Products and compositions

Abstract

Nucleic acid products and compositions, and methods of their use, are provided for modulating, particularly interfering or inhibiting expression of CFB and C5 genes.

Claims

1. A nucleic acid construct comprising at least: (a) a first nucleic acid portion that is at least partially complementary to at least a first portion of an RNA transcribed from a CFB gene; (b) a second nucleic acid portion that is at least partially complementary to at least a second portion of RNA transcribed from the C5 gene; (c) a third nucleic acid portion that is at least partially complementary to the first nucleic acid portion in (a) so as to form a first nucleic acid double-stranded region therewith; (d) a fourth nucleic acid portion that is at least partially complementary to the second nucleic acid portion in (b) so as to form a second nucleic acid double-stranded region therewith.

2. The construct of claim 1 , wherein the construct is designed to break down upon in vivo administration to produce at least first and second discrete nucleic acid targeting molecules, the first and second discrete nucleic acid targeting molecules targeting the portion of the RNA transcribed from the target gene of (a) and (b), respectively; wherein (i) the first nucleic acid targeting molecule is capable of regulating the expression of the target gene of (a) and comprises or is derived from at least the first nucleic acid portion of (a), and (ii) the second nucleic acid targeting molecule is capable of regulating the expression of the target gene of (b) and comprises or is derived from the second nucleic acid portion of (b).

3. The construct according to claim 1 or 2, wherein the construct is designed to be dissociable (cleavable) so that the first and second discrete nucleic acid targeting molecules are processed by independent RNA interference-inducing silencing complexes, respectively.

4. The construct according to any one of claims 1 to 3, further comprising at least one destabilizing function such that upon in vivo administration, the construct is cleaved to produce the at least first and second discrete nucleic acid targeting molecules.

5. The construct of claim 4, wherein the destabilizing function comprises one or more unmodified nucleotides.

6. The construct of claim 5, wherein the one or more unmodified nucleotides of the labile function represent one or more cleavage sites within the construct, wherein upon in vivo administration, the construct is cleaved at the one or more cleavage sites to produce the at least first and second discrete nucleic acid targeting molecules.

7. The construct of claim 6, wherein the cleavage sites are respectively located within the construct such that, after cleavage, the first discrete nucleic acid targeting molecule comprises or is derived from the first nucleic acid duplex region, and the second discrete nucleic acid targeting molecule comprises or is derived from the second nucleic acid duplex region.

8. The construct of claim 7, wherein the first discrete nucleic acid targeting molecule comprises or consists of the first nucleic acid portion of (a) and the third nucleic acid portion of (c), and / or the second discrete nucleic acid targeting molecule comprises or consists of the second nucleic acid portion of (b) and the fourth nucleic acid portion of (d).

9. The construct according to any one of claims 1 to 8, wherein (a) the first nucleic acid portion has a base sequence and is selected from the group consisting of SEQ ID NOs: 1-252; (b) the second nucleic acid portion has a base sequence and is selected from the group consisting of SEQ ID NOs: 504-754; (c) the third nucleic acid portion has a base sequence and is selected from the group consisting of SEQ ID NOs: 253-504; and / or (d) the fourth nucleic acid portion has a base sequence selected from the group consisting of SEQ ID NOs: 755-1004, The third and fourth base sequences may be shorter by one, two, three or four bases when they have a length of 15 bases, and may be shorter by one, two or three bases when they have a length of 14 bases. Advantageously, the 5' terminal base does not exist.

10. The construct of any one of claims 1 to 9, wherein the first nucleic acid portion of (a) is directly or indirectly linked to the fourth nucleic acid portion of (d) as a primary structure.

11. The construct according to claim 10, wherein the first and fourth nucleic acid portions have base sequences of sequence numbers 13 and 784, 13 and 791, 106 and 784, 106 and 791, and wherein the sequences of sequence numbers 784 and 791 may be shorter by one, two, three or four bases, and advantageously the 5' end base does not exist.

12. The construct according to any one of claims 1 to 11, wherein the second nucleic acid portion of (b) is directly or indirectly linked to the third nucleic acid portion of (c) as a primary structure.

13. construct according to claim 11 or 12, wherein the second and third nucleic acid portions have base sequences with sequence numbers 534 and 265, 534 and 358, 541 and 265, 541 and 358, advantageously 534 and 358 and / or 541 and 265; and wherein the sequence with sequence numbers 265 and 358 may be shorter by one, two, three or four bases, advantageously the 5' end base does not exist.

14. The construct according to any one of claims 1 to 9, 11 or 13, further comprising 1 to 8, advantageously 2, further nucleic acid portions, each of which is at least partially complementary to 1 to 8 further RNA portions transcribed from one or more target genes, which target genes may be identical or different to each other and / or identical or different to the target genes defined in (a) and / or (b), and wherein each of the 1 to 8 further nucleic acid portions forms a further duplex region with a respective passenger nucleic acid portion, each of which is at least partially complementary to the passenger nucleic acid portion.

15. The construct of claim 14, wherein the second nucleic acid portion of (b) and the 1 to 8 additional nucleic acid portions are linked directly or indirectly to the selected passenger nucleic acid portion as respective primary structures.

16. The construct according to any one of claims 10, 12 or 15, wherein the direct or indirect linkage represents (i) an internucleotide bond, (ii) an internucleotide gap or (iii) a nucleic acid linking portion of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides, which is advantageously single-stranded.

17. The construct of claim 16(i), wherein the ligation is direct, thereby producing a continuous chain.

18. A construct according to any one of claims 1 to 17, in particular the construct of claim 16(i), wherein there is some complementarity between the first nucleic acid part of (a) and the second nucleic acid part of (b), or between the third nucleic acid part of (c) and the fourth nucleic acid part of (d).

19. The construct according to claim 18, wherein the complementarity (i) is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, advantageously 2, 3, 4 or 5 base pairs; and / or (ii) is present between the first nucleic acid portion of (a) and the second nucleic acid portion of (b).

20. The construct according to claims 16(i) to 19, dependent on claim 5, wherein the internucleotide bond involves at least one of the one or more unmodified nucleotides, advantageously cleavage occurring at the 3' position of (at least one of) the unmodified nucleotides.

21. according to the construct described in any one in claim 1 to 20, the length of wherein said first nucleic acid part of (a) and / or said second nucleic acid part of (b) and / or said third nucleic acid part of (c) and / or said fourth nucleic acid part of (d) is respectively 7 to 25 nucleotides.

22. Construct according to claim 21, wherein the length of the first nucleic acid part of (a) and / or the second nucleic acid part of (b) is 18 to 21, more advantageously 18 to 20, even more advantageously 19 nucleotides.

23. construct according to claim 21 or 22, wherein the length of the third nucleic acid portion of (c) and / or the fourth nucleic acid portion of (d) is 11 to 20, more advantageously 13 to 16, even more advantageously 14 or 15, most advantageously 14 nucleotides.

24. according to the construct described in any one in claim 21 to 23, wherein said unmodified nucleotide is positioned at any one in position 18 to 25, more advantageously be positioned at any one and / or 3 ' terminal position in position 18 to 21 of the described first nucleic acid portion of described (a) and / or the described 3rd nucleic acid portion of described (c).

25. The construct of claim 24, wherein the unmodified nucleotide is located at position 19.

26. The construct of claims 17 to 19 or 21 to 23, depending on claim 16(iii), wherein the nucleic acid linking portion has a length of 1 to 8 nucleotides, advantageously 2 to 7 or 3 to 6 nucleotides, more advantageously about 4 or 5, most advantageously 4 nucleotides.

27. The construct of any one of claims 21 to 26, wherein one, more or all of the duplex regions independently have 10 to 19, more advantageously 13 to 19, even more advantageously 13, 14 or 15 base pairs, most advantageously 14 base pairs, wherein optionally one mismatch is present within the duplex region.

28. A construct according to any one of claims 1 to 27, further comprising one or more ligands.

29. The construct of any one of claims 1 to 28, wherein the first nucleic acid part of (a) and / or the second nucleic acid part of (b) and / or the third nucleic acid part of (c) and / or the fourth nucleic acid part of (d), and / or where present, the 1 to 8 further nucleic acid parts as defined in claims 14 and 15, and / or the passenger nucleic acid part as defined in claim 14 or 15, respectively, have a 5' to 3' directionality, thereby defining their 5' and 3' regions.

30. The construct according to any one of claims 28 or 29, wherein one or more ligands are conjugated at the 3' region, advantageously the 3' end, of any of the following: (i) the third nucleic acid portion of (c), and / or (ii) the fourth nucleic acid portion of (d), and / or where present, the (iii) passenger nucleic acid portion as defined in claim 14 or 15.

31. The construct according to any one of claims 28 to 30, wherein one or more ligands are conjugated at one or more regions between the 5' and 3' regions of any of the nucleic acid parts, advantageously at the third nucleic acid part of (c) and / or the fourth nucleic acid part of (d) and / or the passenger nucleic acid part as defined in claim 14 or 15.

32. The construct according to any one of claims 28 to 31, wherein one or more ligands are conjugated to any of the nucleic acid portions in the 5' region, advantageously at the 5' end, or in the 3' region, advantageously at the 3' end.

33. The construct of any one of claims 28 to 32, wherein the one or more ligands are any cell targeting moieties such as lipids, carbohydrates, aptamers, vitamins and / or peptides capable of binding to a specific target on a cell membrane or cell surface.

34. The construct of claim 33, wherein the one or more carbohydrates can be a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide or a polysaccharide.

35. The construct of claim 34, wherein the one or more carbohydrates comprises one or more hexose moieties.

36. The construct of claim 35, wherein the one or more hexose moieties are one or more galactose moieties, one or more lactose moieties, one or more N-acetylgalactosamine moieties and / or one or more mannose moieties.

37. The construct of claim 36 comprising two or three N-acetylgalactosamine moieties.

38. The construct of any one of claims 28 to 37, wherein the one or more ligands are linked in a linear or branched configuration.

39. The construct of claim 38, wherein the one or more ligands are linked in a bifurcated or trifurcated configuration, or in a configuration based on individual ligands at different positions.

40. The construct of claim 37 or 38, wherein the ligand has the structure:

41. according to the construct described in any one in claim 1 to 40, it further comprises one or more phosphorothioate or dithioate internucleotide connections.

42. The construct of claim 41 comprising 1 to 15 phosphorothioate or phosphorodithioate internucleotide linkages.

43. The construct of claim 41 or 42, comprising one or more phosphorothioate or phosphorodithioate internucleotide linkages in one or more 5' and / or 3' regions of the first nucleic acid portion of (a), and / or the second nucleic acid portion of (b), and / or the third nucleic acid portion of (c), and / or the fourth nucleic acid portion of (d), and / or the 1 to 8 additional nucleic acid portions as defined in claim 14 or 15, and / or the passenger nucleic acid portion as defined in claim 14 or 15.

44. The construct according to any one of claims 41 to 43, comprising a phosphorothioate or phosphorodithioate internucleotide linkage between at least two adjacent nucleotides of the nucleic acid linking portion as defined in claim 16(iii).

45. The construct of claim 44, comprising a phosphorothioate or phosphorodithioate internucleotide linkage between each adjacent nucleotide present in the nucleic acid linking portion.

46. ​​The construct of any one of claims 41 to 45, comprising phosphorothioate or phosphorodithioate internucleotide linkages connecting: The first nucleic acid portion of (a) and the nucleic acid linker portion as defined in claim 16(iii); and / or (b) and the nucleic acid linker moiety as defined in claim 16(iii); and / or (c) and the nucleic acid linker portion as defined in claim 16(iii); and / or (d) and the nucleic acid linker moiety as defined in claim 16(iii); and / or 1 to 8 additional nucleic acid moieties as defined in claim 14 or 15 and a nucleic acid linking moiety as defined in claim 16(iii); and / or A passenger nucleic acid portion as defined in claim 14 or 15 and a nucleic acid linker portion as defined in claim 16(iii).

47. The construct of any one of claims 1 to 46, wherein at least one nucleotide of at least one of the following is modified: (a) the first nucleic acid portion; and / or (b) the second nucleic acid portion; and / or (c) a third nucleic acid portion; and / or (d) a fourth nucleic acid portion; and / or Where present, 1 to 8 additional nucleic acid moieties as defined in claim 14 or 15; and / or Where present, a passenger nucleic acid moiety as defined in claim 14 or 15; and / or Where present, a nucleic acid linking moiety as defined in claim 16(iii).

48. The construct of claim 47, wherein one of the following one or more odd-numbered nucleotides starting from the 5' region are modified, and / or one of the following one or more even-numbered nucleotides starting from the 5' region are modified, wherein typically the modification of the even-numbered nucleotides is a second modification that is different from the modification of the odd-numbered nucleotides: (a) the first nucleic acid portion; and / or (b) the second nucleic acid portion; and / or (c) a third nucleic acid portion; and / or (d) a fourth nucleic acid portion; and / or Where present, 1 to 8 additional nucleic acid moieties as defined in claim 14 or 15; and / or Where present, a passenger nucleic acid moiety as defined in claim 14 or 15.

49. according to the construct described in claim 47 or 48, wherein one or more odd numbered nucleotides of the third nucleic acid part (c) starting from the 3' region are modified by a modification, and this modification is different from the modification of the odd numbered nucleotides starting from the 5' region of the first nucleic acid part (a); And / or the fourth nucleic acid portion of (d) is modified at one or more odd-numbered nucleotides from the 3' region by a modification that is different from the modification of the odd-numbered nucleotides from the 5' region of the second nucleic acid portion of (b); and / or where present, the passenger nucleic acid portion as defined in claim 14 or 15 is modified at one or more odd-numbered nucleotides from the 3' region by a modification that is different from the modification of the odd-numbered nucleotides from the 5' region of the 1 to 8 additional nucleic acid portions as defined in claim 14 or 15; and / or Where present, one or more nucleotides of the nucleic acid linking portion as defined in claim 16(iii) are modified by a modification that (i) is different from the modification of the adjacent nucleotides in the 3' region of the first nucleic acid portion of (a); and / or (ii) is different from the modification of the adjacent nucleotides in the 3' region of the second nucleic acid portion of (b); and / or is different from the modification of the adjacent nucleotides in the 3' region of 1 to 8 additional nucleic acid portions as defined in claim 14 or 15, where present.

50. The construct according to any one of claims 47 to 49, wherein one or more of the following even-numbered nucleotides starting from the 3' region: (i) the third nucleic acid portion of (c), and / or (ii) the fourth nucleic acid portion of (d), and / or (iii) the passenger nucleic acid portion as defined in claim 14 or 15, where present, are modified by a modification that is different from the modification of the odd-numbered nucleotides starting from the 3' region of these corresponding portions.

51. The construct of any one of claims 47 to 50, wherein at least one or more modified even-numbered nucleotides in (i) the first nucleic acid portion of (a), and / or (ii) the second nucleic acid portion of (b), and / or (iii) the 1 to 8 additional nucleic acid portions as defined in claim 14 or 15, where present, are adjacent to at least one or more differently modified odd-numbered nucleotides in the corresponding portions.

52. The construct of any one of claims 47 to 51 , wherein at least one or more modified even-numbered nucleotides in (i) of the third nucleic acid portion of (c), and / or (ii) of the fourth nucleic acid portion of (d), and / or (iii) of the passenger nucleic acid portion as defined in claim 14 or 15, where present, are adjacent to at least one or more differently modified odd-numbered nucleotides in these respective portions.

53. The construct of any one of claims 47 to 52, wherein multiple adjacent nucleotides in (i) of the first nucleic acid part of (a), and / or (ii) of the second nucleic acid part of (b), and / or (iii) of the 1 to 8 additional nucleic acid parts as defined in claim 14 or 15, where present, are identically modified.

54. The construct of any one of claims 47 to 53, wherein multiple adjacent nucleotides in (i) of the third nucleic acid portion of (c), and / or (ii) of the fourth nucleic acid portion of (d), and / or (iii) of the passenger nucleic acid portion as defined in claim 14 or 15, where present, are identically modified.

55. according to claim 53 or 54 described construct, wherein said multiple adjacent nucleotides through identical modification are 2 to 4 adjacent nucleotides, advantageously are 3 or 4 adjacent nucleotides.

56. The construct of claim 55, wherein the plurality of adjacent identically modified nucleotides are located in the 5' region of (i) the third nucleic acid portion of (c), and / or (ii) the fourth nucleic acid portion of (d), and / or (iii) the passenger nucleic acid portion as defined in claim 14 or 15, where present.

57. The construct of any one of claims 53 to 56, wherein a plurality of adjacent identically modified nucleotides are located in a nucleic acid linking portion as defined in claim 16(iii).

58. The construct of any one of claims 47 to 57, wherein the one or more modified nucleotides of the first nucleic acid portion of (a) do not have the same modification in the corresponding nucleotides of the third nucleic acid portion of (c) of the first double-stranded region; and / or the one or more modified nucleotides of the second nucleic acid portion of (b) do not have the same modification in the corresponding nucleotides of the fourth nucleic acid portion of (d) of the second double-stranded region; and / or where present, the one or more modified nucleotides of 1 to 8 additional nucleic acid portions as defined in claim 14 or 15 do not have the same modification in the corresponding nucleotides of the corresponding passenger nucleic acid portion of the corresponding double-stranded region.

59. The construct of any one of claims 47 to 58, wherein the one or more modified nucleotides of the first nucleic acid part of (a) are shifted by at least one nucleotide relative to an identically modified nucleotide of the third nucleic acid part of (c); and / or the one or more modified nucleotides of the second nucleic acid part of (b) are shifted by at least one nucleotide relative to an identically modified nucleotide of the fourth nucleic acid part of (d); and / or where present, the one or more modified nucleotides of the 1 to 8 additional nucleic acid parts as defined in claim 14 or 15 are shifted by at least one nucleotide relative to an identically modified nucleotide of the passenger nucleic acid part as defined in claim 14 or 15, where present.

60. The construct of any one of claims 47 to 59, wherein the one or more modifications are each independently a sugar, phosphate or base modification.

61. The construct of claim 60, wherein the modification is selected from nucleotides having a 2' modified sugar; conformationally restricted nucleotide (CRN) sugars such as locked nucleic acids (LNA), (S)-constrained ethyl bicyclic nucleic acids and constrained ethyl (cEt), tricyclic DNA; morpholinos, unlocked nucleic acids (UNA), glycol nucleic acids (GNA), D-hexitol nucleic acids (HNA) and cyclohexene nucleic acids (CeNA).

62. The construct of claim 61, wherein the 2'-modified sugar is selected from 2'-O-alkyl modified sugars, 2'-O-methyl modified sugars, 2'-O-methoxyethyl modified sugars, 2'-O-allyl modified sugars, 2'-C-allyl modified sugars, 2'-deoxy modified sugars such as 2'-deoxyribose, 2'-F modified sugars, 2'-arabino-fluoride modified sugars, 2'-O-benzyl modified sugars, 2'-amino modified sugars, and 2'-O-methyl-4-pyridine modified sugars.

63. according to the construct described in any one in claim 60 to 62, wherein base is modified to be any one in abasic nucleotide and the nucleotide that comprises non-natural base.

64. The construct of any one of claims 47 to 63, wherein at least one modification is a 2'-O-methyl modification in the ribose moiety.

65. The construct of any one of claims 47 to 64, wherein at least one modification is a 2'-F modification in the ribose moiety.

66. A construct according to any one of claims 47 to 65, wherein the nucleotide at any of the 2nd and 14th positions downstream of the first nucleotide of the 5' region of the first nucleic acid part of (a); and / or (ii) of the second nucleic acid part of (b); and / or (iii) of the 1 to 8 additional nucleic acid parts as defined in claim 14 or 15, where present, does not contain a 2'-O-methyl modification.

67. The construct of any one of claims 47 to 66, wherein (i) of the third nucleic acid part (c), and / or (ii) of the fourth nucleic acid part (d), and / or (iii) of the passenger nucleic acid part as defined in claim 14 or 15, if present, does not comprise a nucleotide at any of positions 11 to 13 downstream of the first nucleotide of the 5' region of the first nucleic acid part of (a); and / or (ii) of the second nucleic acid part (b); and / or (iii) of the 1 to 8 additional nucleic acid parts as defined in claim 14 or 15, if present, in the ribose moiety of one, two or all three nucleotides corresponding in position, respectively, do not comprise a 2'-O-methyl modification.

68. The construct according to claim 66 or 67, wherein (i) of the first nucleic acid part of (a), and / or (ii) of the second nucleic acid part of (b), and / or (iii) of the 1 to 8 additional nucleic acid parts as defined in claim 14 or 15, if present, comprises a 2'-F modification in the ribose moiety of the nucleotide at any of the 2nd and 14th positions downstream of the first nucleotide.

69. The construct according to any one of claims 66 to 68, wherein (i) of the third nucleic acid part (c), and / or (ii) of the fourth nucleic acid part (d), and / or (iii) of the passenger nucleic acid part as defined in claim 14 or 15, if present, comprises a nucleotide at any of positions 11 to 13 downstream of the first nucleotide of the 5' region of the first nucleic acid part of (a); and / or (ii) of the second nucleic acid part (b); and / or (iii) of 1 to 8 additional nucleic acid parts as defined in claim 14 or 15, if present, comprises a 2'-F modification in the ribose moiety of one, two or all three nucleotides at the corresponding position, respectively.

70. The construct according to any one of claims 65 to 69, wherein all remaining nucleotides comprise a 2'-O-methyl modification or a 2'-F modification in the ribose moiety, advantageously with the exception of the unmodified nucleotides according to claim 5.

71. The construct of claim 70, wherein the remaining nucleotides comprise a 2'-O-methyl modification in the ribose moiety.

72. The construct according to claim 70 or 71, wherein the one or more, advantageously one, unmodified nucleotide represents any one of the nucleotides of the nucleic acid linking portion as defined in claim 16(iii), advantageously a nucleotide of the nucleic acid linking portion as defined in claim 16(iii) that is adjacent to (i) of the third nucleic acid portion of (c), and / or (ii) of the fourth nucleic acid portion of (d), and / or (iii) of the passenger nucleic acid portion as defined in claim 14 or 15, where present.

73. A construct according to any preceding claim, wherein (a) the sequence of the first nucleic acid portion is selected from the first 19 nucleotides of the oligonucleotide of the group consisting of SEQ ID NOs: 1505-1758, or is represented by the following nucleic acid sequence: 5'[Phosphate]mU#fU#mG fA mA fU mG fA mA fA mC fG mAfC mU#fU#mC#fU#rC (SEQ ID NO: 2075); or 5'[Phosphate]mU#fU#mG fC mC fA mC fA mG fA mC fUmC fA mG fA#mG#mA#rG (SEQ ID NO: 2076); (b) the second nucleic acid portion is selected from the group consisting of SEQ ID NOs: 1759-1858, or represented by the following nucleic acid sequence: 5'[Phosphate]mG#fA#mU fA mG fU mU fG mU fA mA fA mC fA mG#fU#fU#fC#rC (SEQ ID NO: 2077); or 5'[Phosphate]mU#fU#mA fC mA fA mC fA mG fA mA fU mA fU mG#fG#mU#fA#rU (SEQ ID NO: 2078); (c) the fourth nucleic acid portion is selected from the group consisting of SEQ ID NOs: 1859-1958, or is represented by the following nucleic acid sequence: fC#mU#fG mU fU mU fA mC fA mA fC mU mA#mU#mC#[3XGalNAc] (SEQ ID NO: 2079); or fC#mA#fUmA fU mU fC mU fG mU fU mG mU#mA#mA#[3XGalNAC] (SEQ ID NO: 2090); and / or (d) the third nucleic acid portion is selected from the group consisting of: (i) the last 15 nucleotides of each of sequence numbers 1505 to 1756, (ii) the last 14 nucleotides of sequence number 1757, and (iii) the last 11 nucleotides of sequence number 1758, or is represented by the following nucleic acid sequence: fC mU fG mA fG mU fC mU fG mU fG mG mC#mA#mA#[3XGalNAc] (SEQ ID NO: 2080); or fC mU fG mA fG mU fC mU fG mU fG mG mC#mA#mA# (SEQ ID NO: 2081).

74. The construct of any preceding claim, wherein the construct comprises two chains, wherein the nucleotide base sequence of the first chain is represented by Construct ID No. B106-C5-30, B106-C5-37, B13-C5-30 or B13-C5-37, preferably selected from the group consisting of SEQ ID Nos. 2059-2066, and the nucleotide base sequence of the second chain is represented by the corresponding Construct ID No. B106-C5-30, B106-C5-37, B13-C5-30 or B13-C5-37, preferably selected from the group consisting of SEQ ID Nos. 2067-2074.

75. The construct of claim 74, wherein the first strand has the sequence: 5'[Phosphoric acid]mU#fU#mG fA mA fU mG fA mA fA mC fG mA fC mU#fU#mC#fU#rC fC#mU#fGmU fU mU fA mC fA mA fC mU mA#mU#mC#[3XGalNAC](Serial No. 2082); 5'[Phosphoric acid]mU#fU#mGfA mA fU mG fA mA fA mC fG mA fC mU#fU#mC#fU#rC fC#mA#fU mA fU mU fC mU fG mUfU mG mU#mA#mA#[3XGalNAc](Serial No. 2083); 5'[Phosphoric Acid]mU#fU#mG fC mC fA mC fA mG fAmC fU mC fA mG fA#mG#mA#rG fC#mU#fG mU fU mU fA mC fA mA fC mU mA#mU#mC#[3XGalNAc](serial number 2084); or 5'[Phosphate]mU#fU#mG fC mC fA mC fA mG fA mC fU mC fA mG fA#mG#mA#rG fC#mA#fUmA fU mU fC mU fG mU fU mG mU#mA#mA#[3XGalNAc] (SEQ ID NO: 2085); and / or wherein the second strand has the following sequence: 5'[Phosphoric acid]mG#fA#mU fA mG fU mU fG mU fA mA fA mC fA mG#fU#fU#fC#rC fA#mG#fUmC fG mU fU mU fC mA fU mU mC#mA#mA#[3XGalNAc](Serial No. 2086); 5'[Phosphoric acid]mU#fU#mAfC mA fA mC fA mG fA mA fU mA fU mG#fG#mU#fA#rU fA#mG#fU mC fG mU fU mU fC mAfU mU mC#mA#mA#[3XGalNAc](Serial No. 2087); 5'[Phosphoric Acid]mG#fA#mU fA mG fU mU fG mU fAmA fA mC fA mG#fU#fU#fC#rC fC mU fG mA fG mU fC mU fG mU fG mG mC#mA#mA#[3XGalNAc] (SEQ ID NO: 2088); or 5'[Phosphate] mU#fU#mA fC mA fA mC fA mG fA mA fU mA fUmG#fG#mU#fA#rU fC mU fG mA fG mU fC mU fG mU fG mG mC#mA#mA#[3XGalNAc] (SEQ ID NO: 2089), wherein Phos represents phosphate; [mN], N is any nucleoside, represents 2'-OMe; [fN], N is any nucleoside, represents 2'-F; [rA], N is any nucleoside, represents 2'-OH; [#] represents a phosphorothioate linking two adjacent nucleosides; and [3XGalNAc] represents the ligand shown below: And 5Phos is optional.

76. according to the construct described in any one in claim 73 to 75, wherein said construct is selected from the group that construct ID number is B106-C5-30, B106-C5-37, B13-C5-30 and B13-C5-37 (sequence ID number 2059-2074), and wherein said construct is preferably construct ID number B106-C5-30 (sequence ID number 2067-2068).

77. The construct of any one of claims 73 to 76, wherein the 3' terminal positions of the first and third nucleic acid portions are substituted with unmodified nucleotides.

78. The construct of any one of claims 1 to 77, comprising at least one vinylphosphonate modification, e.g., at least one vinylphosphonate modification in the 5' region of the first nucleic acid portion of (a); and / or at least one vinylphosphonate modification in the second nucleic acid portion of (b); and / or (iii), where present, at least one vinylphosphonate modification in 1 to 8 additional nucleic acid portions as defined in claim 14 or 15.

79. The construct of any one of claims 1 to 78, wherein (a) the first nucleic acid portion; and / or (b) the second nucleic acid portion; and / or (c) a third nucleic acid portion; and / or (d) a fourth nucleic acid portion; and / or where present, 1 to 8 additional nucleic acid moieties as defined in claim 14 or 15; and / or where present, a passenger nucleic acid moiety as defined in claim 14 or 15; One or more nucleotides in the sequence is an inverted nucleotide and is linked to an adjacent nucleotide via its 3' carbon and the 3' carbon of the adjacent nucleotide, and / or the inverted nucleotide is linked to an adjacent nucleotide via its 5' carbon and the 5' carbon of the adjacent nucleotide.

80. construct according to claim 79, wherein the reverse nucleotide is connected to the adjacent nucleotide via a phosphate group through a phosphodiester bond; or is connected to the adjacent nucleotide through a phosphorothioate group; or is connected to the adjacent nucleotide through a phosphorodithioate group.

81. The construct of any one of claims 1 to 80 which is blunt-ended.

82. The construct of any one of claims 1 to 80, wherein (a) the first nucleic acid portion; and / or (b) the second nucleic acid portion; and / or (c) a third nucleic acid portion; and / or (d) a fourth nucleic acid portion; and / or where present, 1 to 8 additional nucleic acid moieties as defined in claim 14 or 15; and / or where present, a passenger nucleic acid moiety as defined in claim 14 or 15; Having a protruding end.

83. The construct of any one of claims 1 to 82, wherein the target RNA is an mRNA or other RNA molecule.

84. according to the construct described in any one in claim 1 to 83, the total length of wherein said construct is 30 to 35 nucleosides, is preferably 33 or 34 nucleosides.

85. A composition comprising the nucleic acid construct according to any one of claims 1 to 84 and a physiologically acceptable excipient.

86. A pharmaceutical composition comprising the nucleic acid construct according to any one of claims 1 to 84.

87. The pharmaceutical composition of claim 86, further comprising a pharmaceutically acceptable excipient, diluent, antioxidant and / or preservative.

88. A pharmaceutical composition according to claim 86 or 87, wherein the construct according to any one of claims 1 to 84 is the sole pharmaceutically active agent.

89. The pharmaceutical composition of claim 86 or 87, wherein the pharmaceutical composition further comprises one or more other pharmaceutically active agents.

90. The pharmaceutical composition according to claim 89, wherein the additional pharmaceutically active agent is an agent that modulates the innate and / or adaptive immune system, such as another oligomeric compound directed against an immune system target, and / or a compound directed against other components of the immune system, such as components of the proximal complement pathway, in particular the lectin pathway: a MASP-2 targeting compound and / or a C3 targeting compound and / or a compound selected from sutelimumab, nesoprizumab, pegoluzumab AMY-102, IONIS-FB-LRx-LPN023, lapalizumab, Mini-FH / AMY-201 MicroCept and GLG561, or a combination thereof.

91. The pharmaceutical composition of claim 89 or 90, wherein the nucleic acid construct and the other pharmaceutically active agent are administered simultaneously or in any order.

92. A nucleic acid construct according to any one of claims 1 to 84 for use in human or veterinary medicine or therapy.

93. according to any one of claims 1 to 84 nucleic acid constructs, for use in the method for treating, improving and / or preventing disease or illness.

94. The compound and / or construct for use according to claim 83, wherein the disease or condition is a disease or condition associated with CFB and / or C5, or a disease or condition requiring reduction of CFB and / or C5 expression.

95. The construct for use according to claim 94, wherein the disease or condition is selected from a blood disease, such as paroxysmal nocturnal hemoglobinuria (PNH); a kidney disease, such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephritis, dense deposit disease, immune complex membranoproliferative glomerulonephritis, IgA nephropathy; a nervous system disease, such as myasthenia gravis (GMG), relapsing neuromyelitis optica (NMO), amyotrophic lateral sclerosis (ALS); an ophthalmological disease, such as age-related macular degeneration, geographic atrophy; a neoplastic disease; a rheumatic disease; and a transplant-related disease, wherein the disease or condition is preferably PNH.

96. A method of treating a disease or condition comprising administering a nucleic acid construct according to any one of claims 1 to 84 to an individual in need of treatment.

97. The method of claim 96, wherein the nucleic acid construct is administered to the individual subcutaneously or intravenously.

98. The nucleic acid construct according to any one of claims 1 to 84 is used in research as a gene function analysis tool.

99. The purposes of the nucleic acid construct according to any one of claims 1 to 84 in the preparation of a medicine for the treatment of a disease or illness.

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