COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF THE LECT2 GENE

1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a LECT2 RNA transcript, which antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences listed in Tables 2A-2B, 3A-3B, 6 or 7, or a pharmaceutically acceptable salt thereof.

2 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand that is 15-30 nucleotides in length and an antisense strand that is 15-30 nucleotides in length and the antisense strand is complementary to at least 15 contiguous nucleotides of a target sequence listed in Table 2A, 2B, 3A, 3B, 6, or 7, or a pharmaceutically acceptable salt thereof.

3 . The dsRNA of claim 1 or 2 , wherein said dsRNA comprises at least one modified nucleotide.

4 . The dsRNA of any of the preceding claims, wherein the dsRNA comprises a duplex region that is 15-30 base pairs in length.

5 . The dsRNA of claim 4 , wherein the duplex region is 17-25 base pairs in length.

6 . The dsRNA of claim 4 or 5 , wherein the duplex region is 19-22 base pairs in length.

7 . The dsRNA of any of claims 4 - 6 , wherein the duplex region is 21 base pairs in length.

8 . The dsRNA of any of claims 1 or 3 - 7 , wherein the region of complementarity is at least 17 nucleotides in length.

9 . The dsRNA of any of claims 1 or 3 - 8 , wherein the region of complementarity is between 21 and 25 nucleotides in length.

10 . The dsRNA of any of claims 1 or 3 - 9 , wherein the region of complementarity is 23 nucleotides in length.

11 . The dsRNA of any of the preceding claims, wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide or 2 nucleotides.

12 . The dsRNA of any of the preceding claims, wherein dsRNA comprises a blunt end.

13 . The dsRNA of any of claims 3 - 12 , wherein at least one of said modified nucleotides is chosen from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group.

14 . The dsRNA of any of claims 3 - 12 , wherein at least one of said modified nucleotides is chosen from the group consisting of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleic acid (LNA), an acyclic nucleotide, an abasic nucleotide, a glycol nucleotide (GNA), 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.

15 . The dsRNA of any of claims 3 - 12 , wherein the modifications on the nucleotides are selected from the group consisting of a locked nucleic acid (LNA), an acyclic nucleotide, a hexitol or hexose nucleic acid (HNA), a cyclohexene nucleic acid (CeNA), a glycol nucleic acid (GNA), 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-C-allyl, 2′-fluoro, 2′-O-methyl, 2′-deoxy, 2′-hydroxyl, and combinations thereof.

16 . The dsRNA of any of claims 3 - 12 , wherein the modifications on the nucleotides are 2′-O-methyl, 2′-fluoro, or both, and optionally GNA.

17 . The dsRNA of any of the preceding claims wherein the sense strand is conjugated to at least one ligand.

18 . The dsRNA of claim 17 , wherein the ligand is attached to the 3′ end of the sense strand.

19 . The dsRNA of claim 17 or 18 , wherein the ligand comprises a carbohydrate.

20 . The dsRNA of any of claims 17 - 19 , wherein the ligand is a GalNAc ligand.

21 . The dsRNA of any of claims 17 - 20 , wherein the ligand is

22 . The dsRNA of any of claims 17 - 21 , wherein the ligand is attached via a linker.

23 . The dsRNA of claim 22 , wherein the linker is a bivalent or trivalent branched linker.

24 . The dsRNA of claim 22 , wherein the ligand and linker are as shown in Formula XXIV:

25 . The dsRNA of any of claims 17 - 24 , wherein the ligand targets the dsRNA to hepatocytes.

26 . The dsRNA of any of the preceding claims, wherein the region of complementarity consists of an antisense sequence selected from the antisense sequences disclosed in Tables 2A-2B, 3A-3B, 6 or 7.

27 . The dsRNA of any of the preceding claims, wherein the dsRNA comprises a sense strand consisting of a sense sequence selected from the sense sequences disclosed in Tables 2A-2B, 3A-3B, 6 or 7, and an antisense strand consisting of an antisense sequence selected from the antisense sequences disclosed in Tables 2A-2B, 3A-3B, 6 or 7.

28 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a LECT2 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of gsgsucagAfuCfUfUfcaaaauaaauL96 (SEQ ID NO: 143) and the antisense strand comprises the sequence and all of the modifications of asUfsuuaUfuUfUfgaagAfuCfugaccsgsg (SEQ ID NO: 144).

29 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of LECT2, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a LECT2 RNA transcript, wherein the region of complementarity is substantially complementary to nucleotides 669-691 of SEQ ID NO: 1.

30 . A cell containing the dsRNA of any of the preceding claims.

31 . A pharmaceutical composition for inhibiting expression of a LECT2 gene, the composition comprising the dsRNA of any of claims 1 - 29 .

32 . The pharmaceutical composition of claim 31 , wherein dsRNA is administered in an unbuffered solution.

33 . The pharmaceutical composition of claim 32 , wherein said unbuffered solution is saline or water.

34 . The pharmaceutical composition of claim 31 , wherein said dsRNA is administered with a buffer solution.

35 . The pharmaceutical composition of claim 34 , wherein said buffer solution comprises acetate, citrate, prolamine, carbonate, phosphate or any combination thereof.

36 . The pharmaceutical composition of claim 34 or 35 , wherein said buffer solution is phosphate buffered saline (PBS).

37 . The pharmaceutical composition of any of claims 31 - 36 , wherein said composition comprises a lipid formulation.

38 . The pharmaceutical composition of claim 37 , wherein the lipid formulation is an LNP formulation.

39 . The pharmaceutical composition of claim 37 or 38 , wherein the lipid formulation is an LNP11 formulation.

40 . The pharmaceutical composition of any of claims 31 - 39 , wherein the dsRNA is targeted to a liver cell or a hepatocyte.

41 . The pharmaceutical composition of any of claims 31 - 40 , wherein said composition is administered intravenously.

42 . The pharmaceutical composition of any of claims 31 - 40 , wherein said composition is administered subcutaneously.

43 . The pharmaceutical composition of claim 41 , wherein said composition comprises a lipid formulation and is administered intravenously.

44 . The pharmaceutical composition of any of claims 31 - 43 , wherein said composition comprises a dsRNA that is conjugated to a ligand chosen from a carbohydrate ligand or a GalNAc ligand.

45 . A method of inhibiting LECT2 expression in a cell, the method comprising:

(a) contacting, e.g., introducing into the cell the dsRNA of any of claims 1 - 29 , 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.

46 . The method of claim 45 , wherein the cell is treated ex vivo, in vitro, or in vivo.

47 . The method of claim 45 or 46 , wherein the cell is present in a subject in need of treatment, prevention and/or management of a disorder related to LECT2 expression.

48 . The method of claim 47 , wherein said disorder is amyloidosis.

49 . The method of claim 48 , wherein the amyloidosis is a LECT2 amyloidosis.

50 . The method of any of claims 45 - 49 , wherein the cell is a liver cell or a hepatocyte.

51 . The method of any of claims 45 - 50 , wherein the expression of LECT2 is inhibited by at least 20%.

52 . The method of any of claims 45 - 51 , wherein the expression of LECT2 is inhibited by at least 90%.

53 . A method of treating a disorder related to LECT2 expression, comprising administering to a subject in need of such treatment a therapeutically effective amount of

(i) the dsRNA of any of claims 1 - 29 or

(ii) the pharmaceutical composition of any of claims 31 - 44 .

54 . A method of treating LECT2 amyloidosis, comprising administering to a subject in need of such treatment a therapeutically effective amount of

(i) the dsRNA of any of claims 1 - 29 or

(ii) the pharmaceutical composition of any of claims 31 - 44 .

55 . The method of claim 52 or 53 , wherein the subject has amyloidosis or is at risk for developing amyloidosis.

56 . The method of any of claims 53 - 55 , wherein the amyloidosis is a LECT2 amyloidosis.

57 . The method of any of claims 45 - 56 , wherein the dsRNA or composition comprising the dsRNA is administered according to a dosing regimen.

58 . The method of claim 57 , wherein the dosing regimen is weekly, biweekly, or monthly.

59 . The method of any of claims 45 - 58 , wherein the method reduces LECT2 amyloid deposition.

60 . A method of reducing LECT2 amyloid deposition in a subject having a LECT2 amyloidosis, the method comprising administering to the subject

(i) the dsRNA of any of claims 1 - 29 or

(ii) the pharmaceutical composition of any of claims 31 - 44 .

61 . The method of any of claims 53 - 60 , wherein the dsRNA is administered at a dose of 0.05-50 mg/kg.

62 . The method of any of claims 53 - 61 , wherein the dsRNA is administered at a concentration of 0.01 mg/kg to 5 mg/kg bodyweight of the subject.

63 . The method of any of claims 53 - 62 , wherein the dsRNA is formulated as an LNP formulation and is administered at a dose of 0.1 mg/kg to 0.5 mg/kg.

64 . The method of any of claims 53 - 63 , wherein the dsRNA is conjugated to a GalNAc ligand.

65 . The method of any of claims 53 - 64 , wherein the dsRNA is conjugated to a GalNAc ligand and is administered at a dose of 1 mg/kg to 10 mg/kg, optionally at a dose of 1 mg/kg or 3 mg/kg.

66 . A vector encoding at least one strand of the dsRNA of any of claims 1 - 29 .

67 . A cell comprising the vector of claim 66 .