Methods of treating cardiovascular disease with an ASGR inhibitor
Antigen binding proteins that interact with ASGR, ASGR-1 and/or ASGR-2 are described as well as methods of making and using such antigen binding proteins. Methods of treating and preventing cardiovascular disease by administering a pharmaceutically effective amount of ASGR, ASGR-1 and/or ASGR-2 antigen binding proteins. Methods of treating and preventing cardiovascular disease by administering a pharmaceutically effective amount of interfering RNA compositions that reduce expression of ASGR, ASGR-1 and/or ASGR-2 are described.
1. A method of treating or preventing a cardiovascular disease comprising administering to a patient in need thereof a therapeutically effective dose of an interfering RNA of ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2).
2. The method of claim 1 , wherein said cardiovascular disease is coronary artery disease or myocardial infarction.
3. A method of reducing LDL (low density lipoprotein) cholesterol levels in a patient comprising administering to a patient in need thereof a therapeutically effective dose of an interfering RNA of ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2).
4. A method of reducing non-HDL (non-high density lipoprotein) cholesterol levels in a patient comprising administering to a patient in need thereof a therapeutically effective dose of an interfering RNA of ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2).
5. A method of increasing ALP (alkaline phosphatase) levels in a patient comprising administering to a patient in need thereof a therapeutically effective dose of an interfering RNA of ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2).
6. The methods of any one of claims 1 - 5 , wherein the interfering RNA comprises siRNA or shRNA.
7. The method of claim 1 , wherein the interfering RNA is siRNA or shRNA.
8. The method of claim 3 , wherein the interfering RNA is siRNA or shRNA.
9. The method of claim 4 , wherein the interfering RNA is siRNA or shRNA.
10. The method of claim 5 , wherein the interfering RNA is siRNA or shRNA.
11. The method of claim 1 , wherein the interfering RNA is administered simultaneously or sequentially with at least one agent that lowers cholesterol.
12. The method of claim 11 , wherein the at least one agent is a statin, an anti-PCSK9 inhibitor or a combination thereof.
13. The method of claim 3 , wherein the interfering RNA is administered simultaneously or sequentially with at least one agent that lowers cholesterol.
14. The methods of claim 13 , wherein the at least one agent is a statin, an anti-PCSK9 inhibitor or a combination thereof.
15. The method of claim 4 , wherein the interfering RNA is administered simultaneously or sequentially with at least one agent that lowers cholesterol.
16. The methods of claim 15 , wherein the at least one agent is a statin, an anti-PCSK9 inhibitor or a combination thereof.
17. The method of claim 5 , wherein the interfering RNA is administered simultaneously or sequentially with at least one agent that lowers cholesterol.
18. The methods of claim 17 , wherein the at least one agent is a statin, an anti-PCSK9 inhibitor or a combination thereof.
19. The method of claim 3 , wherein the patient has coronary artery disease or myocardial infarction.
20. The method of claim 4 , wherein the patient has coronary artery disease or myocardial infarction.
21. The method of claim 5 , wherein the patient has coronary artery disease or myocardial infarction.
22. The method of claim 1 , wherein the interfering RNA reduces expression of ASGR-1 (asialoglycoprotein receptor 1).
23. The method of claim 3 , wherein the interfering RNA reduces expression of ASGR-1 (asialoglycoprotein receptor 1).
24. The method of claim 4 , wherein the interfering RNA reduces expression of ASGR-1 (asialoglycoprotein receptor 1).
25. The method of claim 5 , wherein the interfering RNA reduces expression of ASGR-1 (asialoglycoprotein receptor 1).
26. The method of claim 1 , wherein the interfering RNA reduces expression of ASGR-2 (asialoglycoprotein receptor 2).
27. The method of claim 3 , wherein the interfering RNA reduces expression of ASGR-2 (asialoglycoprotein receptor 2).
28. The method of claim 4 , wherein the interfering RNA reduces expression of ASGR-2 (asialoglycoprotein receptor 2).
29. The method of claim 5 , wherein the interfering RNA reduces expression of ASGR-2 (asialoglycoprotein receptor 2).
30. The method of claim 1 , wherein the interfering RNA is siRNA.
31. The method of claim 1 , wherein the interfering RNA is at least partially double stranded.
32. The method of claim 30 , wherein the siRNA comprises a duplex region of about 19 to about 25 base pairs in length.
33. The method of claim 30 , wherein the siRNA comprises:
a sense strand of about 15-30 nucleotides; and
an antisense strand of about 15-30 nucleotides.
34. The method of claim 30 , wherein the siRNA comprises:
a sense strand of about 19-25 nucleotides; and
an antisense strand of about 19-25 nucleotides.
35. The method of claim 3 , wherein the interfering RNA is siRNA.
36. The method of claim 3 , wherein the interfering RNA is at least partially double stranded.
37. The method of claim 35 , wherein the siRNA comprises a duplex region of about 19 to about 25 base pairs in length.
38. The method of claim 35 , wherein the siRNA comprises:
a sense strand of about 15-30 nucleotides; and
an antisense strand of about 15-30 nucleotides.
39. The method of claim 35 , wherein the siRNA comprises:
a sense strand of about 19-25 nucleotides; and
an antisense strand of about 19-25 nucleotides.
40. The method of claim 4 , wherein the interfering RNA is siRNA.
41. The method of claim 4 , wherein the interfering RNA is at least partially double stranded.
42. The method of claim 40 , wherein the siRNA comprises a duplex region of about 19 to about 25 base pairs in length.
43. The method of claim 40 , wherein the siRNA comprises:
a sense strand of about 15-30 nucleotides; and
an antisense strand of about 15-30 nucleotides.
44. The method of claim 40 , wherein the siRNA comprises:
a sense strand of about 19-25 nucleotides; and
an antisense strand of about 19-25 nucleotides.
45. The method of claim 5 , wherein the interfering RNA is siRNA.
46. The method of claim 5 , wherein the interfering RNA is at least partially double stranded.
47. The method of claim 45 , wherein the siRNA comprises a duplex region of about 19 to about 25 base pairs in length.
48. The method of claim 45 , wherein the siRNA comprises:
a sense strand of about 15-30 nucleotides; and
an antisense strand of about 15-30 nucleotides.
49. The method of claim 45 , wherein the siRNA comprises:
a sense strand of about 19-25 nucleotides; and
an antisense strand of about 19-25 nucleotides.
50. The method of claim 1 , wherein the interfering RNA is shRNA.
51. The method of claim 3 , wherein the interfering RNA is shRNA.
52. The method of claim 4 , wherein the interfering RNA is shRNA.
53. The method of claim 5 , wherein the interfering RNA is shRNA.
54. The method of claim 1 , wherein the interfering RNA is a siRNA that comprises a sense strand and an antisense strand, wherein the antisense strand comprises a region having a sequence that is complementary to an ASGR-1 (asialoglycoprotein receptor 1) sequence, or an ASGR-2 (asialoglycoprotein receptor 2) sequence, and wherein said region comprises at least 15 contiguous nucleotides.
55. The method of claim 3 , wherein the interfering RNA is a siRNA that comprises a sense strand and an antisense strand, wherein the antisense strand comprises a region having a sequence that is complementary to an ASGR-1 (asialoglycoprotein receptor 1) sequence, or an ASGR-2 (asialoglycoprotein receptor 2) sequence, and wherein said region comprises at least 15 contiguous nucleotides.
56. The method of claim 4 , wherein the interfering RNA is a siRNA that comprises a sense strand and an antisense strand, wherein the antisense strand comprises a region having a sequence that is complementary to an ASGR-1 (asialoglycoprotein receptor 1) sequence, or an ASGR-2 (asialoglycoprotein receptor 2) sequence, and wherein said region comprises at least 15 contiguous nucleotides.
57. The method of claim 5 , wherein the interfering RNA is a siRNA that comprises a sense strand and an antisense strand, wherein the antisense strand comprises a region having a sequence that is complementary to an ASGR-1 (asialoglycoprotein receptor 1) sequence, or an ASGR-2 (asialoglycoprotein receptor 2) sequence, and wherein said region comprises at least 15 contiguous nucleotides.
58. The method of claim 1 , wherein the interfering RNA comprises a sense strand and an anti-sense strand, wherein the sense strand comprises a sequence that is substantially complementary to a sequence of the antisense strand to form a duplex region of about 15 to about 30 base pairs in length.
59. The method of claim 3 , wherein the interfering RNA comprises a sense strand and an anti-sense strand, wherein the sense strand comprises a sequence that is substantially complementary to a sequence of the antisense strand to form a duplex region of about 15 to about 30 base pairs in length.
60. The method of claim 4 , wherein the interfering RNA comprises a sense strand and an anti-sense strand, wherein the sense strand comprises a sequence that is substantially complementary to a sequence of the antisense strand to form a duplex region of about 15 to about 30 base pairs in length.
61. The method of claim 5 , wherein the interfering RNA comprises a sense strand and an anti-sense strand, wherein the sense strand comprises a sequence that is substantially complementary to a sequence of the antisense strand to form a duplex region of about 15 to about 30 base pairs in length.
62. The method of claim 1 , wherein the interfering RNA comprises a sense strand and an anti-sense strand, wherein the sense strand comprises a sequence that is complementary to a sequence of the antisense strand to form a duplex region of about 15 to about 30 base pairs in length.
63. The method of claim 3 , wherein the interfering RNA comprises a sense strand and an anti-sense strand, wherein the sense strand comprises a sequence that is complementary to a sequence of the antisense strand to form a duplex region of about 15 to about 30 base pairs in length.
64. The method of claim 4 , wherein the interfering RNA comprises a sense strand and an anti-sense strand, wherein the sense strand comprises a sequence that is complementary to a sequence of the antisense strand to form a duplex region of about 15 to about 30 base pairs in length.
65. The method of claim 5 , wherein the interfering RNA comprises a sense strand and an anti-sense strand, wherein the sense strand comprises a sequence that is complementary to a sequence of the antisense strand to form a duplex region of about 15 to about 30 base pairs in length.
66. The method of claim 1 , wherein the cardiovascular disease is thereby treated.
67. The method of claim 1 , wherein the cardiovascular disease is thereby prevented.
68. The method of claim 3 , wherein LDL is reduced by at least 20%.
69. The method of claim 4 , wherein non-HDL is reduced by at least 20%.
70. The method of claim 5 , wherein ALP is increased by at least 40%.
71. The method of claim 1 , wherein the interfering RNA comprises a duplex region of about 19 to about 25 base pairs in length.
72. The method of claim 3 , wherein the interfering RNA comprises a duplex region of about 19 to about 25 base pairs in length.
73. The method of claim 4 , wherein the interfering RNA comprises a duplex region of about 19 to about 25 base pairs in length.
74. The method of claim 5 , wherein the interfering RNA comprises a duplex region of about 19 to about 25 base pairs in length.
75. The method of claim 1 , wherein the interfering RNA comprises a modified nucleotide.
76. The method of claim 3 , wherein the interfering RNA comprises a modified nucleotide.
77. The method of claim 4 , wherein the interfering RNA comprises a modified nucleotide.
78. The method of claim 5 , wherein the interfering RNA comprises a modified nucleotide.
79. The method of claim 1 , wherein the interfering RNA comprises a sequence that is 15 to 30 nucleotides in length and is 100% complementary to a sequence within ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2), wherein the sequence within ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2) is 15 to 30 nucleotides in length.
80. The method of claim 79 , wherein the ASGR-1 (asialoglycoprotein receptor 1) is a human ASGR-1 having the sequence in SEQ ID NO: 32699), and the ASGR-2 (asialoglycoprotein receptor 2) is a human ASGR-2 having the sequence in SEQ ID NO: 32713.
81. The method of claim 80 , wherein the interfering RNA consists essentially of:
a sense strand that is 15 to 30 nucleotides in length; and
an anti-sense strand that is 15 to 30 nucleotides in length.
82. The method of claim 81 , wherein, the sense strand is at least 90% complementary to the anti-sense strand, wherein a duplex formed by the sense stand and the anti-sense strand is from 15-30 base pairs in length.
83. The method of claim 3 , wherein the interfering RNA comprises a sequence that is 15 to 30 nucleotides in length and is 100% complementary to a sequence within ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2), wherein the sequence within ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2) is 15 to 30 nucleotides in length.
84. The method of claim 83 , wherein the ASGR-1 (asialoglycoprotein receptor 1) is a human ASGR-1 having the sequence in SEQ ID NO: 32699), and the ASGR-2 (asialoglycoprotein receptor 2) is a human ASGR-2 having the sequence in SEQ ID NO: 32713.
85. The method of claim 84 , wherein the interfering RNA consists essentially of:
a sense strand that is 15 to 30 nucleotides in length; and
an anti-sense strand that is 15 to 30 nucleotides in length.
86. The method of claim 85 , wherein, wherein the sense strand is at least 90% complementary to the anti-sense strand, and wherein a duplex formed by the sense stand and the anti-sense strand is from 15-30 base pairs in length.
87. The method of claim 4 , wherein the interfering RNA comprises a sequence that is 15 to 30 nucleotides in length and is 100% complementary to a sequence within ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2), wherein the sequence within ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2) is 15 to 30 nucleotides in length.
88. The method of claim 87 , wherein the ASGR-1 (asialoglycoprotein receptor 1) is a human ASGR-1 having the sequence in SEQ ID NO: 32699), and the ASGR-2 (asialoglycoprotein receptor 2) is a human ASGR-2 having the sequence in SEQ ID NO: 32713.
89. The method of claim 88 , wherein the interfering RNA consists essentially of:
a sense strand that is 15 to 30 nucleotides in length; and
an anti-sense strand that is 15 to 30 nucleotides in length.
90. The method of claim 89 , wherein, the sense strand is at least 90% complementary to the anti-sense strand, and wherein a duplex formed by the sense stand and the anti-sense strand is from 15-30 base pairs in length.
91. The method of claim 5 , wherein the interfering RNA comprises a sequence that is 15 to 30 nucleotides in length and is 100% complementary to a sequence within ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2), wherein the sequence within ASGR (asialoglycoprotein receptor), ASGR-1 (asialoglycoprotein receptor 1), and/or ASGR-2 (asialoglycoprotein receptor 2) is 15 to 30 nucleotides in length.
92. The method of claim 91 , wherein the ASGR-1 (asialoglycoprotein receptor 1) is a human ASGR-1 having the sequence in SEQ ID NO: 32699), and the ASGR-2 (asialoglycoprotein receptor 2) is a human ASGR-2 having the sequence in SEQ ID NO: 32713.
93. The method of claim 92 , wherein the interfering RNA consists essentially of:
a sense strand that is 15 to 30 nucleotides in length; and
an anti-sense strand that is 15 to 30 nucleotides in length.
94. The method of claim 93 , wherein, the sense strand is at least 90% complementary to the anti-sense strand, and wherein a duplex formed by the sense stand and the anti-sense strand is from 15-30 base pairs in length.
95. The method of claim 1 , wherein the interfering RNA is conjugated to a targeting moiety, wherein the targeting moiety targets a cell in the liver.
96. The method of claim 3 , wherein the interfering RNA is conjugated to a targeting moiety, wherein the targeting moiety targets a cell in the liver.
97. The method of claim 4 , wherein the interfering RNA is conjugated to a targeting moiety, wherein the targeting moiety targets a cell in the liver.
98. The method of claim 5 , wherein the interfering RNA is conjugated to a targeting moiety, wherein the targeting moiety targets a cell in the liver.
99. The method of claim 1 , wherein the interfering RNA is administered parenterally.
100. The method of claim 3 , wherein the interfering RNA is administered parenterally.
101. The method of claim 4 , wherein the interfering RNA is administered parenterally.
102. The method of claim 5 , wherein the interfering RNA is administered parenterally.
103. The method of claim 1 , wherein the interfering RNA consists of a small interfering RNA.
104. The method of claim 3 , wherein the interfering RNA consists of a small interfering RNA.
105. The method of claim 4 , wherein the interfering RNA consists of a small interfering RNA.
106. The method of claim 5 , wherein the interfering RNA consists of a small interfering RNA.
107. A method of treating a cardiovascular disease or myocardial infarction, said method comprising administering to a patient in need thereof a therapeutically effective dose of an siRNA targeting ASGR-1 (asialoglycoprotein receptor 1), wherein the siRNA comprises:
a sense strand that is about 15 to about 30 nucleotides in length; and
an anti-sense strand that is about 15 to about 30 nucleotides in length,
wherein the antisense strand comprises a sequence that is complementary to an ASGR1 sequence, and wherein the sense strand comprises a sequence that is complementary to a sequence of the antisense strand and thereby forms a duplex that is about 15 to about 30 base pairs in length, wherein said cardiovascular disease is coronary artery disease or myocardial infarction.
108. A method of increasing ALP (alkaline phosphatase) levels in a patient comprising administering to a patient in need thereof a therapeutically effective dose of an siRNA targeting ASGR-1 (asialoglycoprotein receptor 1), wherein the siRNA comprises:
a sense strand that is about 15 to about 30 nucleotides in length; and
an anti-sense strand that is about 15 to about 30 nucleotides in length,
wherein the antisense strand comprises a sequence that is complementary to an ASGR1 sequence, and wherein the sense strand comprises a sequence that is complementary to a sequence of the antisense strand and thereby forms a duplex that is about 15 to about 30 base pairs in length.