Compositions and methods for inhibiting expression of the LECT2 gene
View Patent ↗The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the LECT2 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of LECT2.
1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand, each of which is 19-30 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a LECT2 RNA transcript and is complementary to at least nucleotides 668-686 of SEQ ID NO: 1, and wherein the antisense strand comprises at least 19 contiguous nucleotides from SEQ ID NO: 682.
2. The dsRNA of claim 1 , wherein said dsRNA comprises at least one modified nucleotide.
3. The dsRNA of claim of claim 1 , wherein said dsRNA comprises a duplex region of 15-30, 17-23, 19-21, or 21-23 nucleotide pairs in length.
4. The dsRNA of claim 1 , wherein the region of complementarity is 19-24 nucleotides in length.
5. The dsRNA of claim 1 , wherein the region of complementarity is 19, 20, or 21 nucleotides in length.
6. The dsRNA of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 or 2 nucleotides.
7. The dsRNA of claim 2 , wherein the at least one modified nucleotide is chosen from a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, or both.
8. The dsRNA of claim 7 , wherein the dsRNA comprises one or more phosphorothioate linkages.
9. The dsRNA of claim 2 , wherein the dsRNA comprises at least 20 modified nucleotides.
10. The dsRNA of claim 1 , wherein the sense strand is conjugated to at least one ligand.
11. The dsRNA of claim 10 , wherein the ligand is attached to the 3′ end of the sense strand.
12. The dsRNA of claim 10 , wherein the ligand is a GalNAc ligand.
13. The dsRNA of claim 10 , wherein the ligand is
14. The dsRNA of claim 10 , wherein the ligand is attached via a linker, and the ligand and linker are as shown in Formula XXIV:
15. The dsRNA of claim 1 , wherein the region of complementarity consists of an antisense sequence of SEQ ID NO: 682.
16. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of a sense sequence of SEQ ID NO: 681 and an antisense strand consisting of an antisense sequence of SEQ ID NO: 682.
17. A cell containing the dsRNA of claim 1 .
18. A pharmaceutical composition for inhibiting expression of a LECT2 gene, the composition comprising the dsRNA of claim 1 .
19. The pharmaceutical composition of claim 18 , wherein said composition comprises a lipid formulation.
20. The pharmaceutical composition of claim 19 , wherein the lipid formulation is a LNP11 formulation.
21. A method of inhibiting LECT2 expression in a cell, the method comprising:
(a) introducing into the cell the dsRNA of claim 1 , and
(b) maintaining the cell of step (a) for a time sufficient to obtain degradation of the mRNA transcript of a LECT2 gene, thereby inhibiting expression of the LECT2 gene in the cell.
22. The method of claim 21 , wherein the cell is treated ex vivo, in vitro, or in vivo.
23. The method of claim 21 , wherein the cell is a liver cell or a hepatocyte.
24. The method of claim 21 , wherein the expression of LECT2 is inhibited by at least 30%.
25. A method of treating a LECT2 amyloidosis comprising administering to a subject in need of such treatment the dsRNA of claim 1 .
26. The method of claim 25 , wherein the dosing regimen is weekly, biweekly, or monthly.
27. The method of claim 25 , wherein the dsRNA is administered at a dose of 0.05-50, 0.01-5, 0.1-0.5, or 1-10 mg/kg body weight of the subject.
28. The method of claim 27 , wherein the dsRNA is conjugated to a GalNAc ligand.
29. The method of claim 25 , wherein the antisense strand comprises an antisense sequence of SEQ ID NO: 682.
30. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence and all of the modifications of SEQ ID NO: 587 and an antisense strand consisting of the sequence and all of the modifications of SEQ ID NO: 588.
31. The dsRNA of claim 1 , wherein the antisense strand comprises an antisense sequence chosen from SEQ ID NOs: 682, 678, 680, or 684.
32. The dsRNA of claim 1 , wherein the region of complementarity consists of an antisense sequence chosen from SEQ ID NOs: 682, 678, 680, or 684.
33. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of a sense sequence chosen from SEQ ID NOs: 681, 677, 679, or 683, and an antisense strand consisting of an antisense sequence chosen from SEQ ID NOs: 682, 678, 680, or 684.
34. The dsRNA of claim 1 , wherein the antisense strand comprises the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 588, 584, 586, or 590.
35. The dsRNA of claim 1 , wherein the region of complementarity consists of the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 588, 584, 586, or 590.
36. The dsRNA of claim 1 , wherein the dsRNA comprises a sense strand consisting of the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 587, 583, 585, or 589 529, and an antisense strand consisting of the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 588, 584, 586, or 590.
37. A dsRNA for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand, each of which is 20-30 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a LECT2 RNA transcript, wherein the antisense strand comprises at least 20 contiguous nucleotides from SEQ ID NOs: 682, 678, 680, or 684.
38. The dsRNA of claim 37 , wherein the dsRNA comprises a sense strand consisting of a sense sequence chosen from SEQ ID NOs: 681, 677, 679, or 683.
39. The dsRNA of claim 37 , wherein said dsRNA comprises at least one modified nucleotide.
40. The dsRNA of claim 37 , wherein the antisense strand comprises the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 588, 584, 586, or 590.
41. The dsRNA of claim 37 , wherein the dsRNA comprises a sense strand consisting of the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 587, 583, 585, or 589, and an antisense strand consisting of the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 588, 584, 586, or 590.
42. The dsRNA of claim 37 , wherein the sense strand is conjugated to at least one ligand.
43. A dsRNA for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand, each of which is 20-30 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a LECT2 RNA transcript, wherein the antisense strand comprises at least 20 contiguous nucleotides of one of the antisense sequences chosen from SEQ ID NOs: 660, 650, 654, 636, 676, or 624.
44. The dsRNA of claim 43 , wherein said dsRNA comprises at least one modified nucleotide.
45. The dsRNA of claim 43 , wherein the region of complementarity is 19-24 nucleotides in length.
46. The dsRNA of claim 43 , wherein at least one strand comprises a 3′ overhang of at least 1 or 2 nucleotides.
47. The dsRNA of claim 44 , wherein the at least one modified nucleotide is chosen from a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, or both.
48. The dsRNA of claim 47 , wherein the dsRNA comprises one or more phosphorothioate linkages.
49. The dsRNA of claim 43 , wherein the sense strand is conjugated to at least one ligand.
50. The dsRNA of claim 49 , wherein the ligand is attached to the 3′ end of the sense strand.
51. The dsRNA of claim 49 , wherein the ligand is a GalNAc ligand.
52. The dsRNA of claim 49 , wherein the ligand is
53. The dsRNA of claim 49 , wherein the ligand is attached via a linker, and the ligand and linker are as shown in Formula XXIV:
54. The dsRNA of claim 43 , wherein the antisense strand comprises an antisense sequence chosen from SEQ ID NOs: 660, 650, 654, 636, 676, or 624.
55. The dsRNA of claim 43 , wherein the region of complementarity consists of an antisense sequence chosen from SEQ ID NOs: 660, 650, 654, 636, 676, or 624.
56. The dsRNA of claim 43 , wherein the dsRNA comprises a sense strand consisting of a sense sequence chosen from SEQ ID NOs: 659, 649, 653, 635, 675, or 623, and an antisense strand consisting of an antisense sequence chosen from SEQ ID NOs: 660, 650, 654, 636, 676, or 624.
57. The dsRNA of claim 43 , wherein the antisense strand comprises the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 566, 556, 560, 542, 582, or 530.
58. The dsRNA of claim 43 , wherein the region of complementarity consists of the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 566, 556, 560, 542, 582, or 530.
59. The dsRNA of claim 43 , wherein the dsRNA comprises a sense strand consisting of the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 565, 555, 559, 541, 581, or 529, and an antisense strand consisting of the sequence and all of the modifications of an antisense sequence chosen from SEQ ID NOs: 566, 556, 560, 542, 582, or 530.
60. A cell containing the dsRNA of claim 37 .
61. A pharmaceutical composition for inhibiting expression of a LECT2 gene, the composition comprising the dsRNA of claim 37 .
62. The pharmaceutical composition of claim 61 , wherein said composition comprises a lipid formulation.
63. A method of inhibiting LECT2 expression in a cell, the method comprising:
(a) introducing into the cell the dsRNA of claim 37 , and
(b) maintaining the cell of step (a) for a time sufficient to obtain degradation of the mRNA transcript of a LECT2 gene, thereby inhibiting expression of the LECT2 gene in the cell.
64. A method of treating a LECT2 amyloidosis comprising administering to a subject in need of such treatment the dsRNA of claim 37 .
65. The method of claim 64 , wherein the dsRNA is conjugated to a GalNAc ligand.
66. A cell containing the dsRNA of claim 43 .
67. A pharmaceutical composition for inhibiting expression of a LECT2 gene, the composition comprising the dsRNA of claim 43 .
68. The pharmaceutical composition of claim 67 , wherein said composition comprises a lipid formulation.
69. A method of inhibiting LECT2 expression in a cell, the method comprising:
(a) introducing into the cell the dsRNA of claim 43 , and
(b) maintaining the cell of step (a) for a time sufficient to obtain degradation of the mRNA transcript of a LECT2 gene, thereby inhibiting expression of the LECT2 gene in the cell.
70. A method of treating a LECT2 amyloidosis comprising administering to a subject in need of such treatment the dsRNA of claim 43 .
71. The method of claim 70 , wherein the dsRNA is conjugated to a GalNAc ligand.