Oligonucleotide for the Treatment of Muscular Dystrophy Patients

• US 20150191725A1
• Filed: 12/23/2014
• Published: 07/09/2015
• Est. Priority Date: 07/03/2012
• Status: Abandoned Application

• Current Assignee: BioMarin Technologies B.V.
• Original Assignee: Prosensa Technologies B.V.
• Inventors: van Deutekom, Judith Christina Theodora
• Application Number:
  US14/581,633
• Publication Number:
  US 20150191725A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/31 of the backbone
• CPC Class Codes: C12N 2310/32 of the sugar
• CPC Class Codes: C12N 2310/33 of the base
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

The invention relates to an oligonucleotide and to a pharmaceutical composition comprising said oligonucleotide. This oligonucleotide is able to bind to a region of a first exon from a dystrophin pre-mRNA and to a region of a second exon within the same pre-mRNA, wherein said region of said second exon has at least 50% identity with said region of said first exon, wherein said oligonucleotide is suitable for the skipping of said first and second exons of said pre-mRNA, and preferably the entire stretch of exons in between.

Claims

1. A method for designing an oligonucleotide for producing an at least partially functional protein, wherein said method comprises the following steps:

(a) identifying an in-frame combination of a first and a second exon in a same pre-mRNA, wherein a region of said second exon has at least 50% identity with a region of said first exon;

(b) designing an oligonucleotide that is functional to bind to said region of said first exon and said region of said second exon, and

(c) wherein said binding results in the skipping of said first and said second exon.

2. A method according to claim 1, wherein the oligonucleotide is functional to bind to a portion of a region within a first exon and a portion of a region within a second region.

3. A method according to claim 1, wherein the binding of said oligonucleotide is functional to interfere with at least one splicing regulatory sequence in said regions of said first and second exons and/or with the secondary structure encompassing at least said first and/or said second exon in said pre-mRNA.

4. A method according to claim 3, wherein said splicing regulatory sequence comprises an exonic splicing enhancer (ESE), an exon recognition sequence (ERS) and/or a binding site for a serine-arginine (SR) protein.

5. A method according to claim to claim 1, wherein said oligonucleotide is not functional to bind to non-exon sequences.

6. A method according to claim to claim 1, wherein at least a third exon is present between said first and second exons and wherein the oligonucleotide is functional to induce skipping of said first and said at least a third exon.

7. A method according to claim 6, wherein at least a third and a fourth exon are present between said first and second exons, and wherein said oligonucleotide is functional to skip said first and said at least a third and a fourth exon.

8. A method according to claim 1, wherein said oligonucleotide comprises 10 to 40 nucleotides.

9. A method according to any one of claim 1, wherein said oligonucleotide comprises at least one modification compared to a naturally occurring ribonucleotide- or deoxyribonucleotide-based oligonucleotide, more preferably

(a) at least one base modification, preferably selected from 2-thiouracil, 2-thiothymine, 5-methylcytosine, 5-methyluracil, thymine, 2,6-diaminopurine, more preferably selected from 5-methylpyrimidine and 2,6-diaminopurine;

and/or

(b) at least one sugar modification, preferably selected from 2′

-O-methyl, 2′

-O-(2-methoxyl)ethyl, 2′

-O-deoxy (DNA), 2′

-F, morpholino, a bridged nucleotide or BNA, or the oligonucleotide comprises both bridged nucleotides and 2′

-deoxy modified nucleotides (BNA/DNA mixmers), more preferably the sugar modification is 2′

-O-methyl; and

/or

(c) at least one backbone modification, preferably selected from phosphorothioate or phosphorodiamidate, more preferably the backbone modification is phosphorothioate.

10. A method according to claim 1, wherein said oligonucleotide comprises one or more conjugate groups, optionally protected, selected from the group consisting of peptides, proteins, carbohydrates, drugs, targeting moieties, uptake enhancing moieties, solubility enhancing moieties, pharmacodynamics enhancing moieties, pharmacokinetics enhancing moieties, polymers, ethylene glycol derivatives, vitamins, lipids, polyfluoroalkyl moieties, steroids, cholesterol, fluorescent moieties, reporter molecules, radioactively labeled moieties and combinations thereof, attached directly or via a divalent or multivalent linker, to a terminal or internal residue.

11. A method according to claim 1, wherein said first and second exon are selected from exons 10, 18, 30, 8, 9, 11, 13, 19, 22, 23, 34, 40, 42, 44, 45, 47, 51, 53, 55, 56, 57 or 60 of the dystrophin pre-mRNA.

12. A method according to claim 11, wherein said first exon is exon 10 and said second exon is exon 12, 13, 14, 15, 16, 18, 20, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 46, 47, 48, 49, 51, 53, 55, 57, 59 or 60.

13. A method according to claim 12, wherein the oligonucleotide is functional to induce skipping of dystrophin exons 10 to 18, exons 10 to 30, exons 10 to 42, exons 10 to 47, exons 10 to 57, exons 10 to 60, exons 8 to 19, exons 9 to 22, exons 9 to 30, exons 11 to 23, exons 13 to 30, exons 23 to 42, exons 34 to 53, exons 40 to 53, exons 44 to 56, exons 45 to 51, exons 45 to 53, exons 45 to 55, exons 45 to 60, and/or exons 56 to 60.

14. A method of preventing, delaying, ameliorating and/or treating a disease in a subject, comprising

administering a formulation comprising an oligonucleotide which is functional to bind to a region within a first exon and a a region within a second exon, wherein said region of said second exon has at least 50% identity with said region of said first exon,

wherein said oligonucleotide is not capable of binding to non-exon sequences,

wherein said first and said second exons are within a same pre-mRNA in said subject,

wherein said binding of said oligonucleotide is functional to interfere with at least one splicing regulatory sequence in said regions of said first and second exons and/or with the secondary structure encompassing at least said first and/or said second exon in said pre-mRNA,

wherein said splicing regulatory sequence comprises an exonic splicing enhancer (ESE), an exon recognition sequence (ERS) and/or a binding site for a serine-arginine (SR) protein, or and/or

wherein said binding of said oligonucleotide results in the skipping of said first exon and of said second exon, preferably in the skipping of a multi-exon stretch starting with said first exon and encompassing one or more exons present between said first and said second exons and at the most in the skipping of the entire stretch of exons in between said first and said second exons,

wherein an in-frame transcript is obtained allowing production of an at least partially functional protein and

wherein said oligonucleotide sequence is not part of a formulation comprising a combination of two or more distinct oligonucleotide sequences linked with one or more linker(s).

15. The method of claim 14, wherein said oligonucleotide comprises the base sequence as defined in any one of SEQ ID NO:

1679, 1688, 1671 to 1678, 1680 to 1687, 1689 to 1741 or 1778 to 1891, and having a length, which is defined by the number of nucleotides present in said base sequence or which is 1, 2, 3, 4, or 5 nucleotides longer.

16. The method of claim 15, wherein said oligonucleotide comprises the base sequence as defined in any one of SEQ ID NO:

1679, 1688, 1671 to 1678, 1680 to 1687, 1689 to 1741 wherein said part corresponds to the base sequence as defined in any of said sequences with 1, 2, 3, 4 or 5 nucleotides less than defined in said base sequence.

17. The method of claim 16, wherein said oligonucleotide comprises:

(a) the base sequence as defined in any one of SEQ ID NO;

1679 to 1681, 1778, 1812, 1813, 1884 to 1886, 1890, or 1891, and having a length of 25, 26, 27, 28, 29 or 30 nucleotides or SEQ ID NO;

1814 and having a length of 26, 27, 28, 29 or 30 nucleotides;

or

(b) the base sequence as defined in SEQ ID NO;

1688, 1689, or 1839 to 1844, and having a length of 26, 27, 28, 29 or 30 nucleotides;

or

(c) the base sequence as defined in SEQ ID NO;

1673 or 1674 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides;

or

(d) the base sequence as defined in SEQ ID NO;

1675 or 1676 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides;

or

(e) the base sequence as defined in SEQ ID NO;

1677 or 1678 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides;

or

(f) the base sequence as defined in any one of SEQ ID NO;

1684 to 1686 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides;

or

(g) the base sequence as defined in any one of SEQ ID NO;

1704 to 1706 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(h) the base sequence as defined in any one of SEQ ID NO;

1707 to 1709 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides;

or

(i) the base sequence as defined in any one of SEQ ID NO;

1710, 1713 to 1717 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides or

(j) the base sequence as defined in any one of SEQ ID NO;

1815 to 1819 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(k) the base sequence as defined in any one of SEQ ID NO;

1820, 1824, and having a length of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(l) the base sequence as defined in any one of SEQ ID NO;

1826, 1780, 1782, 1832 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(m) base sequence as defined in any one of SEQ ID NO;

1821, 1825 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(n) base sequence as defined in any one of SEQ ID NO;

1822 and having a length of 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(o) base sequence as defined in any one of SEQ ID NO;

1823, 1781, 1829, 1830, 1831 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(p) base sequence as defined in any one of SEQ ID NO;

1783, 1833, 1834, 1835 and having a length of 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(q) base sequence as defined in any one of SEQ ID NO;

1887 and and have a length of 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(r) base sequence as defined in any one of SEQ ID NO;

1888 or 1889 and and have a length of 26, 27, 28, 29 or 30 nucleotides, or

(s) base sequence as defined in SEQ ID NO;

1827 and have a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(t) base sequence as defined in SEQ ID NO;

1828 and have a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(u) base sequence as defined in any one of SEQ ID NO;

1784, 1836 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(v) base sequence as defined in any one of SEQ ID NO;

1786, 1838 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(w) base sequence as defined in any one of SEQ ID NO;

1780 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(x) base sequence as defined in any one of SEQ ID NO;

1785, 1837 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(y) base sequence as defined in any one of SEQ ID NO;

1845, 1846, 1847, 1848 and having a length of 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(z) base sequence as defined in any one of SEQ ID NO;

1849, 1850 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(a1) base sequence as defined in any one of SEQ ID NO;

1787, 1851 and having a length of 26, 27, 28, 29 or 30 nucleotides, or

(b1) base sequence as defined in any one of SEQ ID NO;

1788, 1852, 1789, 1853 and having a length of 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(c1) base sequence as defined in any one of SEQ ID NO;

1790, 1854, 1792, 1855 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(d1) base sequence as defined in any one of SEQ ID NO;

1794, 1861, 1795, 1862 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(e1) base sequence as defined in any one of SEQ ID NO;

1796, 1863, 1797, 1864 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(f1) base sequence as defined in any one of SEQ ID NO;

1798, 1865, 1799, 1866 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(g1) base sequence as defined in any one of SEQ ID NO;

1808, 1867, 1809, 1868, 1810, 1869, 1858, 1873 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(h1) base sequence as defined in any one of SEQ ID NO;

1811, 1870, 1859, 1874 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(i1) base sequence as defined in any one of SEQ ID NO;

1856, 1871, 1860, 1875 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(j1) base sequence as defined in any one of SEQ ID NO;

1857, 1872 and having a length of 26, 27, 28, 29 or 30 nucleotides, or

(k1) base sequence as defined in any one of SEQ ID NO;

1800, 1876, 1801, 1877 and having a length of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(l1) base sequence as defined in any one of SEQ ID NO;

1802, 1878, 1803, 1879 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(m1) base sequence as defined in any one of SEQ ID NO;

1804, 1880 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(n1) base sequence as defined in any one of SEQ ID NO;

1805, 1881 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(o1) base sequence as defined in any one of SEQ ID NO;

1806, 1882, 1807, 1883 and having a length of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides.

18. A composition comprising an oligonucleotide, and optionally further comprising a pharmaceutically acceptable carrier, diluent, excipient, salt, adjuvant and/or solvent, said oligonucleotide comprising a sequence complementary a first exon, wherein a region of said second exon has at least 50% identity with said region of said first exon, and each of said first and said second exons are independently selected from the group consisting of:

exons 10, 18, 30, 8, 9, 11, 13, 19, 22, 23, 34, 40, 42, 44, 45, 47, 51, 53, 55, 56, 57 and 60 of the dystrophin pre-mRNA, wherein said first and said second exons are not the same exon, wherein said oligonucleotide comprises a modification selected from the group consisting of;

at least one backbone modification, at least one base modification, at least one sugar modification, and a moiety which is conjugated to said oligonucleotide, wherein said oligonucleotide sequence is not part of a formulation comprising cocktail or a combination of two or more distinct oligonucleotide sequences possibly linked with one or more linker(s).

19. The composition of claim 18, wherein said oligonucleotide comprises said sequence complementary to said first exon, and said first exon is exon 10, and said second exon is exon selected from the group consisting of:

12, 13, 14, 15, 16, 18, 20, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 46, 47, 48, 49, 51, 53, 55, 57, 59 and 60.

20. The composition of claim 19, wherein said oligonucleotide is functional to induce skipping of dystrophin exons selected from the group consisting of:

exons 10 to 18;

exons 10 to 30;

exons 10 to 42;

exons 10 to 47;

exons 10 to 57;

exons 10 to 60;

exons 8 to 19;

exons 9 to 22;

exons 9 to 30;

exons 11 to 23;

exons 13 to 30;

exons 23 to 42;

exons 34 to 53;

exons 40 to 53;

exons 44 to 56;

exons 45 to 51;

exons 45 to 53;

exons 45 to 55;

exons 45 to 60; and

exons 56 to 60.

21. The oligonucleotide of claim 18, wherein said oligonucleotide consists of 10-40 bases, inclusive.

22. A composition comprising an oligonucleotide, wherein said oligonucleotide comprises the base sequence as defined in any one of SEQ ID NO selected from the group consisting of:

SEQ ID NO;

1679, 1688, 1671 to 1678, 1680 to 1687, 1689 to 1741 and 1778 to 1891, and having a length, which is defined by the number of nucleotides present in said base sequence or which is 1, 2, 3, 4, or 5 nucleotides longer.

23. The composition of claim 22, wherein said oligonucleotides comprises:

(a) the base sequence as defined in any one of SEQ ID NO;

1679 to 1681, 1778, 1812, 1813, 1884 to 1886, 1890, or 1891, and having a length of 25, 26, 27, 28, 29 or 30 nucleotides or SEQ ID NO;

1814 and having a length of 26, 27, 28, 29 or 30 nucleotides;

or

(b) the base sequence as defined in SEQ ID NO;

1688, 1689, or 1839 to 1844, and having a length of 26, 27, 28, 29 or 30 nucleotides;

or

(c) the base sequence as defined in SEQ ID NO;

1673 or 1674 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides;

or

(d) the base sequence as defined in SEQ ID NO;

1675 or 1676 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides;

or

(e) the base sequence as defined in SEQ ID NO;

1677 or 1678 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides;

or

(f) the base sequence as defined in any one of SEQ ID NO;

1684 to 1686 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides;

or

(g) the base sequence as defined in any one of SEQ ID NO;

1704 to 1706 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(h) the base sequence as defined in any one of SEQ ID NO;

1707 to 1709 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides;

or

(i) the base sequence as defined in any one of SEQ ID NO;

1710, 1713 to 1717 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides or

(j) the base sequence as defined in any one of SEQ ID NO;

1815 to 1819 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(k) the base sequence as defined in any one of SEQ ID NO;

1820, 1824, and having a length of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(l) the base sequence as defined in any one of SEQ ID NO;

1826, 1780, 1782, 1832 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(m) base sequence as defined in any one of SEQ ID NO;

1821, 1825 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(n) base sequence as defined in any one of SEQ ID NO;

1822 and having a length of 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(o) base sequence as defined in any one of SEQ ID NO;

1823, 1781, 1829, 1830, 1831 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(p) base sequence as defined in any one of SEQ ID NO;

1783, 1833, 1834, 1835 and having a length of 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(q) base sequence as defined in any one of SEQ ID NO;

1887 and and have a length of 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(r) base sequence as defined in any one of SEQ ID NO;

1888 or 1889 and and have a length of 26, 27, 28, 29 or 30 nucleotides, or

(s) base sequence as defined in SEQ ID NO;

1827 and have a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(t) base sequence as defined in SEQ ID NO;

1828 and have a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(u) base sequence as defined in any one of SEQ ID NO;

1784, 1836 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(v) base sequence as defined in any one of SEQ ID NO;

1786, 1838 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(w) base sequence as defined in any one of SEQ ID NO;

1780 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(x) base sequence as defined in any one of SEQ ID NO;

1785, 1837 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(y) base sequence as defined in any one of SEQ ID NO;

1845, 1846, 1847, 1848 and having a length of 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(z) base sequence as defined in any one of SEQ ID NO;

1849, 1850 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(a1) base sequence as defined in any one of SEQ ID NO;

1787, 1851 and having a length of 26, 27, 28, 29 or 30 nucleotides, or

(b1) base sequence as defined in any one of SEQ ID NO;

1788, 1852, 1789, 1853 and having a length of 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(c1) base sequence as defined in any one of SEQ ID NO;

1790, 1854, 1792, 1855 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(d1) base sequence as defined in any one of SEQ ID NO;

1794, 1861, 1795, 1862 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(e1) base sequence as defined in any one of SEQ ID NO;

1796, 1863, 1797, 1864 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(f1) base sequence as defined in any one of SEQ ID NO;

1798, 1865, 1799, 1866 and having a length of 25, 26, 27, 28, 29 or 30 nucleotides, or

(g1) base sequence as defined in any one of SEQ ID NO;

1808, 1867, 1809, 1868, 1810, 1869, 1858, 1873 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(h1) base sequence as defined in any one of SEQ ID NO;

1811, 1870, 1859, 1874 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(i1) base sequence as defined in any one of SEQ ID NO;

1856, 1871, 1860, 1875 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(j1) base sequence as defined in any one of SEQ ID NO;

1857, 1872 and having a length of 26, 27, 28, 29 or 30 nucleotides, or

(k1) base sequence as defined in any one of SEQ ID NO;

1800, 1876, 1801, 1877 and having a length of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(l1) base sequence as defined in any one of SEQ ID NO;

1802, 1878, 1803, 1879 and having a length of 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(m1) base sequence as defined in any one of SEQ ID NO;

1804, 1880 and having a length of 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(n1) base sequence as defined in any one of SEQ ID NO;

1805, 1881 and having a length of 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides, or

(o1) base sequence as defined in any one of SEQ ID NO;

1806, 1882, 1807, 1883 and having a length of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides; and

wherein said oligonucleotide comprises a modification selected from the group consisting of;

at least one backbone modification, at least one base modification, at least one sugar modification, and a moiety which is conjugated to said oligonucleotide.