 114, 115, 118, 121, 124)
-
111. The oligomer of claim 110 wherein each of said first and said second regions has at least 10 nucleotides.
-
112. The oligomer of claim 110 wherein said first region in a 5′
- to 3′
direction is complementary to said second region in a 3′
to 5′
direction.
- to 3′
-
113. The oligomer of claim 110 wherein said oligomer includes a hairpin structure.
-
114. The oligomer of claim 110 wherein said first region of said oligomer is spaced from said second region of said oligomer by a third region and where said third region comprises at least two nucleotides.
-
115. The oligomer of claim 110 wherein said first region of said oligomer is spaced from said second region of said oligomer by a third region and where said third region comprises a non-nucleotide region.
-
118. A pharmaceutical composition comprising the oligomeric compound of claim 110 and a pharmaceutically acceptable carrier.
-
121. A method of modulating the expression of a target nucleic acid in a cell comprising contacting said cell with an oligomeric compound of claim 110.
-
124. A method of treating or preventing a disease or disorder associated with a target nucleic acid comprising administering to an animal having or predisposed to said disease or disorder a therapeutically effective amount of a composition of claim 110.
-
111. The oligomer of claim 110 wherein each of said first and said second regions has at least 10 nucleotides.
Specification
- Resources
-
Current AssigneeISIS Pharmaceuticals Incorporated
-
Original AssigneeISIS Pharmaceuticals Incorporated
-
InventorsBhat, Balkrishen, Griffey, Richard H., Swayze, Eric E., Baker, Brenda F., Manoharan, Muthiah, Crooke, Stanley T., Eldrup, Anne B.
-
Application NumberUS10/859,825Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current435/6CPC Class CodesA61K 31/713 Double-stranded nucleic aci...