Antisense modulation of kinesin-like 1 expression
View Patent ↗Antisense compounds, compositions and methods are provided for modulating the expression of kinesin-like 1. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding kinesin-like 1. Methods of using these compounds for modulation of kinesin-like 1 expression and for treatment of diseases associated with expression of kinesin-like 1 are provided.
1. A compound comprising a modified oligonucleotide consisting of 13 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in any one of SEQ ID NOs: 11-20, 23, 35, 82-84, and 122, and wherein the nucleobase sequence of the modified oligonucleotide is at least 85% complementary to the nucleobase sequence recited in any one of SEQ ID NOs: 3, 76, 77, 78, 79, 155 and 156.
2. The compound of claim 1 , consisting of a single-stranded modified oligonucleotide.
3. The compound of claim 2 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 3.
4. The compound of claim 2 , wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage.
5. The compound of claim 4 , wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate internucleoside linkage.
6. The compound of claim 2 , wherein at least one nucleoside of said modified oligonucleotide comprises a modified sugar.
7. The compound of claim 6 , wherein at least one modified sugar is a bicyclic sugar.
8. The compound of claim 6 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2.
9. The compound of claim 2 , wherein at least one nucleoside of said modified oligonucleotide comprises a modified nucleobase.
10. The compound of claim 9 , wherein the modified nucleobase is a 5-methylcytosine.
11. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
12. The compound of claim 11 , wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar;
wherein each cytosine in said modified oligonucleotide is a 5-methylcytosine, and wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage.
13. The compound of claim 12 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
14. A composition comprising a modified oligonucleotide consisting of 13 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in any one of SEQ ID NOs: 11-20, 23, 35, 82-84, and 122, and wherein the nucleobase sequence of the modified oligonucleotide is at least 85% complementary to the nucleobase sequence recited in any one of SEQ ID NOs: 3, 76, 77, 78, 79, 155 and 156, or a salt thereof and a pharmaceutically acceptable carrier or diluent.
15. The composition of claim 14 , wherein said modified oligonucleotide consists of a single-stranded oligonucleotide.
16. The composition of claim 14 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
17. A method comprising administering to an animal the compound of claim 1 .
18. The method of claim 17 , wherein the animal is a human.
19. The method of claim 18 , wherein administering the compound treats a disease or condition associated with kinesin-like 1.
20. The method of claim 18 , comprising co-administering the compound and a chemotherapeutic agent.
21. The method of claim 20 , wherein the compound and the chemotherapeutic agent are administered concomitantly.
22. The method of claim 18 , wherein the administering is topical, pulmonary, oral or parenteral.
23. A method comprising identifying a human with a disease or condition associated with kinesin-like 1 and administering to the human a therapeutically effective amount of the composition of claim 14 .
24. The method of claim 23 , wherein the administration slows the growth of a tumor in said human.
25. The method of claim 23 , comprising co-administering the compound and a chemotherapeutic agent.
26. The method of claim 19 , wherein said disease or condition associated with kinesin-like 1 is a hyperproliferative disorder.
27. The method of claim 26 , wherein said hyperproliferative disorder is cancer.
28. The method of claim 23 , wherein said disease or condition associated with kinesin-like 1 is a hyperproliferative disorder.
29. The method of claim 28 , wherein said hyperproliferative disorder is cancer.
30. A compound comprising a modified oligonucleotide consisting of 13 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NO: 21, wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
31. The compound of claim 1 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NOs: 82, 83, or 84.
32. The compound of claim 31 , consisting of a single-stranded modified oligonucleotide.
33. The compound of claim 31 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 3.
34. The compound of claim 31 , wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage.
35. The compound of claim 34 , wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate internucleoside linkage.
36. The compound of claim 31 , wherein at least one nucleoside of said modified oligonucleotide comprises a modified sugar.
37. The compound of claim 36 , wherein at least one modified sugar is a bicyclic sugar.
38. The compound of claim 36 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2.
39. The compound of claim 31 , wherein at least one nucleoside of said modified oligonucleotide comprises a modified nucleobase.
40. The compound of claim 39 , wherein the modified nucleobase is a 5-methylcytosine.
41. The compound of claim 33 , wherein the modified oligonucleotide is an RNA oligonucleotide.
42. The compound of claim 41 , wherein the RNA oligonucleotide consists of 15 to 30 linked nucleosides and has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NO: 82.
43. The compound of claim 41 , wherein the RNA oligonucleotide consists of 15 to 30 linked nucleosides and has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NO: 83.
44. The compound of claim 41 , wherein the RNA oligonucleotide consists of 15 to 30 linked nucleosides and has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NOs: 84.
45. The compound of claim 42 , wherein the RNA oligonucleotide comprises at least one modified sugar, wherein the modified sugar comprises 2′-O—CH 3 .
46. The compound of claim 43 , wherein the RNA oligonucleotide comprises at least one modified sugar, wherein the modified sugar comprises 2′-O—CH 3 .
47. The compound of claim 44 , wherein the RNA oligonucleotide comprises at least one modified sugar, wherein the modified sugar comprises 2′-O—CH 3 .
48. The compound of claim 45 , wherein the RNA oligonucleotide comprises at least one phosphorothioate internucleoside linkage.
49. The compound of claim 46 , wherein the RNA oligonucleotide comprises at least one phosphorothioate internucleoside linkage.
50. The compound of claim 47 , wherein the RNA oligonucleotide comprises at least one phosphorothioate internucleoside linkage.
51. The compound of claim 41 , wherein the compound comprises a double-stranded RNA oligonucleotide, wherein one strand of the double-stranded RNA oligonucleotide is the RNA oligonucleotide having a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NOs: 82, 83, or 84.
52. The compound of claim 51 , wherein the RNA oligonucleotide having a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NOs: 82, 83, or 84 comprises at least one modified sugar, wherein the modified sugar comprises 2′-O—CH 3 .
53. The compound of claim 52 , wherein the RNA oligonucleotide having a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NOs: 82, 83, or 84 comprises at least one phosphorothioate internucleoside linkage.
54. The compound of claim 53 , wherein each strand of the double-stranded RNA oligonucleotide consists of 15 to 30 linked nucleosides.