Inhibitors of expression and / or function

Abstract

The present invention relates to inhibitors, and compositions containing inhibitors, and uses of the same in the treatment or prevention of a disease related to HFrEF, such as an ischaemic heart diseases.

Description

[0001] INHIBITORS OF EXPRESSION AND / OR FUNCTION FIELD The present invention provides inhibitors, such as nucleic acid compounds, such as siRNA, suitable for therapeutic use. Additionally, the present invention provides methods of making these compounds, as well as methods of using such compounds for the treatment of various diseases and conditions. BACKGROUND OF THE INVENTION Inhibitors, such as oligonucleoside / oligonucleotide compounds which are inhibitors of gene expression and / or expression or function of other targets such as LNCRNAs, can have important therapeutic applications in medicine. Oligonucleotides / oligonucleosides can be used to silence genes that are responsible for a particular disease. Gene-silencing prevents formation of a protein by inhibiting translation. Importantly, gene-silencing agents are a promising alternative to traditional small, organic compounds that inhibit the function of the protein linked to the disease. siRNA, antisense RNA, and micro-RNA are oligonucleoside / oligonucleotides that prevent the formation of proteins by gene-silencing. A number of modified siRNA compounds in particular have been developed in the last two decades for diagnostic and therapeutic purposes, including siRNA / RNAi therapeutic agents for the treatment of various diseases including central-nervous-system diseases, inflammatory diseases, metabolic disorders, oncology, infectious diseases, and ocular diseases. The present invention relates to inhibitors, such oligomers e.g. nucleic acids, e.g. oligonucleoside / oligonucleotide compounds, and their use in the treatment and / or prevention of disease. The present invention relates to nucleic acid compounds that inhibit the expression of the gene NR3C2, for use in the treatment and / or prevention of disease. The NR3C2 gene is located on chromosome 4 at q31.23 and encodes the nuclear receptor subfamily 3 group C member 2 protein, also known as mineralocorticoid receptor. The protein functions as a ligand-dependent transcription factor that mediates the effects of aldosterone on a variety of target tissues, including the distal parts of the nephron, the distal colon, the cardiovascular and central nervous systems, and brown adipose tissue. In addition, the variety of target tissues includes heart and liver. STATEMENTS OF INVENTION The invention is defined as in the claims and relates to, inter alia: In one aspect, the invention relates to an inhibitor of expression and / or function of NR3C2, wherein said inhibitor is conjugated to one or more ligand moieties. In a further aspect, the invention relates to an inhibitor according to the invention, wherein said inhibitor is an siRNA oligomer. In another aspect, the invention relates to an inhibitor of expression and / or function of NR3C2, wherein said inhibitor is an siRNA oligomer. In a further aspect, the invention relates to an inhibitor according to the invention, wherein said inhibitor comprises an siRNA oligomer conjugated to one or more ligand moieties. In a further aspect, the invention relates to an inhibitor according to the invention, for use in prevention or treatment of an ischaemic heart disease, such as myocardial infarction. In a particular aspect of the invention, the inhibitor according to the invention is for use in the treatment of an ischaemic heart disease, such as myocardial infarction, whereby the inhibitor alleviates symptoms of an ischaemic heart disease, in particular myocardial infarction, more particularly an acute myocardial infarction. Within the present invention, the inhibitor of the invention may be administered after myocardial infarction, in particular for cardioprotection, for reducing infarct size and / or reducing reperfusion arrhythmias. In a further aspect, the invention relates to an inhibitor according to the invention, wherein said one or more ligand moieties comprise one or more GalNAc ligands or comprise one or more GalNAc ligand derivatives. In a further aspect, the invention relates to an inhibitor for use according to the invention, wherein said one or more ligand moieties comprise one or more GalNAc ligand derivatives. In a further aspect, the invention relates to an inhibitor for use according to the invention, wherein the target of the inhibitor is NR3C2. In a further aspect (Aspect A), there is provided a nucleic acid for inhibiting expression of NR3C2, comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand sequences as listed in Table 2. In a further aspect (Aspect B), there is provided a nucleic acid for inhibiting expression of NR3C2, comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand modified sequences as listed in Table 3. In a further aspect, there is provided a nucleic acid as described herein, wherein the first strand comprises nucleosides 2-18 of any one of the sequences according to the above Aspect A and Aspect B of the present invention. In a further aspect, there is provided a nucleic acid according to the above Aspect A of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand sequences as listed in Table 2, and wherein the second strand has a region of at least 85% complementarity over the 17 contiguous nucleosides to the first strand. In a further aspect, there is provided a nucleic acid according to the above Aspect A of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand sequences as listed in Table 2, and wherein the duplex region comprises at least 14, 15, 16 or 17 complementary base pairs. In a further aspect, there is provided a nucleic acid according to the above Aspect B of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand modified sequences as listed in Table 4, and wherein the second strand has a region of at least 85% complementarity over the 17 contiguous nucleosides to the first strand. In a further aspect, there is provided a nucleic acid according to the above further Aspect B of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand modified sequences as listed in Table 4, and wherein the duplex region comprises at least 14, 15, 16 or 17 complementary base pairs. In a further aspect, there is provided a nucleic acid according to the above Aspect A of the present invention, wherein the first strand comprises any one of the first strand sequences as listed in Table 2. In a further aspect, there is provided a nucleic acid according to the above Aspect B of the present invention, wherein the first strand comprises any one of the first strand modified sequences as listed in Table 3. In a further aspect, there is provided a nucleic acid according to the above Aspect A of the present invention, wherein the second strand comprises any one of the second strand sequences as listed in Table 2. In a further aspect, there is provided a nucleic acid according to the above Aspect B of the present invention, wherein the second strand comprises any one of the second strand modified sequences as listed in Table 4. In a further aspect, there is provided a conjugate for inhibiting expression of NR3C2 target gene in a cell, said conjugate comprising a nucleic acid as disclosed herein and one or more ligand moieties. In a further aspect, there is provided a pharmaceutical composition comprising a nucleic acid as disclosed herein, in combination with a pharmaceutically acceptable excipient or carrier. In a further aspect, there is provided a nucleic acid or pharmaceutical composition, for use in therapy. In a further aspect, there is provided a nucleic acid or pharmaceutical composition, for use in the treatment of an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof. In a further aspect, there is provided a nucleic acid or pharmaceutical composition as disclosed herein, wherein the nucleic acid or the pharmaceutical composition is administered after myocardial infarction. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, which is an siRNA oligomer having a first and a second strand wherein: i) the first strand of the siRNA has a length in the range of 15 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 23 or 25; even more preferably 23; and / or ii) the second strand of the siRNA has a length in the range of 15 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 21 nucleosides. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the second sense strand further comprises one or more abasic nucleosides in a terminal region of the second strand, and wherein said abasic nucleoside(s) is / are connected to an adjacent nucleoside through a reversed internucleoside linkage. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the second strand comprises: i) 2, or more than 2, abasic nucleosides in a terminal region of the second strand; and / or ii) 2, or more than 2, abasic nucleosides in either the 5’ or 3’ terminal region of the second strand; and / or iii) 2, or more than 2, abasic nucleosides in either the 5’ or 3’ terminal region of the second strand, wherein the abasic nucleosides are present in an overhang as herein described; and / or iv) 2, or more than 2, consecutive abasic nucleosides in a terminal region of the second strand, wherein preferably one such abasic nucleoside is a terminal nucleoside; and / or v) 2, or more than 2, consecutive abasic nucleosides in either the 5’ or 3’ terminal region of the second strand, wherein preferably one such abasic nucleoside is a terminal nucleoside in either the 5’ or 3’ terminal region of the second strand; and / or vi) a reversed internucleoside linkage connects at least one abasic nucleoside to an adjacent basic nucleoside in a terminal region of the second strand; and / or vii) a reversed internucleoside linkage connects at least one abasic nucleoside to an adjacent basic nucleoside in either the 5’ or 3’ terminal region of the second strand; and / or viii) an abasic nucleoside as the penultimate nucleoside which is connected via the reversed linkage to the nucleoside which is not the terminal nucleoside (called the antepenultimate nucleoside herein); and / or ix) abasic nucleosides as the 2 terminal nucleosides connected via a 5’-3’ linkage when reading the strand in the direction towards that terminus; x) abasic nucleosides as the 2 terminal nucleosides connected via a 3’-5’ linkage when reading the strand in the direction towards the terminus comprising the terminal nucleosides; xi) abasic nucleosides as the terminal 2 positions, wherein the penultimate nucleoside is connected via the reversed linkage to the antepenultimate nucleoside, and wherein the reversed linkage is a 5-5’ reversed linkage or a 3’-3’ reversed linkage; xii) abasic nucleosides as the terminal 2 positions, wherein the penultimate nucleoside is connected via the reversed linkage to the antepenultimate nucleoside, and wherein either (1) the reversed linkage is a 5-5’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides; or (2) the reversed linkage is a 3-3’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 5’3’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the reversed internucleoside linkage is at a terminal region which is distal to the 5’ terminal region of the second strand, or at a terminal region which is distal to the 3’ terminal region of the second strand. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the reversed internucleoside linkage is a 3’3 reversed linkage. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the reversed internucleoside linkage is a 5’5 reversed linkage. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein one or more nucleosides on the first strand and / or the second strand is / are modified, to form modified nucleosides. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the modification is a modification at the 2’-OH group of the ribose sugar, optionally selected from 2'-Me or 2’-F modifications. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the first strand comprises a 2’-F at any of position 14, position 2, position 6, or any combination thereof, counting from position 1 of said first strand. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the second strand comprises a 2’-F modification at position 7 and / or 9, and / or 11 and / or 13, counting from position 1 of said second strand. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the first and second strand each comprise 2'-Me and 2’-F modifications. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, which is an siRNA, wherein the siRNA comprises at least one thermally destabilizing modification, suitably at one or more of positions 1 to 9 of the first strand counting from position 1 of the first strand, and / or at one or more of positions on the second strand aligned with positions 1 to 9 of the first strand, wherein the destabilizing modification is selected from a modified unlocked nucleic acid (IMUNA) and a glycol nucleic acid (GNA), preferably a glycol nucleic acid. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the siRNA comprises at least one thermally destabilizing modification at position 7 of the first strand, counting from position 1 of the first strand. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, which is an siRNA, wherein the siRNA comprises 3 or more 2’-F modifications at positions 7 to 13 of the second strand, such as 4, 5, 6 or 72’-F modifications at positions 7 to 13 of the second strand, counting from position 1 of said second strand In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, which is an siRNA, wherein said second strand comprises at least 3, such as 4, 5 or 6, 2’-Me modifications at positions 1 to 6 of the second strand, counting from position 1 of said second strand. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, which is an siRNA, wherein said first strand comprises at least 52’-Me consecutive modifications at the 3’ terminal region, preferably including the terminal nucleoside at the 3’ terminal region, or at least within 1 or 2 nucleosides from the terminal nucleoside at the 3’ terminal region. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, which is an siRNA wherein said first strand comprises 7 2’-Me consecutive modifications at the 3’ terminal region, preferably including the terminal nucleoside at the 3’ terminal region. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the siRNA oligomer further comprises one or more phosphorothioate internucleoside linkages. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein said one or more phosphorothioate internucleoside linkages are respectively between at least three consecutive positions in a 5’ or 3’ near terminal region of the second strand, whereby said near terminal region is preferably adjacent said terminal region wherein said one or more abasic nucleosides of said second strand is / are located as defined herein. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein said one or more phosphorothioate internucleoside linkages are respectively between at least three consecutive positions in a 5’ and / or 3’ terminal region of the first strand, whereby preferably a terminal position at the 5’ and / or 3’ terminal region of said first strand is attached to its adjacent position by a phosphorothioate internucleoside linkage. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the oligomer is an siRNA and the second strand of the siRNA is conjugated directly or indirectly to one or more ligand moiety(s), wherein said ligand moiety is typically present at a terminal region of the second strand, preferably at the 3’ terminal region thereof. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the ligand moiety comprises i) one or more GalNAc ligands; and / or ii) one or more GalNAc ligand derivatives; and / or iii) one or more GalNAc ligands and / or GalNAc ligand derivatives conjugated to said siRNA through a linker. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein said one or more GalNAc ligands and / or GalNAc ligand derivatives are conjugated directly or indirectly to the 5’ or 3’ terminal region of the second strand of the siRNA oligomer, preferably at the 3’ terminal region thereof. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein the ligand moiety comprises In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, having the structure: wherein: R1 at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; R2 is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X1and X2at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; m is an integer of from 1 to 6; n is an integer of from 1 to 10; q, r, s, t, v are independently integers from 0 to 4, with the proviso that: (i) q and r cannot both be 0 at the same time; and (ii) s, t and v cannot all be 0 at the same time; Z is an oligomer In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, having the structure wherein: r and s are independently an integer selected from 1 to 16; and Z is an oligomer. In a further aspect, the invention relates to an inhibitor or an inhibitor for use according to the invention, formulated as a pharmaceutical composition with an excipient and / or carrier. In another aspect, the invention relates to a pharmaceutical composition comprising an inhibitor according to one or more preceding claims, in combination with a pharmaceutically acceptable excipient or carrier. In a further aspect, the invention relates to a pharmaceutical composition comprising an inhibitor according to the invention, in combination with a pharmaceutically acceptable excipient or carrier, for use in the treatment of an ischaemic heart disease, such as myocardial infarction. In a particular aspect of the invention, the pharmaceutical composition according to the invention is for use in the treatment of an ischaemic heart disease, such as myocardial infarction, whereby the pharmaceutical composition alleviates symptoms of an ischaemic heart disease, in particular myocardial infarction, more particularly an acute myocardial infarction. Within the present invention, the pharmaceutical composition of the invention may be administered after myocardial infarction, in particular for cardioprotection, for reducing infarct size and / or reducing reperfusion arrhythmias In another aspect, the invention relates to the use of NR3C2 as a target for identifying one or more therapeutic agents for the treatment of an ischaemic heart disease, such as myocardial infarction. In another aspect, the invention relates to a method of treating or preventing a disease or disorder related to an ischaemic heart disease, such as myocardial infarction, which comprises administering to a patient an inhibitor of NR3C2, such as an inhibitor as defined according to one or more preceding aspects. In another aspect, the invention relates to NR3C2 for use as a biomarker of heart failure with reduced ejection fraction (HFrEF) and associated conditions such as ischaemic heart disease, such as myocardial infarction. In another aspect, the invention relates to NR3C2 for use in an in vivo method of predicting susceptibility to an ischaemic heart disease, such as myocardial infarction, typically by monitoring the sequence and / or level of expression and / or function of NR3C2 in a sample obtained from a patient. In another aspect, the invention relates to a method of predicting susceptibility to an ischaemic heart disease, such as myocardial infarction, and optionally treating an ischaemic heart disease, such as myocardial infarction, in a patient, said method comprising: (a) obtaining a sample from the patient, (b) detecting the sequence and / or expression and / or function of NR3C2 in said sample obtained from the patient, (c) predicting susceptibility to an ischaemic heart disease, such as myocardial infarction, based on the sequence and / or expression and / or function of NR3C2 in said sample obtained from the patient, (d) preferably administering to the diagnosed patient an effective amount of an inhibitor of NR3C2. In another aspect, the invention relates to an inhibitor or composition according to the invention, in the preparation of a medicament for use in the treatment of an ischaemic heart disease, such as myocardial infarction. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 228, SEQ ID NO: 238, SEQ ID NO: 243, SEQ ID NO: 235, SEQ ID NO: 245 and SEQ ID NO: 250. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 238. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 245. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 674, SEQ ID NO: 684, SEQ ID NO: 689, SEQ ID NO: 681, SEQ ID NO: 691 and SEQ ID NO: 696. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 684. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 691. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 451, SEQ ID NO: 461, SEQ ID NO: 466, SEQ ID NO: 458, SEQ ID NO: 468 and SEQ ID NO: 473. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 461. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 468. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 907. In a further aspect, the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 914. In a further aspect, the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences: Unmodified first strand Unmodified second strandSEQ ID NO: 228SEQ ID NO: 451SEQ ID NO: 238 SEQ ID NO: 461 SEQ ID NO: 243 SEQ ID NO: 466 SEQ ID NO: 235 SEQ ID NO: 458 SEQ ID NO: 245 SEQ ID NO: 468 SEQ ID NO: 250 SEQ ID NO: 473 In a further aspect, the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences: Unmodified first strand Unmodified second strand SEQ ID NO: 238 SEQ ID NO: 461 In a further aspect, the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences: Unmodified first strand Unmodified second strand SEQ ID NO: 245 SEQ ID NO: 468 In a further aspect, the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences: Modified first strand Modified second strand SEQ ID NO: 674 SEQ ID NO: 897 SEQ ID NO: 684 SEQ ID NO: 907 SEQ ID NO: 689 SEQ ID NO: 912 SEQ ID NO: 681 SEQ ID NO: 904 SEQ ID NO: 691 SEQ ID NO: 914 SEQ ID NO: 696 SEQ ID NO: 919 In a further aspect, the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences: Modified first strand Modified second strand SEQ ID NO: 684SEQ ID NO: 907In a further aspect, the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences: Modified first strand Modified second strand SEQ ID NO: 691 SEQ ID NO: 914 FIGURES Figure 1: Linker and ligand portions of constructs suitable for use according to the present invention including tether 1a. While Figure 1 depicts the linker to be conjugated to an oligonucleotide, it is to be understood that the present invention also encompasses conjugates of the same linker with an oligonucleoside as disclosed herein. It should also be understood that while Figure 1 depicts as a product molecules based on the linker and ligand portions as specifically depicted in Figure 1 attached to an oligonucleoside moiety as also depicted herein, this product may alternatively further comprise, or consist essentially of, molecules wherein the linker and ligand portions are essentially as depicted in Figure 1 attached to an oligonucleoside moiety but having the F substituent as shown in Figure 1 on the cyclo-octyl ring replaced by a substituent, which could occur as a result of hydrolytic displacement, such as an OH substituent, or the OH substituent could be synthesized as a linker in its own right. In this way, (a) tether 1a constructs can consist essentially of molecules having linker and ligand portions specifically as depicted in Figure 1, with a F substituent on the cyclo-octyl ring; or (b) tether 1a constructs can consist essentially of molecules having linker and ligand portions essentially as depicted in Figure 1 but having the F substituent as shown in Figure 1 on the cyclo-octyl ring replaced by an OH substituent, or (c) tether 1a constructs can comprise a mixture of molecules as defined in (a) and / or (b). Figure 2: Linker and ligand portions of constructs suitable for use according to the present invention including tether 1b. While Figure 2 depicts the linker to be conjugated to an oligonucleotide, it is to be understood that the present invention also encompasses conjugates of the same linker with an oligonucleoside as disclosed herein. The comments made in relation to Figure 1 and the possible replacement of the F substituent as shown in Figure 1 on the cyclo-octyl ring replaced by a substituent, which could occur as a result of hydrolytic displacement, such as an OH substituent, or the OH substituent could be synthesized as a linker in its own right, apply equally to tether 1b constructs. In this way, (a) tether 1b constructs can consist essentially of molecules having linker and ligand portions specifically as depicted in Figure 2, with a F substituent on the cyclo-octyl ring; or (b) tether 1b constructs can consist essentially of molecules having linker and ligand portions essentially as depicted in Figure 2 but having the F substituent as shown in Figure 2 on the cyclo-octyl ring replaced by an OH substituent, or (c) tether 1b constructs can comprise a mixture of molecules as defined in (a) and / or (b). Figure 3: Linker and ligand portions of constructs suitable for use according to the present invention including tether 2a. While Figure 3 depicts the linker to be conjugated to an oligonucleotide, it is to be understood that the present invention also encompasses conjugates of the same linker with an oligonucleoside as disclosed herein. Figure 4: Linker and ligand portions of constructs suitable for use according to the present invention including tether 2b. While Figure 4 depicts the linker to be conjugated to an oligonucleotide, it is to be understood that the present invention also encompasses conjugates of the same linker with an oligonucleoside as disclosed herein. Figure 5: Formulae described in Sentences 1-101 disclosed herein. Figure 6: Formulae described in Clauses 1-56 disclosed herein Figures 7a and 7b: Inverted abasic constructs that can be used with nucleic acid sequences according to the present invention as described herein. For Figure 7a, a GalNAc linker is attached to the 5’ end region of the sense strand in use (not depicted in Figure 7a). For Figure 7b, a GalNAc linker is attached to the 3’ end region of the sense strand in use (not depicted in Figure 7b). iaia as shown at the 3’ end region of the sense strand in Figure 7a represents (i) two abasic nucleosides provided as the penultimate and terminal nucleosides at the 3’ end region of the sense strand, (ii) wherein a 3’-3’ reversed linkage is provided between the antepenultimate nucleoside (namely at position 21 of the sense strand, wherein position 1 is the terminal 5’ nucleoside of the sense strand) and the adjacent penultimate abasic residue of the sense strand, and (iii) the linkage between the terminal and penultimate abasic nucleosides is 5’-3’ when reading towards the 3’ end region comprising the terminal and penultimate abasic nucleosides. iaia as shown at the 5’ end region of the sense strand in Figure 7b represents (i) two abasic nucleosides provided as the penultimate and terminal nucleosides at the 5’ end region of the sense strand, (ii) wherein a 5’-5’ reversed linkage is provided between the antepenultimate nucleoside (namely at position 1 of the sense strand, not including the iaia motif at the 5’ end region of the sense strand in the nucleoside position numbering on the sense strand) and the adjacent penultimate abasic residue of the sense strand, and (iii) the linkage between the terminal and penultimate abasic nucleosides is 3’-5’ when reading towards the 5’ end region comprising the terminal and penultimate abasic nucleosides. Figures 8a and 8b: Duplex constructs according to Table 5. Figure 9: The correlation between predicted and experimentally determined siRNA efficacy values i.e. maximum RNA knockdown where 1 represents maximum knockdown and 0 is no reduction in mRNA levels. Data displayed are for the test dataset in the best performing siRNAdesignR model. Figure 10: Performance metrics for the best performing siRNAdesignR model in the test data set and also the validation dataset. In both cases the model scored above 0.5 in the Precision@20 metric, and the best performing siRNA (experimentally determined) was in the top 20 predictions of the model (nSiRNAsForBest). Figure 11: siRNAdesignR ranking for 276 siRNAs. These rankings were tested in an in vitro model (Huh7 cells) demonstrating strong correlation (Spearman correlation coefficient 0.743). Figure 12: A dose response curve of SLC25A5 mRNA knockdown following 24 hour exposure to siRNA. Cells were tested in triplicate repeats on two separate days (replicates 1 and 2). Data are mean + / - standard deviation with knockdown normalised to untreated wells. Figure 13: Change in SLC25A5 mRNA knockdown over 28 days following one subcutaneous dose of siRNA at day 0. As mRNA measurements are taken from liver tissue measurements are taken from different mice at each time point. Data are mean + / - standard deviation from 16 mice per timepoint per dose, normalised to saline control. Figure 14: Change in SLC25A5 protein expression over 28 days following one subcutaneous dose of siRNA at day 0. As mRNA measurements are taken from liver tissue measurements are taken from different mice at each time point. Data are mean + / - standard deviation from 16 mice per timepoint per dose, normalized to saline control. Figure 15a shows an exemplary linear configuration for a conjugate. Figure 15b shows an exemplary branched configuration for a conjugate. Figures 16-19 show preferred oligomer – linker – ligand constructs of the invention.Figure 20: Hepatic target mRNA knockdown in mice following injection of GalNAc-siRNA. Figure 21: No change in markers of liver health following injection of GalNAc-siRNAs. Figure 22: Hepatic knockdown and trend towards increased FGF21 levels with ETXM-2590 treatment. Figure 23: No treatment effects on survival, body weight or food intake in the MI mouse model. Figure 24: Improvements in main parameters of cardiac function and structure post-MI in mice treated with GalNAc-siRNA to reduce hepatic NR3C2 expression. Figure 25: Reduced hepatic expression of human NR3C2 in a hydrodynamic injection (HDI) mouse model injected with GalNAc siRNAs. DETAILED DESCRIPTION The present invention, inter alia, provides inhibitors, for example oligomers such as nucleic acids, such as inhibitory RNA molecules (which may be referred to as iRNA or siRNA), and compositions containing the same which can affect expression of a target, for example by binding to mRNA transcribed from a gene. The target may be within a cell, e.g. a cell within a subject, such as a human. The inhibitors can be used to prevent and / or treat medical conditions associated with the e.g. the expression of a target gene. In particular the present invention identifies inhibitors of NR3C2 as useful in the prevention and / or treatment of a ischaemic heart disease, such as myocardial infarction and / or the disorder or diseases as a symptom of myocardial infarction. The mineralocorticoid receptor (MR or NR3C2) is a protein / receptor that belongs to the nuclear receptor family. As such, binding of the ligand to NR3C2 affects specific gene expression in the nucleus of human cells. In humans, NR3C2 is encoded by the NR3C2 gene (ENSG00000151623). The inhibition disclosed herein may be of the gene or protein resulting from expression of the gene and reference to NR3C2 hereby explicitly incorporates a reference to inhibition of the expression or function of the gene and, separately, of the protein product. Ischemic heart disease is the primary etiology of heart failure with reduced ejection fraction (HFrEF). The present invention extends equally to other indications associated with, or resulting from, HFrEF or ischemic heart disease. References herein to ischemic heart disease can be applied equally to HFrEF and associated indications. Other etiologies of HFrEF include valvular disease, hypertension and cardiomyopathies. The present invention also extends equally to such other etiologies of HFrEF. References herein to ischemic heart disease can be applied equally to these. DEFINITIONS The “first strand”, also called the antisense strand or guide strand herein and which can be used interchangeably herein, refers to the nucleic acid strand, e.g. the strand of an siRNA, e.g. a dsiRNA, which includes a region that is substantially complementary to a target sequence, e.g. to an mRNA. As used herein, the term "region of complementarity" refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence. Where the region of complementarity is not fully complementary to the target sequence, the mismatches can be in the internal or terminal regions of the molecule. In some embodiments, a double stranded nucleic acid e.g. an siRNA agent of the invention includes a nucleotide mismatch in the antisense strand. The “second strand” (also called the sense strand or passenger strand herein, and which can be used interchangeably herein), refers to the strand of a nucleic acid e.g. siRNA that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein. In the context of molecule comprising a nucleic acid provided with a ligand moiety, optionally also with a linker moiety, the nucleic acid of the invention may be referred to as an oligonucleotide moiety or oligonucleoside moiety. Oligonucleotides are short nucleic acid polymers. Whilst oligonucleotides contain phosphodiester bonds between the nucleoside component thereof (base plus sugar), the present invention is not limited to oligonucleotides always joined by such a phosphodiester bond between adjacent nucleosides, and other oligomers of nucleosides joined by bonds which are bonds other than a phosphate bond are contemplated. For example, a bond between nucleotides may be a phosphorothioate bond. Therefore, the term “oligonucleoside” herein covers both oligonucleotides and other oligomers of nucleosides. An oligonucleoside which is a nucleic acid having at least a portion which is an oligonucleotide is preferred according to the present invention. An oligonucleoside having one or more, or a majority of, phosphodiester backbone bonds between nucleosides is also preferred according to the present invention. An oligonucleoside having one or more, or a majority of, phosphodiester backbone bonds between nucleosides, and also having one or more phosphorothioate backbone bonds between nucleosides (typically in a terminal region of the first and / or second strands) is also preferred according to the present invention. It is preferred herein that the nucleic acid according to the invention is a double stranded oligonucleoside comprising one or more phosphorothioate backbone bonds between nucleosides. Accordingly, in all instances in which the present application refers to an oligonucleotide, particularly in the chemical structures disclosed herein, the oligonucleotide may equally be an oligonucleoside as defined herein. In some embodiments, a double stranded nucleic acid e.g. siRNA agent of the invention includes a nucleoside mismatch in the sense strand. In some embodiments, the nucleoside mismatch is, for example, within 5, 4, 3, 2, or 1 nucleosides from the 3 '-end of the nucleic acid e.g. siRNA. In another embodiment, the nucleoside mismatch is, for example, in the 3'- terminal nucleoside of the nucleic acid e.g. siRNA. A "target sequence" (which may be called a target RNA or a target mRNA) refers to a contiguous portion of the nucleoside sequence of an mRNA molecule formed during the transcription of a gene, including mRNA that is a product of RNA processing of a primary transcription product, or can be a contiguous portion of the nucleotide sequence of any RNA molecule such as a LNCRNA which it is desired to inhibit. The target sequence may be from about 10-35 nucleosides in length, e.g., about 15-30 nucleosides in length. For example, the target sequence can be from about 15-30 nucleosides, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18- 28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20- 23, 20-22, 20- 21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleosides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. The term “ribonucleoside” or “nucleoside” can also refer to a modified nucleoside as further detailed below. A nucleic acid can be a DNA or an RNA, and can comprise modified nucleosides. RNA is a preferred nucleic acid. The terms "iRNA", “siRNA”, "RNAi agent," and "iRNA agent," "RNA interference agent" as used interchangeably herein, refer to an agent that contains RNA, and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. siRNA directs the sequence-specific degradation of mRNA through RNA interference (RNAi). A double stranded RNA is referred to herein as a "double stranded siRNA (dsiRNA) agent", "double stranded siRNA (dsiRNA) molecule", "double stranded RNA (dsRNA) agent", "double stranded RNA (dsRNA) molecule", "dsiRNA agent", "dsiRNA molecule", or "dsiRNA", which refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti- parallel and substantially complementary nucleic acid strands, referred to as having "sense" and "antisense" orientations with respect to a target RNA. The majority of nucleosides of each strand of the nucleic acid, e.g. a dsRNA molecule, are preferably ribonucleosides, but in that case each or both strands can also include one or more non- ribonucleosides, e.g., a deoxyribonucleoside or a modified ribonucleoside. In addition, as used in this specification, an "siRNA" may include ribonucleosides with chemical modifications. The term "modified nucleoside" refers to a nucleoside having, independently, a modified sugar moiety, a modified internucleoside linkage, or modified nucleobase, or any combination thereof. Thus, the term modified nucleoside encompasses substitutions, additions or removal of, e.g., a functional group or atom, to internucleoside linkages, sugar moieties, or nucleobases. Any such modifications, as used in a siRNA type molecule, are encompassed by "iRNA" or "RNAi agent" or “siRNA” or “siRNA agent” for the purposes of this specification and claims. The duplex region of a nucleic acid of the invention e.g. a dsRNA may range from about 9 to 40 base pairs in length such as 9 to 36 base pairs in length, e.g., about 15- 30 base pairs in length, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 base pairs in length, such as about 15-30, 15-29, 15-28, 15-27, 15-26, 15- 25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18- 27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19- 23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21- 30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. The two strands forming the duplex structure may be different portions of one larger molecule, or they may be separate molecules e.g. RNA molecules. The term "nucleoside overhang" refers to at least one unpaired nucleoside that extends from the duplex structure of a double stranded nucleic acid. A ds nucleic acid can comprise an overhang of at least one nucleoside; alternatively the overhang can comprise at least two nucleosides, at least three nucleosides, at least four nucleosides, at least five nucleosides, or more. A nucleoside overhang can comprise or consist of a nucleoside analog, including a deoxynucleoside. The overhang(s) can be on the sense strand, the antisense strand, or any combination thereof. Furthermore, the / nucleoside(s) of an overhang can be present on the 5'-end, 3'-end, or both ends of either an antisense or sense strand. In certain embodiments, the antisense strand has a 1-10 nucleoside, e.g., 0-3, 1-3, 2-4, 2-5, 4-10, 5-10, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleoside overhang at the 3'-end or the 5'-end. "Blunt" or "blunt end" means that there are no unpaired nucleoside at that end of the double stranded nucleic acid, i.e., no nucleoside overhang. The nucleic acids of the invention include those with no nucleoside overhang at one end or with no nucleoside overhangs at either end. Unless otherwise indicated, the term "complementary," when used to describe a first nucleoside sequence in relation to a second nucleoside sequence, refers to the ability of an oligonucleoside comprising the first nucleoside sequence to hybridize and form a duplex structure under certain conditions with an oligonucleoside or polynucleoside comprising the second nucleoside sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50°C or 70°C for 12-16 hours followed by washing (see, e.g., "Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press). Complementary sequences within nucleic acid e.g. a dsiRNA, as described herein, include base- pairing of the oligonucleoside or polynucleoside comprising a first nucleoside sequence to an oligonucleoside or polynucleoside comprising a second nucleoside sequence over the entire length of one or both nucleoside sequences. Such sequences can be referred to as "fully complementary" with respect to each other herein. However, where a first sequence is referred to as "substantially complementary" with respect to a second sequence herein, the two sequences can be fully complementary, or they can form one or more mismatched base pairs, such as 2, 4, or 5 mismatched base pairs, but preferably not more than 5, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RISC pathway. Overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a nucleic acid e.g. dsRNA comprising one oligonucleoside 17 nucleosides in length and another oligonucleoside 19 nucleosides in length, wherein the longer oligonucleoside comprises a sequence of 17 nucleosides that is fully complementary to the shorter oligonucleoside, can yet be referred to as "fully complementary". "Complementary" sequences, as used herein, can also include, or be formed entirely from, non- Watson-Crick base pairs or base pairs formed from non-natural and modified nucleosides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non- Watson-Crick base pairs include, but are not limited to, G:U Wobble or Hoogstein base pairing. The terms "complementary," "fully complementary" and "substantially complementary" herein can be used with respect to the base matching between the sense strand and the antisense strand of a nucleic acid e.g. dsiRNA, or between the antisense strand of a double stranded nucleic acid e.g. siRNA agent and a target sequence. Within the present invention, the second strand of the nucleic acid according to the invention, in particular a dsiRNA for inhibiting expression of NR3C2, is at least partially complementary to the first strand of said nucleic acid. In certain embodiments, a first and second strand of a nucleic acid according to the invention are partially complementary if they form a duplex region having a length of at least 17 base pairs and comprising not more than 1, 2, 3, 4, or 5 mismatched base pairs. In certain embodiments, a first and second strand of the nucleic acid according to the invention are partially complementary if they form a duplex region having a length of 19 base pairs and comprising not more than 1, 2, 3, 4, or 5 mismatched base pairs. In certain embodiments, a first and second strand of the nucleic acid according to the invention are partially complementary if they form a duplex region having a length of 21 base pairs comprising not more than 1, 2, 3, 4, or 5 mismatched base pairs. Alternatively, a first and second strand of the nucleic acid according to the invention are partially complementary if they form a duplex region having a length of at least 17 base pairs, wherein at least 14, 15, 16 or 17 of said base pairs are complementary base pairs, in particular Watson-Crick base pairs. In certain embodiments, a first and second strand of the nucleic acid according to the invention are partially complementary if they form a duplex region having a length of 19 base pairs, wherein at least 14, 15, 16, 17, 18 or all 19 base pairs are complementary base pairs, in particular Watson- Crick base pairs. In certain embodiments, a first and second strand of the nucleic acid according to the invention are partially complementary if they form a duplex region having a length of 21 base pairs, wherein at least 16, 17, 18, 19, 20 or all 21 base pairs are complementary base pairs, in particular Watson-Crick base pairs. As used herein, a nucleic acid that is "substantially complementary” to at least part of a messenger RNA (mRNA) refers to a polynucleoside that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding a gene). For example, a polynucleoside is complementary to at least a part of an mRNA of a gene of interest if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding that gene. Accordingly, in some preferred embodiments, the antisense oligonucleosides as disclosed herein are fully complementary to the target gene sequence. In other embodiments, the antisense oligonucleosides disclosed herein are substantially complementary to a target RNA sequence and comprise a contiguous nucleoside sequence which is at least about 80% complementary over its entire length to the equivalent region of the target RNA sequence, such as at least about 85%, 86%, 87%, 88%, 89%, about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% complementary or 100% complementary. In certain embodiments, the first (antisense) strand of a nucleic acid according to the invention is partially or fully complementary to a contiguous portion of RNA transcribed from the NR3C2 gene. In certain embodiments, the first strand of the nucleic acid according to the invention is partially or fully complementary to a contiguous portion of at least 17 nucleosides of the NR3C2 mRNA. In certain embodiments, the first strand of the nucleic acid according to the invention is partially or fully complementary to a contiguous portion of 17, 18, 19, 20, 21, 22 or 23 nucleosides of the NR3C2 mRNA. In certain embodiments, the first strand of the nucleic acid according to the invention is partially or fully complementary to a contiguous portion of 17, 18, 19, 20, 21, 22 or 23 nucleosides of any one of the sequences as listed in Table 1, i.e., any one of SEQ ID NOs:1- 223. In certain embodiments, the first (antisense) strand of the nucleic acid according to the invention is partially complementary to a contiguous portion of the NR3C2 mRNA if it comprises a contiguous nucleoside sequence of at least 17 nucleosides, wherein at least 14, 15, 16 or 17 nucleosides of said contiguous nucleoside sequence are complementary to a contiguous portion of the NR3C2 mRNA. In certain embodiments, the first strand of the nucleic acid according to the invention comprises a contiguous nucleoside sequence of at least 17 nucleosides, wherein at least 14, 15, 16 or 17 nucleosides of said contiguous nucleoside sequence are complementary to a contiguous portion of any one of the sequences listed in Table 1, i.e., any one of SEQ ID NOs: 1- 223. In certain embodiments, the first strand of the nucleic acid according to the invention comprises a contiguous nucleoside sequence of 19 nucleosides, wherein at least 14, 15, 16, 17, 18 or all 19 nucleosides of said contiguous nucleoside sequence are complementary to a contiguous portion of any one of the sequences listed in Table 1, i.e., any one of SEQ ID NOs: 1-223. In certain embodiments, the first strand of the nucleic acid according to the invention comprises a contiguous nucleoside sequence of 23 nucleosides, wherein at least 18, 19, 20, 21, 22 or all 23 nucleosides of said contiguous nucleoside sequence are complementary to a contiguous portion of any one of the sequences listed in Table 1, i.e., any one of SEQ ID NOs: 1-223. In some embodiments, a nucleic acid e.g. an siRNA of the invention includes a sense strand that is substantially complementary to an antisense polynucleoside which, in turn, is complementary to a target gene sequence and comprises a contiguous nucleoside sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleoside sequence of the antisense strand, such as about 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% complementary, or 100% complementary. In some embodiments, a nucleic acid e.g. an siRNA of the invention includes an antisense strand that is substantially complementary to the target sequence and comprises a contiguous nucleoside sequence which is at least 80% complementary over its entire length to the target sequence such as about 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% complementary, or 100% complementary. As used herein, a "subject" is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), or a non-primate or a bird that expresses the target gene, either endogenously or heterologously, when the target gene sequence has sufficient complementarity to the nucleic acid e.g. iRNA agent to promote target knockdown. In certain preferred embodiments, the subject is a human. The terms "treating" or "treatment" refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more symptoms associated with gene expression. "Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Treatment can include prevention of development of co-morbidities. As used herein, the term “treatment”, in particular treatment of myocardial infarction, encompasses the treatment of consequences / symptoms of myocardial infarction such as damage of heart muscle tissue. As such, the inhibitors of the invention, have cardioprotective effect and, inter alia, reduce infarct size and / or reperfusion arrythmias. The terms “prevent” or “prevention” as used herein are defined as eliminating or reducing the likelihood of occurrence of one or more symptoms of a disease or disorder. For example, the inhibitor disclosed herein can be used to prevent the occurrence of ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof. "Therapeutically effective amount," as used herein, is intended to include the amount of a nucleic acid e.g. an iRNA that, when administered to a patient for treating a subject having disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease or its related comorbidities). The phrase "pharmaceutically acceptable" is employed herein to refer to compounds, materials, compositions, or dosage forms which are suitable for use in contact with the tissues of human subjects and animal subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Where a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this invention. The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to". The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise. For example, "sense strand or antisense strand" is understood as "sense strand or antisense strand or sense strand and antisense strand." The term "about" is used herein to mean within the typical ranges of tolerances in the art. For example, "about" can be understood as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When about is present before a series of numbers or a range, it is understood that "about" can modify each of the numbers in the series or range. The term "at least" prior to a number or series of numbers is understood to include the number adjacent to the term "at least", and all subsequent numbers or integers that could logically be included, as clear from context. For example, the number of nucleotides in a nucleic acid molecule must be an integer. For example, "at least 18 nucleosides of a 21 nucleoside nucleic acid molecule" means that 18, 19, 20, or 21 nucleosides have the indicated property. When at least is present before a series of numbers or a range, it is understood that "at least" can modify each of the numbers in the series or range. As used herein, "no more than" or "less than" is understood as the value adjacent to the phrase and logical lower values or integers, as logical from context, to zero. For example, a duplex with an overhang of "no more than 2 nucleosides" has a 2, 1, or 0 nucleoside overhang. When "no more than" is present before a series of numbers or a range, it is understood that "no more than" can modify each of the numbers in the series or range. The terminal region of a strand is the last 5 nucleotides from the 5’ or the 3’ end. A nucleobase sequence is the sequence of the bases of the nucleic acid in an oligomer. Various embodiments of the invention can be combined as determined appropriate by one of skill in the art. TARGET A target for inhibition disclosed herein may be, without limitation, an mRNA, polypeptide, protein, or gene. These targets are a target the inhibition of which helps in the prevention or treatment of an ischaemic heart disease such as myocardial infarction. The target for inhibition is NR3C2, and inhibition may be effected by inhibition of expression or function of the NR3C2 gene or protein or both. Disease / conditions The invention relates to an inhibitor suitable for use, or for use, in treatment of an ischaemic heart disease, in particular myocardial infarction. INHIBITORS Inhibitors of the invention include nucleic acids such as siRNAs, antibodies and antigen binding fragments thereof, e.g., monoclonal antibodies, polypeptides, antibody–drug conjugates, and small molecules. Preferred are nucleic acids such as siRNA. Certain preferred features of inhibitors of the invention, where these are oligonucelosides such as siRNA, are given below. In certain embodiments, the nucleic acid comprises a first strand comprising a sequence that is at least partially complementary to a portion of RNA transcribed from the NR3C2 gene (SEQ ID NO: 1116). In a preferred embodiment, the nucleic acid comprises a first strand comprising a sequence that is at least partially complementary to a NR3C2 mRNA. In certain embodiments, the nucleic acid for inhibiting expression of NR3C2 comprises a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is at least partially complementary to a portion of RNA transcribed from the NR3C2 gene. In certain embodiments, the nucleic acid for inhibiting expression of NR3C2 comprises a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is at least partially complementary to a portion of RNA transcribed from the NR3C2 gene. ABASIC NUCLEOTIDES In certain embodiments, there are 1, e.g. 2, e.g. 3, e.g. 4 or more abasic nucleosides present in nucleic acids according to the invention. Abasic nucleosides are modified nucleosides because they lack the base normally seen at position 1 of the sugar moiety. Typically, there will be a hydrogen at position 1 of the sugar moiety of the abasic nucleosides present in a nucleic acid according to the present invention. The abasic nucleosides are in the terminal region of the second strand, preferably located within the terminal 5 nucleosides of the end of the strand. The terminal region may be the terminal 5 nucleosides, which includes abasic nucleosides. The second strand may comprise, as preferred features (which are all specifically contemplated in combination unless mutually exclusive): 2, or more than 2, abasic nucleosides in a terminal region of the second strand; and / or 2, or more than 2, abasic nucleosides in either the 5’ or 3’ terminal region of the second strand; and / or 2, or more than 2, abasic nucleosides in either the 5’ or 3’ terminal region of the second strand, wherein the abasic nucleosides are present in an overhang as herein described; and / or 2, or more than 2, consecutive abasic nucleosides in a terminal region of the second strand, wherein preferably one such abasic nucleosides is a terminal nucleosides; and / or 2, or more than 2, consecutive abasic nucleosides in either the 5’ or 3’ terminal region of the second strand, wherein preferably one such abasic nucleosides is a terminal nucleosides in either the 5’ or 3’ terminal region of the second strand; and / or a reversed internucleoside linkage connects at least one abasic nucleoside to an adjacent basic nucleoside in a terminal region of the second strand; and / or a reversed internucleoside linkage connects at least one abasic nucleoside to an adjacent basic nucleoside in either the 5’ or 3’ terminal region of the second strand; and / or an abasic nucleoside as the penultimate nucleoside which is connected via the reversed linkage to the nucleoside which is not the terminal nucleoside (called the antepenultimate nucleoside herein); and / or abasic nucleosides as the 2 terminal nucleosides connected via a 5’-3’ linkage when reading the strand in the direction towards the terminus comprising the terminal nucleosides; abasic nucleosides as the 2 terminal nucleosides connected via a 3’-5’ linkage when reading the strand in the direction towards the terminus comprising the terminal nucleosides; abasic nucleosides as the terminal 2 positions, wherein the penultimate nucleoside is connected via the reversed linkage to the antepenultimate nucleoside, and wherein the reversed linkage is a 5-5’ reversed linkage or a 3’-3’ reversed linkage; abasic nucleosides as the terminal 2 positions, wherein the penultimate nucleoside is connected via the reversed linkage to the antepenultimate nucleoside, and wherein either (1) the reversed linkage is a 5-5’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides; or (2) the reversed linkage is a 3-3’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 5’3’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides. Preferably there is an abasic nucleoside at the terminus of the second strand. Preferably there are 2 or at least 2 abasic nucleosides in the terminal region of the second strand, preferably at the terminal and penultimate positions. Preferably 2 or more abasic nucleosides are consecutive, for example all abasic nucleosides may be consecutive. For example, the terminal 1 or terminal 2 or terminal 3 or terminal 4 nucelotides may be abasic nucleosides. An abasic nucleoside may also be linked to an adjacent nucleoside through a 5’-3’ phosphodiester linkage or reversed linkage unless there is only 1 abasic nucleoside at the terminus, in which case it will have a reversed linkage to the adjacent nucleoside. A reversed linkage (which may also be referred to as an inverted linkage, which is also seen in the art), comprises either a 5’-5’, a 3-’3’, a 3’-2’ or a 2’-3’ phosphodiester linkage between the adjacent sugar moieties of the nucleosides. Abasic nucleosides which are not terminal will have 2 phosphodiester bonds, one with each adjacent nucleoside, and these may be a reversed linkage or may be a 5’-3 phosphodiester bond or may be one of each. A preferred embodiment comprises 2 abasic nucleosides at the terminal and penultimate positions of the second strand, and wherein the reversed internucleoside linkage is located between the penultimate (abasic) nucleoside and the antepenultimate nucleoside. Preferably there are 2 abasic nucleosides at the terminal and penultimate positions of the second strand and the penultimate nucleoside is linked to the antepenultimate nucleoside through a reversed internucleoside linkage and is linked to the terminal nucleoside through a 5’-3’ or 3’-5’ phosphodiester linkage (reading in the direction of the terminus of the molecule). Preferably a nucleic acid according to the present invention comprises one or more abasic nucleosides, optionally wherein the one or more abasic nucleosides are in a terminal region of the second strand, and / or wherein at least one abasic nucleoside is linked to an adjacent basic nucleoside through a reversed internucleoside linkage. Different preferred features are as follows: The reversed internucleoside linkage is a 3’-3’ reversed linkage. The reversed internucleoside linkage is at a terminal region which is distal to the 5’ terminal phosphate of the second strand. The reversed internucleoside linkage is a 5’-5’ reversed linkage. The reversed internucleoside linkage is at a terminal region which is distal to the 3’ terminal hydroxide of the second strand. In certain embodiments, the second strand comprises 2 consecutive abasic nucleosides in the 5’ terminal region of the second strand, wherein one such abasic nucleoside is a terminal nucleoside at the 5’ terminal region of the second strand and the other abasic nucleoside is a penultimate nucleoside at the 5’ terminal region of the second strand, wherein: (a) said penultimate abasic nucleoside is connected to an adjacent first basic nucleoside in an adjacent 5’ near terminal region through a reversed internucleoside linkage; and (b) the reversed linkage is a 5-5’ reversed linkage; and (c) the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides. More typically, (i) the first strand and the second strand each has a length of 23 nucleosides; (ii) two phosphorothioate internucleoside linkages are respectively between three consecutive positions in said 5’ near terminal region of the second strand, wherein a first phosphorothioate internucleoside linkage is present between said adjacent first basic nucleoside of (a) and an adjacent second basic nucleoside in said 5’ near terminal region of the second strand, and a second phosphorothioate internucleoside linkage is present between said adjacent second basic nucleoside and an adjacent third basic nucleoside in said 5’ near terminal region of the second strand; (iii) two phosphorothioate internucleoside linkages are respectively between three consecutive positions in both 5’ and 3’ terminal regions of the first strand, whereby a terminal nucleoside respectively at each of the 5’ and 3’ terminal regions of said first strand is each attached to a respective 5’ and 3’ adjacent penultimate nucleoside by a phosphorothioate internucleoside linkage, and each first 5’ and 3’ penultimate nucleoside is attached to a respective 5’ and 3’ adjacent antepenultimate nucleoside by a phosphorothioate internucleoside linkage; and (iv) the second strand of the nucleic acid is conjugated directly or indirectly to one or more ligand moieties at the 3’ terminal region of the second strand. Alternatively the second strand comprises 2 consecutive abasic nucleosides preferably in an overhang in the 3’ terminal region of the second strand, wherein one such abasic nucleoside is a terminal nucleoside at the 3’ terminal region of the second strand and the other abasic nucleoside is a penultimate nucleoside at the 3’ terminal region of the second strand, wherein: (a) said penultimate abasic nucleoside is connected to an adjacent first basic nucleoside in an adjacent 3’ near terminal region through a reversed internucleoside linkage; and (b) the reversed linkage is a 3-3’ reversed linkage; and (c) the linkage between the terminal and penultimate abasic nucleosides is 5’-3’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides. More typically, (i) the first strand and the second strand each has a length of 23 nucleosides; (ii) two phosphorothioate internucleoside linkages are respectively between three consecutive positions in said 3’ near terminal region of the second strand, wherein a first phosphorothioate internucleoside linkage is present between said adjacent first basic nucleoside of (a) and an adjacent second basic nucleoside in said 3’ near terminal region of the second strand, and a second phosphorothioate internucleoside linkage is present between said adjacent second basic nucleoside and an adjacent third basic nucleoside in said 3’ near terminal region of the second strand; (iii) two phosphorothioate internucleoside linkages are respectively between three consecutive positions in both 5’ and 3’ terminal regions of the first strand, whereby a terminal nucleoside respectively at each of the 5’ and 3’ terminal regions of said first strand is each attached to a respective 5’ and 3’ adjacent penultimate nucleoside by a phosphorothioate internucleoside linkage, and each first 5’ and 3’ penultimate nucleoside is attached to a respective 5’ and 3’ adjacent antepenultimate nucleoside by a phosphorothioate internucleoside linkage; and (iv) the second strand of the nucleic acid is conjugated directly or indirectly to one or more ligand moieties at the 5’ terminal region of the second strand. Examples of the structures are as follows (where the specific RNA nucleosides shown are not limiting and could be any RNA nucleoside): A A 3’-3’ reversed bond (and also showing the 5’-3 direction of the last phosphodiester bond between the two abasic molecules reading towards the terminus of the molecule)

[0002] B Illustrating a 5’-5’ reversed bond (and also showing the 3’-5’ direction of the last phosphodiester bond between the two abasic molecules reading towards the terminus of the molecule) The abasic nucleoside or abasic nucleosides present in the nucleic acid are provided in the presence of a reversed internucleoside linkage or linkages, namely a 5’-5’ or a 3’-3’ reversed internucleoside linkage. A reversed linkage occurs as a result of a change of orientation of an adjacent nucleoside sugar, such that the sugar will have a 3’ – 5’ orientation as opposed to the conventional 5’ – 3’ orientation (with reference to the numbering of ring atoms on the nucleoside sugars). The abasic nucleoside or nucleosides as present in the nucleic acids of the invention preferably include such inverted nucleoside sugars. In the case of a terminal nucleoside having an inverted orientation, then this will result in an “inverted” end configuration for the overall nucleic acid. Whilst certain structures drawn and referenced herein are represented using conventional 5’ - 3’ direction (with reference to the numbering of ring atoms on the nucleoside sugars), it will be appreciated that the presence of a terminal nucleoside having a change of orientation and a proximal 3’-3’ reversed linkage, will result in a nucleic acid having an overall 5’- 5’ end structure (i.e. the conventional 3’ end nucleoside becomes a 5’ end nucleoside). Alternatively, it will be appreciated that the presence of a terminal nucleoside having a change of orientation and a proximal 5’-5’ reversed linkage will result in a nucleic acid with an overall 3’- 3’ end structure. The proximal 3’-3’ or 5’-5’ reversed linkage as herein described, may comprise the reversed linkage being directly adjacent / attached to a terminal nucleoside having an inverted orientation, such as a single terminal nucleoside having an inverted orientation. Alternatively, the proximal 3’-3’ or 5’-5’ reversed linkage as herein described, may comprise the reversed linkage being adjacent 2, or more than 2, nucleosides having an inverted orientation, such as 2, or more than 2, terminal region nucleosides having an inverted orientation, such as the terminal and penultimate nucleosides. In this way, the reversed linkage may be attached to a penultimate nucleoside having an inverted orientation. While a skilled addressee will appreciate that inverted orientations as described above can result in nucleic acid molecules having overall 3’ - 3’ or 5’- 5’ end structures as described herein, it will also be appreciated that with the presence of one or more additional reversed linkages and / or nucleosides having an inverted orientation, then the overall nucleic acid may have 3’ - 5’ end structures corresponding to the conventionally positioned 5’ / 3’ ends. In one aspect the nucleic acid may have a 3’-3’ reversed linkage, and the terminal sugar moiety may comprise a 5’ OH rather than a 5’ phosphate group at the 5’ position of that terminal sugar. A skilled person would therefore clearly understand that 5’-5’, 3’-3’ and 3’-5’ (reading in the direction of that terminus) end variants of the more conventional 5’-3’ structures (with reference to the numbering of ring atoms on the end nucleoside sugars) drawn herein are included in the scope of the disclosure, where a reversed linkage or linkages is / are present. In the situation of e.g. a reversed internucleoside linkage and / or one or more nucleosides having an inverted orientation creating an inverted end, and where the relative position of a linkage (e.g. to a linker) or the location of an internal feature (such as a modified nucleoside) is defined relative to the 5’ or 3’ end of the nucleic acid, then the 5’ or 3’ end is the conventional 5’ or 3’ end which would have existed had a reversed linkage not been in place, and wherein the conventional 5’ or 3’ end is determined by consideration of the directionality of the majority of the internal nucleoside linkages and / or nucleoside orientation within the nucleic acid. It is possible to tell from these internal bonds and / or nucleoside orientation which ends of the nucleic acid would constitute the conventional 5’ and 3’ ends (with reference to the numbering of ring atoms on the end nucleoside sugars) of the molecule absent the reversed linkage. For example, in the structure shown below there are abasic residues in the first 2 positions located at the “5’” end. Where the terminal nucleoside has an inverted orientation then the “5’” end indicated in the diagram below, which is the conventional 5’ end, can in fact comprise a 3’ OH in view of the inverted nucleoside at the terminal position. Nevertheless the majority of the molecule will comprise conventional internucleoside linkages that run from the 3’ OH of the sugar to the 5’ phosphate of the next sugar, when reading in the standard 5’ [PO4] to 3’ [OH] direction of a nucleic acid molecule (with reference to the numbering of ring atoms on the nucleoside sugars), which can be used to determine the conventional 5’ and 3’ ends that would be found absent the inverted end configuration. A 5’ A-A-Me-Me-Me-Me-Me-Me-F-Me-F-F-F-Me-Me-Me-Me-Me-Me-Me-Me-Me-Me 3’ In some embodiments, the second (sense) strand of the nucleic acid according to the invention comprises 2 consecutive abasic nucleosides in the 5’ terminal region as shown in the following 5’ terminal motif

[0003] wherein: B represents a nucleoside base, T represent H, OH or a 2’ ribose modification, Z represents the remaining nucleosides of said second strand. In some embodiments, the second (sense) strand of the nucleic acid according to the invention comprises 2 consecutive abasic nucleosides in the 5’ terminal region as shown in the following 5’ terminal motif

[0004] wherein: B represents a nucleoside base, T represents H, OH or a 2’ ribose modification (preferably a 2’ ribose modification, more preferably a 2’Me or 2’F ribose modification), V represents O or S (preferably O), R represents H or C1-4 alkyl (preferably H), Z represents the remaining nucleosides of said second strand, more preferably the following 5’ terminal motif wherein: B represents a nucleoside base, T represents a 2’ ribose modification (preferably a 2’Me or 2’F ribose modification), Z represents the remaining nucleosides of said second strand. The reversed bond is preferably located at the end of the nucleic acid e.g. RNA which is distal to a ligand moiety, such as a GalNAc containing portion, of the molecule. GalNAc-siRNA constructs with a 5’-GalNAc on the sense strand can have a reversed linkage on the opposite end of the sense strand. GalNAc-siRNA constructs with a 3’-GalNAc on the sense strand can have a reversed linkage on the opposite end of the sense strand. In a preferred embodiment, the second (sense) strand of the nucleic acid according to the invention comprises 2 consecutive abasic nucleosides in the 5’ terminal region as shown in the following 5’ terminal motif wherein: B represents a nucleoside base, T represent H, OH or a 2’ ribose modification (preferably a 2’ ribose modification, more preferably a 2’Me or 2’F ribose modification), V represent O or S (preferably O), R represent H or C1-4 alkyl (preferably H), Z comprises 11 to 26 contiguous nucleosides, preferably 15 to 21 contiguous nucleosides, and more preferably 19 contiguous nucleosides, more preferably the following 5’ terminal motif wherein: B represents a nucleoside base, T represents a 2’ ribose modification (preferably a 2’Me or 2’F ribose modification), Z comprises 19 contiguous nucleosides.NUCLEIC ACID LENGTHS In one aspect the i) the first strand of the nucleic acid has a length in the range of 17 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 19 or 23 nucleosides; and / or ii) the second strand of the nucleic acid has a length in the range of 17 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 19 or 21 nucleosides. Typically the duplex region of the nucleic acid is between 17 and 30 nucleosides in length, more preferably is 19 or 21 nucleosides in length. Similarly, the region of complementarity between the first strand and the portion of RNA transcribed from the NR3C2 gene is between 17 and 30 nucleosides in length. Generally, the duplex structure of the nucleic acid e.g. an iRNA is about 15 to 30 base pairs in length, e.g., 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19- 29, 19-28, 19-27, 19-26, 19-25, 19-24, 19- 23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. Similarly, the region of complementarity of an antisense sequence to a target sequence and / or the region of complementarity of an antisense sequence to a sense sequence is about 15 to 30 nucleosides in length, e.g., 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18- 20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20- 24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21- 25, 21-24, 21-23, or 21-22 nucleosides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. In certain preferred embodiments, the region of complementarity of an antisense sequence to a target sequence and / or the region of complementarity of an antisense sequence to a sense sequence is at least 17 nucleosides in length. For example, the region of complementarity between the antisense strand and the target is 19 to 21 nucleosides in length, for example, the region of complementarity is 21 nucleosides in length. In preferred embodiments, each strand is no more than 30 nucleosides in length. In certain preferred embodiments, the duplex structure of the nucleic acid e.g. an siRNA is 19 or 21 base pairs in length. In particularly preferred embodiment, the duplex may have one of the following structures:

[0005] A nucleic acid e.g. a dsRNA as described herein can further include one or more single-stranded nucleoside overhangs e.g., 1-4, 2-4, 1-3, 2-3, 1, 2, 3, or 4 nucleosides. A nucleoside overhang can comprise or consist of a nucleoside / nucleoside analog, including a deoxynucleoside / nucleoside. The overhang(s) can be on the sense strand, the antisense strand, or any combination thereof. Furthermore, the nucleoside(s) of an overhang can be present on the 5'-end, 3'- end, or both ends of an antisense or sense strand of a nucleic acid e.g. a dsRNA. In certain preferred embodiments, at least one strand comprises a 3' overhang of at least 1 nucleoside, e.g. , at least one strand comprises a 3' overhang of at least 2 nucleosides. The overhang is suitably on the antisense / guide strand and / or the sense / passenger strand. NUCLEIC ACID MODIFICATIONS In certain embodiments, the nucleic acid e.g. an RNA of the invention e.g., a dsiRNA, does not comprise further modifications, e.g., chemical modifications or conjugations known in the art and described herein. In other preferred embodiments, the nucleic acid e.g. RNA of the invention, e.g., a dsiRNA, is further chemically modified to enhance stability or other beneficial characteristics. In certain embodiments of the invention, substantially all of the nucleosides are modified. The nucleic acids featured in the invention can be synthesized or modified by methods well established in the art, such as those described in "Current protocols in nucleic acid chemistry," Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA, which is hereby incorporated herein by reference. Modifications include, for example, end modifications, e.g., 5'-end modifications (phosphorylation, conjugation, inverted linkages) or 3 '-end modifications (conjugation, DNA nucleosides within an RNA, or RNA nucleosides within a DNA, inverted linkages, etc.); base modifications, e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, conjugated bases; sugar modifications (e.g. , at the 2'- position or 4'- position) or replacement of the sugar; or backbone modifications, including modification or replacement of the phosphodiester linkages. Specific examples of nucleic acids such as siRNA compounds useful in the embodiments described herein include, but are not limited to RNAs containing modified backbones or no natural internucleoside linkages. Nucleic acids such as RNAs having modified backbones include, among others, those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified nucleic acids e.g. RNAs that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides. In some embodiments, a modified nucleic acid e.g. an siRNA will have a phosphorus atom in its internucleoside backbone. Modified nucleic acid e.g. RNA backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5'-linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 5'-3' or 5'-2'. Various salts, mixed salts and free acid forms are also included. Modified nucleic acids e.g. RNAs can also contain one or more substituted sugar moieties. The nucleic acids e.g. siRNAs, e.g., dsiRNAs, featured herein can include one of the following at the 2'-position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O- alkyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted. 2’ O- methyl and 2’-F are preferred modifications. In certain preferred embodiments, the nucleic acid comprises at least one modified nucleoside. The nucleic acid of the invention may comprise one or more modified nucleosides on the first strand and / or the second strand. In some embodiments, substantially all of the nucleosides of the sense strand and all of the nucleosides of the antisense strand comprise a modification. In some embodiments, all of the nucleosides of the sense strand and substantially all of the nucleosides of the antisense strand comprise a modification. In some embodiments, all of the nucleosides of the sense strand and all of the nucleosides of the antisense strand comprise a modification. In one embodiment, at least one of the modified nucleosides is selected from the group consisting of a deoxy- nucleoside, a 3 '-terminal deoxy-thymine (dT) nucleoside, a 2'-O-methyl modified nucleoside (also called herein 2’-Me, where Me is a methoxy) , a 2'-fluoro modified nucleoside, a 2'-deoxy- modified nucleoside, a locked nucleoside, an unlocked nucleoside, a conformationally restricted nucleoside, a constrained ethyl nucleoside, an abasic nucleoside, a 2' -amino- modified nucleoside, a 2'-O-allyl- modified nucleoside, 2' -C-alkyl- modified nucleoside, 2'-hydroxly- modified nucleoside, a 2'- methoxyethyl modified nucleoside, a 2'-O-alkyl-modified nucleoside, a morpholino nucleoside, a phosphoramidate, a non-natural base comprising nucleoside, a tetrahydropyran modified nucleoside, a 1 ,5-anhydrohexitol modified nucleoside, a cyclohexenyl modified nucleoside, a nucleoside comprising a phosphorothioate group, a nucleoside comprising a methylphosphonate group, a nucleoside comprising a 5 '-phosphate, and a nucleoside comprising a 5 '-phosphate mimic. In another embodiment, the modified nucleosides comprise a short sequence of 3 '-terminal deoxy-thymine nucleosides (dT). Modifications on the nucleosides may preferably be selected from the group including, but not limited to, LNA, HNA, CeNA, 2 -methoxyethyl, 2'-O-alkyl, 2-O-allyl, 2'-C-allyl, 2'-fluoro, 2'- deoxy, 2'-hydroxyl, and combinations thereof. In another embodiment, the modifications on the nucleosides are 2 -O-methyl (“2-Me”) or 2'-fluoro modifications. One preferred modification is a modification at the 2’-OH group of the ribose sugar, optionally selected from 2'-Me or 2’-F modifications. Preferred nucleic acid comprise one or more nucleosides on the first strand and / or the second strand which are modified, to form modified nucleosides, as follows: A nucleic acid wherein the modification is a modification at the 2’-OH group of the ribose sugar, optionally selected from 2'-Me or 2’-F modifications. A nucleic acid wherein the first strand comprises a 2’-F modification at any of position 2, position 6, position 14, or any combination thereof, counting from position 1 of said first strand. A nucleic acid wherein the second strand comprises a 2’-F modification at any of position 7, position 9, position 11, or any combination thereof, counting from position 1 of said second strand. A nucleic acid wherein the second strand comprises a 2’-F modification at position 7 and / or 9, and / or 11, and / or 13, counting from position 1 of said second strand. A nucleic acid wherein the second strand comprises a 2’-F modification at position 7 and 9 and 11 counting from position 1 of said second strand. A nucleic acid wherein the first and second strand each comprise 2'-Me and 2’-F modifications. A nucleic which comprises at least one thermally destabilizing modification, suitably at one or more of positions 1 to 9 of the first strand counting from position 1 of the first strand, and / or at one or more of positions on the second strand aligned with positions 1 to 9 of the first strand, wherein the destabilizing modification is selected from a modified unlocked nucleic acid (IMUNA) and a glycol nucleic acid (GNA), preferably a glycol nucleic acid.A nucleic acid wherein the nucleic acid comprises 3 or more 2’-F modifications at positions 7 to 13 of the second strand, such as 4, 5, 6 or 72’-F modifications at positions 7 to 13 of the second strand, counting from position 1 of said second strand. A nucleic acid wherein said second strand comprises at least 3, such as 4, 5 or 6, 2’-Me modifications at positions 1 to 6 of the second strand, counting from position 1 of said second strand. A nucleic acid wherein said first strand comprises at least 52’-Me consecutive modifications at the 3’ terminal region, preferably including the terminal nucleoside at the 3’ terminal region, or at least within 1 or 2 nucleosides from the terminal nucleoside at the 3’ terminal region. A nucleic acid wherein said first strand comprises 72’-Me consecutive modifications at the 3’ terminal region, preferably including the terminal nucleoside at the 3’ terminal region. A nucleic acid which comprises at least one thermally destabilizing modification at position 7 of the first strand, counting from position 1 of the first strand. A nucleic acid which is an siRNA oligonucleoside, wherein the siRNA oligonucleoside comprises at least 32’-F modifications at positions 6 to 12 of the second strand, counting from position 1 of said second strand. A nucleic acid which is an siRNA oligonucleoside, wherein said second strand comprises at least 32’-Me modifications at positions 1 to 6 of the second strand, counting from position 1 of said second strand. A nucleic acid which is an siRNA oligonucleoside, wherein each of the first and second strands comprises an alternating modification pattern, preferably a fully alternating modification pattern along the entire length of each of the first and second strands, wherein the nucleosides of the first strand are modified by (i) 2’Me modifications on the odd numbered nucleosides counting from position 1 of the first strand, and (ii) 2’F modifications on the even numbered nucleosides counting from position 1 of the first strand, and nucleosides of the second strand are modified by (i) 2’F modifications on the odd numbered nucleosides counting from position 1 of the second strand, and (ii) 2’Me modifications on the even numbered nucleosides counting from position 1 of the second strand. Typically, such fully alternating modification patterns are present in a blunt ended oligonucleoside, wherein each of the first and second strands are 19 or 23 nucleosides in length. Position 1 of the first or the second strand is the nucleoside which is the closest to the end of the nucleic acid (ignoring any abasic nucleosides) and that is joined to an adjacent nucleoside (at Position 2) via a 3’ to 5’ internal bond, with reference to the bonds between the sugar moieties of the backbone, and reading in a direction away from that end of the molecule. It can therefore be seen that “position 1 of the sense strand” is the 5’ most nucleoside (not including abasic nucleosides) at the conventional 5’ end of the sense strand. Typically, the nucleoside at this position 1 of the sense strand will be equivalent to the 5’ nucleoside of the selected target nucleic acid sequence, and more generally the sense strand will have equivalent nucleosides to those of the target nucleic acid sequence starting from this position 1 of the sense strand, whilst also allowing for acceptable mismatches between the sequences. As used herein, “position 1 of the antisense strand” is the 5’ most nucleoside (not including abasic nucleosides) at the conventional 5’ end of the antisense strand. As hereinbefore described, there will be a region of complementarity between the sense and antisense strands, and in this way the antisense strand will also have a region of complementarity to the target nucleic acid sequence as referred to above. In certain embodiments, the nucleic acid e.g. RNAi agent further comprises at least one phosphorothioate or methylphosphonate internucleoside linkage. For example the phosphorothioate or methylphosphonate internucleoside linkage can be at the 3 '-terminus or in the terminal region of one strand, i.e. , the sense strand or the antisense strand; or at the ends of both strands, the sense strand and the antisense strand. In certain embodiments, the phosphorothioate or methylphosphonate internucleoside linkage is at the 5 'terminus or in the terminal region of one strand, i.e. , the sense strand or the antisense strand; or at the ends of both strands, the sense strand and the antisense strand. In certain embodiments, a phosphorothioate or a methylphosphonate internucleoside linkage is at both the 5'- and 3 '-terminus or in the terminal region of one strand, i.e. , the sense strand or the antisense strand; or at the ends of both strands, the sense strand and the antisense strand. Any nucleic acid may comprise one or more phosphorothioate (PS) modifications within the nucleic acid, such as at least two PS internucleoside bonds at the ends of a strand. At least one of the oligoribonucleoside strands preferably comprises at least two consecutive phosphorothioate modifications in the last 3 nucleosides of the oligonucleoside. The invention therefore also relates to: A nucleic acid disclosed herein which comprises phosphorothioate internucleoside linkages respectively between at least two or three consecutive positions, such as in a 5’ and / or 3’ terminal region and / or near terminal region of the second strand, whereby said near terminal region is preferably adjacent said terminal region wherein said one or more abasic nucleosides of said second strand is / are located. A nucleic acid disclosed herein which comprises phosphorothioate internucleoside linkages respectively between at least two or three consecutive positions in a 5’ and / or 3’ terminal region of the first strand, whereby preferably the terminal position at the 5’ and / or 3’ terminal region of said first strand is attached to its adjacent position by a phosphorothioate internucleoside linkage. The nucleic acid strand may be an RNA comprising a phosphorothioate internucleoside linkage between the three nucleosides contiguous with 2 terminally located abasic nucleosides. A preferred nucleic acid is a double stranded RNA comprising 2 adjacent abasic nucleosides at the 5’ terminus of the second strand and a ligand moiety comprising one or more GalNAc ligand moieties at the opposite 3’ end of the second strand. Further preferred, the same nucleic acid may also comprise a phosphorothioate bond between nucelotides at positions 3-4 and 4-5 of the second strand, reading from the position 1 of the second strand. Further preferred, the same nucleic acid may also comprise a 2’ F modification at positions 7, 9 and 11 of the second strand. Preferred modifications are as follows: A nucleic acid wherein modified nucleosides of said second strand comprise a modification pattern according to any one of the following (5’-3’): Me - Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me – Me, or Me - Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, or Me - Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, or Me - Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, or Me - Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me. A nucleic acid wherein modified nucleosides of said second strand comprise a modification pattern according to any one of the following (5’-3’): Me(s)Me(s)Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me – Me, or Me(s)Me(s)Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, or Me(s)Me(s)Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, or Me(s)Me(s)Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, or Me(s)Me(s)Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, or Me – Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F(s)Me(s)Me, or Me – Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, or Me – Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, or Me – Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, or Me – Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, wherein (s) is a phosphorothioate internucleoside linkage. A nucleic acid wherein modified nucleosides of said second strand comprise a modification pattern according to any one of the following (5’-3’): ia – ia - Me - Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me – Me, or ia – ia - Me - Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, or ia – ia - Me - Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, or ia – ia - Me - Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, or ia – ia - Me - Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, or Me - Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me – Me - ia – ia, or Me - Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me - ia – ia, or Me - Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me - ia – ia, or Me - Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me - ia – ia, or Me - Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me- ia – ia, wherein ia represents an inverted abasic nucleoside, and when the inverted abasic nucleosides as represented by ia - ia are present at the 3’ terminus of the second strand, said inverted abasic nucleosides are present in a 2 nucleoside overhang. A nucleic acid wherein modified nucleosides of said second strand comprise a modification pattern according to any one of the following (5’-3’): ia – ia - Me(s)Me(s)Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me - Me, or ia – ia - Me(s)Me(s)Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me, or ia – ia - Me(s)Me(s)Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me, or ia – ia - Me(s)Me(s)Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, or ia – ia - Me(s)Me(s)Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me - Me, or Me – Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F(s)Me(s)Me - ia – ia, or Me – Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia, or Me – Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia, or Me – Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia , or Me – Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia, wherein: (s) is a phosphorothioate internucleoside linkage, ia represents an inverted abasic nucleoside, and when the inverted abasic nucleosides as represented by ia - ia are present at the 3’ terminus of the second strand, said inverted abasic nucleosides are present in a 2 nucleoside overhang. A nucleic acid wherein modified nucleosides comprise any one of the following modification patterns: Modification pattern 1: Second strand (5’-3’): Me - Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me – Me, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 2: Second strand (5’-3’): Me - Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 3: Second strand (5’-3’): Me - Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 4: Second strand (5’-3’): Me - Me - Me - Me - Me - Me - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 5: Second strand (5’-3’): Me - Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me – Me Or Modification pattern 6: Second strand (5’-3’): Me - Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me – Me. A nucleic acid wherein modified nucleosides comprise any one of the following modification patterns: Modification pattern 1: Second strand (5’-3’): Me(s)Me(s)Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me – Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 2: Second strand (5’-3’): Me(s)Me(s)Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 3: Second strand (5’-3’): Me(s)Me(s)Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 4: Second strand (5’-3’): Me(s)Me(s)Me - Me - Me - Me - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 5: Second strand (5’-3’): Me(s)Me(s)Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me(s)F(s)Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 6: Second strand (5’-3’): Me(s)Me(s)Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me(s)F(s)Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me wherein (s) is a phosphorothioate internucleoside linkage. A nucleic acid wherein modified nucleosides comprise any one of the following modification patterns: Modification pattern 1: Second strand (5’-3’): Me – Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F(s)Me(s)Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 2: Second strand (5’-3’): Me – Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 3: Second strand (5’-3’): Me – Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 4: Second strand (5’-3’): Me – Me - Me - Me - Me - Me - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 5: Second strand (5’-3’): Me – Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, First strand (5’-3’): Me(s)F(s)Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 6: Second strand (5’-3’): Me – Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me, First strand (5’-3’): Me(s)F(s)Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me wherein (s) is a phosphorothioate internucleoside linkage. A nucleic acid wherein modified nucleosides comprise any one of the following modification patterns: Modification pattern 1: Second strand (5’-3’): ia – ia - Me - Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me – Me, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 2: Second strand (5’-3’): ia – ia - Me - Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 3: Second strand (5’-3’): ia – ia - Me - Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 4: Second strand (5’-3’): ia – ia - Me - Me - Me - Me - Me - Me - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 5: Second strand (5’-3’): ia – ia - Me - Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me – Me Or Modification pattern 6: Second strand (5’-3’): ia – ia - Me - Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me - F - Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me – Me, wherein ia represents an inverted abasic nucleoside. A nucleic acid wherein modified nucleosides comprise any one of the following modification patterns: Modification pattern 1: Second strand (5’-3’): Me - Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me – Me - ia – ia, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 2: Second strand (5’-3’): Me - Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me - ia – ia, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 3: Second strand (5’-3’): Me - Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me - ia – ia, First strand (5’-3’): Me - F - Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 4: Second strand (5’-3’): Me - Me - Me - Me - Me - Me - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me - ia – ia, First strand (5’-3’): Me - F - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me Or Modification pattern 5: Second strand (5’-3’): Me - Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me - ia – ia, First strand (5’-3’): Me - F - Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me – Me Or Modification pattern 6: Second strand (5’-3’): Me - Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me - ia – ia,- First strand (5’-3’): Me - F - Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me - Me – Me, wherein ia represents an inverted abasic nucleoside, and when the inverted abasic nucleosides as represented by ia - ia are present at the 3’ terminus of the second strand, said inverted abasic nucleosides are present in a 2 nucleoside overhang. A nucleic acid wherein modified nucleosides comprise any one of the following modification patterns: Modification pattern 1: Second strand (5’-3’): ia – ia - Me(s)Me(s)Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F - Me - Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 2: Second strand (5’-3’): ia – ia - Me(s)Me(s)Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 3: Second strand (5’-3’): ia – ia - Me(s)Me(s)Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 4: Second strand (5’-3’): ia – ia - Me(s)Me(s)Me - Me - Me - Me - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 5: Second strand (5’-3’): ia – ia - Me(s)Me(s)Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me – Me, First strand (5’-3’): Me(s)F(s)Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 6: Second strand (5’-3’): ia – ia - Me(s)Me(s)Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me - Me - Me, First strand (5’-3’): Me(s)F(s)Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me wherein: (s) is a phosphorothioate internucleoside linkage, ia represents an inverted abasic nucleoside. A nucleic acid wherein modified nucleosides comprise any one of the following modification patterns: Modification pattern 1: Second strand (5’-3’): Me – Me - Me - Me - Me - Me - F - F - F - F - F - Me - Me - Me - Me - Me - Me - Me - F(s)Me(s)Me - ia – ia, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 2: Second strand (5’-3’): Me – Me - Me - Me - Me - F - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 3: Second strand (5’-3’): Me – Me - Me - Me - Me - Me -F- Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - F - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 4: Second strand (5’-3’): Me – Me - Me - Me - Me - Me - F - Me - F - F - F - F - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia, First strand (5’-3’): Me(s)F(s)Me - F - Me - F - Me - Me - Me - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 5: Second strand (5’-3’): Me – Me - Me - Me - Me - Me - Me - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia, First strand (5’-3’): Me(s)F(s)Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me Or Modification pattern 6: Second strand (5’-3’): Me – Me - Me - Me - Me - Me - F - Me - F - F - F - Me - Me - Me - Me - Me - Me - Me - Me(s)Me(s)Me - ia – ia, First strand (5’-3’): Me(s)F(s)Me - Me - Me - F - Me - Me - F - Me - Me - Me - Me - F - Me - F - Me - Me - Me - Me - Me(s)Me(s)Me wherein: (s) is a phosphorothioate internucleoside linkage, ia represents an inverted abasic nucleoside, and when the inverted abasic nucleosides as represented by ia - ia are present at the 3’ terminus of the second strand, said inverted abasic nucleosides are present in a 2 nucleoside overhang. Preferred modifications that can be used with sequences according to the present invention can be as follows: Modification 1: First strand modification: NmsNfsNmNfNmNfNmNfNfNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNfNfNfNfNfNmNmNmNmNmNmNmNfNmNm (5’ to 3’) Modification 2: First strand modification: NmsNfsNmNfNmNfNmNfNfNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNfNfNmNfNfNfNfNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 3: First strand modification: NmsNfsNmNfNmNfNmNfNfNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNfNmNfNfNfNfNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 4: First strand modification: NmsNfsNmNfNmNfNmNmNmNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNfNmNfNfNfNfNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 5: First strand modification: NmsNfsNmNmNmNfNmNmNfNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 6: First strand modification: NmsNfsNmNmNmNfNmNmNmNmNmNmNmNfNmNfNmNfNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 7: First strand modification: NmsNfsNmNmNmNyNmNmNmNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 8: First strand modification: NmsNfsNmNmNmNyNmNfNfNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’)Modification 9: First strand modification: NmsNfsNmNmNmNfNmNmNmNmNmNmNmNfNmNfNmNmNmNfNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 10: First strand modification: NmsNfsNmNfNmNfNmNmNmNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 11: First strand modification: NmsNfsNmNfNmNfNmNfNfNmNmNmNmNfNmNfNmNmNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 12: First strand modification: NmsNfsNmNmNmNfNmNfNfNmNmNmNmNfNmNfNmNfNmNmNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’) Modification 13: First strand modification: NmsNfsNmNmNmNfNmNfNfNmNmNmNmNfNmNfNmNmNmNfNmsNmsNm (5’ to 3’) Second strand modification: iaiaNmsNmsNmNmNmNmNmNmNfNfNfNmNmNmNmNmNmNmNmNmNm (5’ to 3’) wherein in each of the above modifications: ia represents an inverted abasic nucleoside; Nm represents a 2’Me ribose modified nucleoside; Nf represents a 2’F ribose modified nucleoside; Ny represents a nucleoside with a thermally destabilizing modification, preferably wherein the destabilizing modification is selected from a modified unlocked nucleic acid (UNA) and a glycol nucleic acid (GNA), more preferably a glycol nucleic acid, most preferably an (S)- glycol nucleic acid; s represents a phosphorothioate internucleoside bond. In certain embodiments, the nucleic acid comprises a 5’ vinylphosphonate (5’VP) modification. The 5’VP modification is preferably on the antisense strand, but can be on the sense strand as well, or instead. Preferably, the 5’VP modification is a 5’-(E)-vinylphosphonate (5’-(E)-VP) modification. A 5'-VP modification is a stable phosphate mimic added at the 5' end of an oligonucleotide. It is a modification in which the 5' carbon forms a double bond to a 6' carbon linked to the phosphorus. Such modifications are described in Haraszti et al 2017 (Haraszti et al., 5΄-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo. Nucleic Acids Res.2017 Jul 27;45(13):7581-7592. doi: 10.1093 / nar / gkx507. PMID: 28591791; PMCID: PMC5570069). CONJUGATION OF NUCLEIC ACID TO LIGAND Another modification of a nucleic acid e.g. RNA e.g. an siRNA of the invention involves linking the nucleic acid e.g. the siRNA to one or more ligand moieties e.g. to enhance the activity, cellular distribution, or cellular uptake of the nucleic acid e.g. siRNA e.g., into a cell. In some embodiments, the ligand moiety described can be attached to a nucleic acid e.g. an siRNA oligonucleoside, via a linker that can be cleavable or non-cleavable. The term "linker" or "linking group" means an organic moiety that connects two parts of a compound, e.g., covalently attaches two parts of a compound. The ligand can be attached to the 3' or 5’ end of the sense strand. The ligand is preferably conjugated to 3’ end of the sense strand of the nucleic acid e.g. an siRNA agent. The invention therefore relates in a further aspect to a conjugate for inhibiting expression of a target e.g. a target gene, in a cell, said conjugate comprising a nucleic acid portion and one or more ligand moieties, said nucleic acid portion comprising a nucleic acid as disclosed herein. In one aspect the second strand of the nucleic acid is conjugated directly or indirectly (e.g. via a linker) to the one or more ligand moiety(s), wherein said ligand moiety is typically present at a terminal region of the second strand, preferably at the 3’ terminal region thereof. In certain embodiments, the ligand moiety comprises a GalNAc or GalNAc derivative attached to the nucleic acid e.g. dsiRNA through a linker. Therefore, the invention relates to a conjugate wherein the ligand moiety comprises i) one or more GalNAc ligands; and / or ii) one or more GalNAc ligand derivatives; and / or iii) one or more GalNAc ligands conjugated to said nucleic acid through a linker. Said GalNAc ligand may be conjugated directly or indirectly to the 5’ or 3’ terminal region of the second strand of the nucleic acid, preferably at the 3’ terminal region thereof. GalNAc ligands are well known in the art and described in, inter alia, EP3775207A1. In some embodiments, the GalNAc ligand is comprised in any one of the linkers shown in Figures 1 to 4 or Figure 5 (Formula XI), wherein the "oligonucleotide" may be any nucleic acid disclosed herein. Accordingly, the "oligonucleotide" may comprise other bonds than a phosphodiester bond, such as one or more phosphorothioate bonds. Preferably, the nucleic acid according to the invention is a double stranded oligonucleoside as defined herein and the linker is conjugated to the second strand, more preferably to the 3' terminal region of the second strand, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figure 3, wherein the "oligonucleotide" may be any nucleic acid disclosed herein. Accordingly, the "oligonucleotide" may comprise other bonds than a phosphodiester bond, such as one or more phosphorothioate bonds. Preferably, the nucleic acid according to the invention is a double stranded oligonucleoside as defined herein and the linker is conjugated to the second strand, more preferably to the 3' terminal region of the second strand, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figure 5 (Formula XI), wherein the "oligonucleotide" may be any nucleic acid disclosed herein. Accordingly, the "oligonucleotide" may comprise other bonds than a phosphodiester bond, such as one or more phosphorothioate bonds. Preferably, the nucleic acid according to the invention is a double stranded oligonucleoside as defined herein and the linker is conjugated to the second strand, more preferably to the 3' terminal region of the second strand, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in any one of the linkers shown in Figures 1 to 4 or Figure 5 (Formula XI), wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified or unmodified second strand comprising or consisting of any one of SEQ ID NO:447 to SEQ ID NO:669, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:447 to SEQ ID NO:669, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figure 3, wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified or unmodified second strand comprising or consisting of any one of SEQ ID NO:447 to SEQ ID NO:669, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:447 to SEQ ID NO:669, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figure 5 (Formula XI), wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified or unmodified second strand comprising or consisting of any one of SEQ ID NO:447 to SEQ ID NO:669, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one SEQ ID NO:447 to SEQ ID NO:669, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in any one of the linkers shown in Figures 1 to 4 or Figure 5 (Formula XI), wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:893 to SEQ ID NO:1115, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figure 3, wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:893 to SEQ ID NO:1115, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figure 5 (Formula XI), wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:893 to SEQ ID NO:1115, via a phosphodiester bond. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figures 1 to 4 or Figure 5 (Formula XI), wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914, wherein the second strand has the following structure wherein: T represents a 2’Me ribose modification, B represents the nucleoside bases of the first two basic nucleosides in the 5’ terminal region of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914 and Z represents the remaining 19 contiguous basic nucleosides of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figure 5 (Formula XI), wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914, wherein the second strand has the following structure wherein: T represents a 2’Me ribose modification, B represents the nucleoside bases of the first two basic nucleosides in the 5' terminal region of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914, and Z represents the remaining 19 contiguous basic nucleosides of any one of SEQ ID NO:893 to SEQ ID NO:1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914. In some embodiments, the GalNAc ligand is comprised in the linker shown in Figure 3, wherein the “oligonucleotide” represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO:1115, wherein the second strand has the following structure wherein: T represents a 2’Me ribose modification, B represents the nucleoside bases of the first two basic nucleosides in the 5' terminal region of any one of SEQ ID NO:893 to SEQ ID NO:1115, and Z represents the remaining 19 contiguous basic nucleosides of any one of SEQ ID NO:893 to SEQ ID NO:1115, respectively. In some embodiments, the ligand moiety comprises one or more ligands. In some embodiments, the ligand moiety comprises one or more carbohydrate ligands. In some embodiments, the one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide and / or polysaccharide. In some embodiments, the one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N-AcetylGalactosamine moieties, and / or one or more mannose moieties. In some embodiments, the one or more carbohydrates comprise one or more N-Acetyl- Galactosamine moieties. In some embodiments, the compounds as described anywhere herein comprise two or three N- AcetylGalactosamine moieties. In some embodiments, the one or more ligands are attached in a linear configuration, or in a branched configuration, for example each configuration being respectively attached to a branch point in an overall linker. Exemplary linear configurations and Exemplary branched configurations are shown in Figures 15a and 15b: In Fig 15a, (linear), (a) and / or (b) can typically represent connecting bonds or groups, such as phosphate or phosphorothioate groups. In Fig 15b, (branched), in some embodiments, the one or more ligands are attached as a biantennary or triantennary branched configuration. Typically, a triantennary branched configuration can be preferred, such as an N-AcetylGalactosamine triantennary branched configuration. LINKER Exemplary compounds of the invention comprise a ‘linker moiety’, such as that as depicted in Formula (I), that is part of an overall ‘linker’. Formula I wherein: R1 at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; R2is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X1 and X2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; m is an integer of from 1 to 6; n is an integer of from 1 to 10; q, r, s, t, v are independently integers from 0 to 4, with the proviso that: (i) q and r cannot both be 0 at the same time; and (ii) s, t and v cannot all be 0 at the same time; Z is an oligonucleoside moiety. As will be further understood in the art, exemplary compounds of the invention comprise an overall linker that is located between the oligonucleoside moiety and the ligand moiety of these compounds. The overall linker, thereby ‘links’ the oligonucleoside moiety and the ligand moiety to each other. The overall linker is often notionally envisaged as comprising one or more linker building blocks. For example, there is a linker portion that is depicted as the ‘linker moiety’ as represented in Formula (I) positioned adjacent the ligand moiety and attaching the ligand moiety, typically via a branch point, directly or indirectly to the oligonucleoside moiety. The linker moiety as depicted in Formula (I) can also often be referred to as the ‘ligand arm or arms’ of the overall linker. There can also, but not always, be a further linker portion between the oligonucleoside moiety and the branch point, that is often referred to as the ‘tether moiety’ of the overall linker, ‘tethering’ the oligonucleoside moiety to the remainder of the conjugated compound. Such ‘ligand arms’ and / or ‘linker moieties’ and / or ‘tether moieties’ can be envisaged by reference to the linear and / or branched configurations as set out above. As can be seen from the claims, and the reminder of the patent specification, the scope of the present invention extends to linear or branched configurations, and with no limitation as to the number of individual ligands that might be present. Furthermore, the addressee will also be aware that there are many structures that could be used as the linker moiety, based on the state of the art and the expertise of an oligonucleoside chemist. The remainder of the overall linker (other than the linker moiety) as set out in the claims, and the remainder of the patent specification, is shown by its chemical constituents in Formula (I), which the inventors consider to be particularly unique to the current invention. In more general terms, however, these chemical constituents could be described as a ‘tether moiety’ as hereinbefore described, wherein the ‘tether moiety’ is that portion of the overall linker which comprises the group of atoms between Z, namely the oligonucleoside moiety, and the linker moiety as depicted in Formula (I). Tether moiety of Formula I In relation to Formula (I), the ‘tether moiety’ comprises the group of atoms between Z, namely the oligonucleoside moiety, and the linker moiety. In some embodiments, R1 is hydrogen at each occurrence. In some embodiments, R1 is methyl. In some embodiments, R1is ethyl. In some embodiments, R2is hydroxy. In some embodiments, R2is halo. In some embodiments, R2is fluoro. In some embodiments, R2 is chloro. In some embodiments, R2 is bromo. In some embodiments, R2 is iodo. In some embodiments, R2 is nitro. In some embodiments, X1is methylene. In some embodiments, X1is oxygen. In some embodiments, X1 is sulfur. In some embodiments, X2 is methylene. In some embodiments, X2 is oxygen. In some embodiments, X2is sulfur. In some embodiments, m = 3. In some embodiments, n = 6. In some embodiments, X1is oxygen and X2is methylene. In some embodiments, both X1and X2are methylene. In some embodiments, q = 1, r = 2, s = 1, t = 1, v = 1. In some embodiments, q = 1, r = 3, s = 1, t = 1, v = 1. In some embodiments, R1is hydrogen at each occurrence, n = 6, m = 3, R2is fluoro, X2is methylene, v = 1, t = 1, s = 1, X1 is methylene, q = 1 and r = 2. Thus, in some embodiments, exemplary compounds of the invention comprise the following structure: Formula (IV) In some embodiments, R1 is hydrogen at each occurrence, n = 6, m = 3, R2 is fluoro, X2 is methylene, v = 1, t = 1, s = 1, X1is oxygen, q = 1 and r = 2. Thus, in some embodiments, exemplary compounds of the invention comprise the following structure: Formula (II) Alternative tether moieties During the synthesis of compounds of the present invention, alternative tether moiety structures may arise. In some embodiments, alternative tether moieties have a change of one or more atoms in the tether moiety of the overall linker compared to tether moieties described anywhere herein. In some embodiments, the alternative tether moiety is a compound of Formula (I) as described anywhere herein, wherein R2is hydroxy. In some embodiments, R1 is hydrogen at each occurrence, n = 6, m = 3, R2 is hydroxy, X2 is methylene, v = 1, t = 1, s = 1, X1 is methylene, q = 1 and r = 2. Thus, in some embodiments, compounds of the invention comprise the following structure: Formula (V) In some embodiments, R1 is hydrogen at each occurrence, n = 6, m = 3, R2 is hydroxy, X2 is methylene, v = 1, t = 1, s = 1, X1 is oxygen, q = 1 and r = 2. Thus, in some embodiments, compounds of the invention comprise the following structure: Formula (III) Linker moiety In relation to Formula (I), the ‘linker moiety’ as depicted in Formula (I) comprises the group of atoms located between the tether moiety as described anywhere herein, and the ligand moiety as described anywhere herein. In some embodiments: as depicted in Formula (I) as described anywhere herein is any of Formulae (VIa), (VIb) or (VIc), preferably Formula (VIa): Formula (VIa) wherein: AIis hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and b is an integer of 2 to 5; or Formula (VIb) wherein: AI is hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and c and d are independently integers of 1 to 6; or

[0006] Formula (VIc) wherein: AI is hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and e is an integer of 2 to 10. In some embodiments, the moiety: as depicted in Formula (I) is Formula (VIa): Formula (VIa) wherein: AI is hydrogen, or a suitable hydroxy protecting group; a is 3; and b is an integer of 3. In some embodiments, the moiety: as depicted in Formula (I) as described anywhere herein is Formula (VII): Formula (VII) wherein: AIis hydrogen; a is an integer of 2 or 3, preferably 3. Other exemplary compounds of the invention comprise a ‘linker moiety’, as depicted in Formula (I*), that is part of an overall ‘linker’. Formula I* Where: r and s are independently an integer selected from 1 to 16; and Z is an oligonucleoside moiety. As will be further understood in the art, exemplary compounds of the invention comprise an overall linker that is located between the oligonucleoside moiety and the ligand moiety of these compounds. The overall linker, thereby ‘links’ the oligonucleoside moiety and the ligand moiety to each other. The overall linker is often notionally envisaged as comprising one or more linker building blocks. For example, there is a linker portion that is depicted as the ‘linker moiety’ as represented in Formula (I*) positioned adjacent the ligand moiety and attaching the ligand moiety, typically via a branch point, directly or indirectly to the oligonucleoside moiety. The linker moiety as depicted in Formula (I*) can also often be referred to as the ‘ligand arm or arms’ of the overall linker. There can also, but not always, be a further linker portion between the oligonucleoside moiety and the branch point, that is often referred to as the ‘tether moiety’ of the overall linker, ‘tethering’ the oligonucleoside moiety to the remainder of the conjugated compound. Such ‘ligand arms’ and / or ‘linker moieties’ and / or ‘tether moieties’ can be envisaged by reference to the linear and / or branched configurations as set out above. As can be seen from the claims, and the reminder of the patent specification, the scope of the present invention extends to linear or branched configurations, and with no limitation as to the number of individual ligands that might be present. Furthermore, the addressee will also be aware that there are many structures that could be used as the linker moiety, based on the state of the art and the expertise of an oligonucleoside chemist. The remainder of the overall linker (other than the linker moiety) as set out in the claims, and the remainder of the patent specification, is shown by its chemical constituents in Formula (I), which the inventors consider to be particularly unique to the current invention. In more general terms, however, these chemical constituents could be described as a ‘tether moiety’ as hereinbefore described, wherein the ‘tether moiety’ is that portion of the overall linker which comprises the group of atoms between Z, namely the oligonucleoside moiety, and the linker moiety as depicted in Formula (I). Tether moiety In relation to Formula (I*), the ‘tether moiety’ comprises the group of atoms between Z, namely the oligonucleoside moiety, and the linker moiety. In some embodiments, s is an integer selected from 4 to 12. In some embodiments, s is 6. In some embodiments, r is an integer selected from 4 to 14. In some embodiments, r is 6. In some embodiments, r is 12. In some embodiments, r is 12 and s is 6. Thus, in some embodiments, exemplary compounds of the invention comprise the following structure: Formula (II*) In some embodiments, r is 6 and s is 6. Thus, in some embodiments, exemplary compounds of the invention comprise the following structure: Formula (III*) Linker moiety In relation to Formula (I*), the ‘linker moiety’ as depicted in Formula (I) comprises the group of atoms located between the tether moiety as described anywhere herein, and the ligand moiety as described anywhere herein. In some embodiments, the moiety: as depicted in Formula (I*) as described anywhere herein is any of Formulae (IV*), (V*) or (VI*), preferably Formula (IV*): Formula (IV*) wherein: AIis hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and b is an integer of 2 to 5; or Formula (V*) wherein: AI is hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and c and d are independently integers of 1 to 6; or

[0007] Formula (VI*) wherein: AI is hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and e is an integer of 2 to 10. In some embodiments, the moiety: as depicted in Formula (I) is Formula (VIa*): Formula (VIa*) wherein: AI is hydrogen, or a suitable hydroxy protecting group; a is 3; and b is an integer of 3. In some embodiments, the moiety: as depicted in Formula (I) as described anywhere herein is Formula (VII*): Formula (VII*) wherein: AI is hydrogen; a is an integer of 2 or 3. In some embodiments, a = 2. In some embodiments, a = 3. In some embodiments, b = 3. VECTOR AND CELL In one aspect, the invention provides a cell containing a nucleic acid, such as inhibitory RNA [RNAi] as described herein. In one aspect, the invention provides a cell comprising a vector as described herein. In one aspect the invention provides a vector comprising an oligonucleotide inhibitor, e.g.an iRNA e.g. siRNA. PHARMACEUTICALLY ACCEPTABLE COMPOSITIONS In one aspect, the invention provides a pharmaceutical composition for inhibiting expression of a target gene, the composition comprising an inhibitor such as an oligomer such as a nucleic acid as disclosed herein. The pharmaceutically acceptable composition may comprise an excipient and or carrier. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or poly anhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g. , magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g. , starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc). Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone, and the like. Formulations for topical administration of nucleic acids can include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions can also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non- parenteral administration which do not deleteriously react with nucleic acids can be used. In one embodiment, the nucleic acid or composition is administered in an unbuffered solution. In certain embodiments, the unbuffered solution is saline or water. In other embodiments, the nucleic acid e.g. RNAi agent is administered in a buffered solution. In such embodiments, the buffer solution can comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. For example, the buffer solution can be phosphate buffered saline (PBS). DOSAGES The pharmaceutical compositions of the invention may be administered in dosages sufficient to inhibit expression of a gene or modify the expression or function of a target. In general, where the composition comprising a nucleic acid, a suitable dose of a nucleic acid e.g. an siRNA of the invention will be in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day. Typically, a suitable dose of a nucleic acid e.g. an siRNA of the invention will be in the range of about 0.1 mg / kg to about 5.0 mg / kg, e.g., about 0.3 mg / kg and about 3.0 mg / kg. A repeat-dose regimen may include administration of a therapeutic amount of a nucleic acid e.g. siRNA on a regular basis, such as every other day or once a year. In certain embodiments, the nucleic acid e.g. siRNA is administered about once per month to about once per quarter (i.e., about once every three months). In the present invention, in particular regarding the treatment of myocardial infarction and / or symptoms thereof, it is preferred that the first administration of the inhibitor is shortly after the myocardial infarction occurred. In particular, the inhibitor of the invention may preferably first be administered at the time a myocardial infarction occurs or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours after myocardial infarction occurred. It is also provided herein that the inhibitor of the invention is first administered within 1 day, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days after myocardial infarction. In various embodiments, the nucleic acid e.g. siRNA agent is administered at a dose of about 0.01 mg / kg to about 10 mg / kg or about 0.5 mg / kg to about 50 mg / kg. In some embodiments, the nucleic acid e.g. siRNA agent is administered at a dose of about 10 mg / kg to about 30 mg / kg. In certain embodiments, the nucleic acid e.g. siRNA agent is administered at a dose selected from about 0.5 mg / kg 1 mg / kg, 1.5 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, and 30 mg / kg. In certain embodiments, the nucleic acid e.g. siRNA agent is administered about once per week, once per month, once every other two months, or once a quarter (i.e., once every three months) at a dose of about 0.1 mg / kg to about 5.0 mg / kg. In certain embodiments, the nucleic acid e.g. siRNA agent is administered to the subject once a week. In certain embodiments, the nucleic acid e.g. siRNA agent is administered to the subject once a month. In certain embodiments, the nucleic acid e.g. siRNA agent is administered once per quarter (i.e., every three months). After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months, or a year; or longer. The pharmaceutical composition can be administered once daily, or administered as two, three, or more sub-doses at appropriate intervals throughout the day or even using continuous infusion or delivery through a controlled release formulation. In that case, the nucleic acid e.g. siRNA contained in each sub-dose must be correspondingly smaller in order to achieve the total daily dosage. The dosage unit can also be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the nucleic acid e.g. siRNA over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention. In this embodiment, the dosage unit contains a corresponding multiple of the daily dose. In other embodiments, a single dose of the pharmaceutical compositions can be long lasting, such that subsequent doses are administered at not more than 3, 4, or 5 day intervals, or at not more than 1, 2, 3, or 4 week intervals. In some embodiments of the invention, a single dose of the pharmaceutical compositions of the invention is administered once per week. In other embodiments of the invention, a single dose of the pharmaceutical compositions of the invention is administered bimonthly. In certain embodiments, the siRNA is administered about once per month to about once per quarter (i.e., about once every three months), or even every 6 months or 12 months. Estimates of effective dosages and in vivo half-lives for the individual nucleic acid e.g. siRNAs encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as known in the art. The pharmaceutical compositions of the present invention can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical {e.g., by a transdermal patch), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; subdermal, e.g., via an implanted device; or intracranial, e.g., by intraparenchymal, intrathecal or intraventricular administration. In certain preferred embodiments, the compositions are administered by intravenous infusion or injection. In certain embodiments, the compositions are administered by subcutaneous injection. In one embodiment, the nucleic acid e.g. siRNA agent is administered to the subject subcutaneously. The inhibitor e.g. nucleic acid e.g. siRNA can be delivered in a manner to target a particular tissue (e.g. in particular heart cells). METHODS FOR INHIBITING GENE EXPRESSION OR INHIBITION OF TARGET EXPRESSION OR FUNCTION The present invention also provides methods of inhibiting expression of a gene in a cell and methods for inhibiting expression and / or function of other target molecules. The methods include contacting a cell with a nucleic acid of the invention e.g. siRNA agent, such as double stranded siRNA in an amount effective to inhibit expression of the gene in the cell, thereby inhibiting expression of the gene in the cell. In a preferred embodiment, the gene is NR3C2. The present invention also provides methods of inhibiting expression of NR3C2 gene in a cell. It is to be noted that a nucleic acid “for inhibiting the expression of NR3C2” is a nucleic acid that is capable of inhibiting NR3C2 expression, preferably as described herein below. Contacting of a cell with the inhibitor e.g. the nucleic acid e.g. an siRNA, such as a double stranded siRNA agent, may be done in vitro or in vivo. Contacting a cell in vivo with the inhibitor nucleic acid e.g. siRNA includes contacting a cell or group of cells within a subject, e.g., a human subject, with the nucleic acid e.g. siRNA. Combinations of in vitro and in vivo methods of contacting a cell are also possible. Contacting a cell may be direct or indirect, as discussed above. Furthermore, contacting a cell may be accomplished via a targeting ligand moiety, including any ligand moiety described herein or known in the art. In preferred embodiments, the targeting ligand moiety is a carbohydrate moiety, e.g. a GalNAc3 ligand, or any other ligand moiety that directs the siRNA agent to a site of interest. The term "inhibiting," as used herein, is used interchangeably with "reducing," "silencing," "downregulating", "suppressing", and other similar terms, and includes any level of inhibition. In some embodiments of the methods of the invention, expression or activity of a gene or an inhibition target is inhibited by at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or to below the level of detection of the assay. In certain embodiments, the methods include a clinically relevant inhibition of expression of a target gene e.g. as demonstrated by a clinically relevant outcome after treatment of a subject with an agent to reduce the expression of the gene and / or activity of the target. In some embodiments, when transfected into the cells, the nucleic acid of the invention inhibits expression of the NR3C2 gene with an EC50 value lower than 2500 pM, 2400 pM, 2300 pM, 2200 pM, 2100 pM, 2000 pM, 1900 pM, 1800 pM, 1700 pM, 1600 pM, 1500 pM, 1400 pM, 1300 pM, 1200 pM, 1100 pM, 1000 pM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 200 pM or 100 pM, preferably when determined by qPCR, more preferably by reverse transcriptase (RT)-qPCR, as described herein. In a preferred embodiment, when transfected into the cells, the nucleic acid of the invention inhibits expression of the NR3C2 gene with an EC50 value lower than 2500 pM. In a more preferred embodiment, when transfected into the cells, the nucleic acid of the invention inhibits expression of the NR3C2 gene with an EC50 value lower than 1000 pM. In an even more preferred embodiment, when transfected into the cells, the nucleic acid of the invention inhibits expression of the NR3C2 gene with an EC50 value lower than 500 pM. In a most preferred embodiment, when transfected into the cells, the nucleic acid of the invention inhibits expression of the NR3C2 gene with an EC50 value lower than 100 pM. Alternatively or in addition, a pEC50 value may be calculated to quantify and or compare the inhibitory potential of the siRNAs according to the invention. In some embodiments, when transfected into the cells, the nucleic acid of the invention inhibits expression of the NR3C2 gene with an pEC50 value lower than 5, 6, 7, 8, 9 or 10, preferably when determined by qPCR, more preferably by reverse transcriptase (RT)-qPCR, as described herein. Alternatively or in addition, inhibition of expression of the NR3C2 gene may be characterized by a reduction of mean relative expression of the NR3C2 gene. In some embodiments, when cells are transfected with 0.1 nM of the nucleic acid of the invention, the mean relative expression of NR3C2 is below 1, 0.9, 0.8, 0.7, 0.6, 0.5, or 0.4, preferably when determined by qPCR, more preferably by reverse transcriptase (RT)-qPCR, as described herein. In some embodiments, when cells are transfected with 5 nM of the nucleic acid of the invention, the mean relative expression of NR3C2 is below 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4 or 0.3, preferably when determined by qPCR, more preferably by reverse transcriptase (RT)-qPCR, as described herein. Inhibition of expression of the NR3C2 gene may be quantified by the following method: HEK293 cells (human kidney-derived cell line, obtained from JCRB Cell Bank) may be maintained in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% FBS and 1% non-essential amino acids at 37˚C, 5% CO2, 95% humidity. Cells may be transfected with siRNA duplexes targeting either NR3C2 mRNA or a negative control siRNA (siRNA-control; sense strand 5’- GCCTGTACCAAGGCTTTAA-3’ (SEQ ID NO:1117), antisense strand 5’- TTAAAGCCTTGGTACAGGC-3’ (SEQ ID NO:1118)) in a 6-point, log dose response curve to give final in assay concentrations of 3nM to 0.03pM. Transfection may be carried out by diluting Lipofectamine RNAiMAX (ThermoFisher) in Opti-MEM (ThermoFisher) medium at a ratio of 48.5:1.5. This solution may be added to an equal volume of siRNA, diluted to the required concentration in phosphate buffered saline. The lipofectamine RNAiMAX and siRNA mixture may be incubated at room temperature for 15 minutes before 20 µL was added to wells of a 96 well plate. HEK293 cells may be dissociated from flasks using trypsin and resuspended at a density of 300,000 cells / mL.100 µL of HEK293 cell suspension may be added to each well of the siRNA- containing 96-well plates. Cells may then be incubated for 24 hours at 37˚C, 5% CO2,95% humidity. Each siRNA may be tested in triplicate wells and on two separate days for a total of six replicates. Intracellular RNA may be isolated using an RNeasy kit (Qiagen) according to the manufacturer’s instructions. cDNA synthesis may be performed using a HiScript III RT SuperMix kit (Vazyme) according to the manufacturer’s instructions. Target cDNA may be quantified by qPCR on an ABI Prism 7900HT or ABI QuantStudio 7 with primers specific for human NR3C2 and human GAPDH (forward: GAAGGTGAAGGTCGGAGTC (SEQ ID NO:1119), reverse: GAAGATGGTGATGGGATTTC (SEQ ID NO:1120)) using an AceQ Universal U+ Probe Master Mix (Vazyme). qPCR may be performed in duplicate on cDNA derived from each well and the mean Ct calculated. Relative NR3C2 expression may be calculated from mean Ct values using the comparative Ct (∆∆Ct) method, normalized to GAPDH and relative to untreated cells. Maximum percent inhibition of NR3C2 expression and EC50 and / or pEC50 values (-log10 of the EC50) may be calculated using a four parameter (variable slope) model using NumPy (Python).Inhibition of the expression of a gene may be manifested by a reduction of the amount of mRNA of the target gene of interest in comparison to a suitable control. Inhibition of the function of a target may be manifested by a reduction of the activity of the target in comparison to a suitable control. In other embodiments, inhibition of the expression of a gene or other target may be assessed in terms of a reduction of a parameter that is functionally linked to gene expression, e.g, protein expression or signalling pathways. METHODS OF TREATING OR PREVENTING DISEASES ASSOCIATED WITH GENE EXPRESSION / EXPRESSION OF FUNCTION OF A TARGET. The present invention also provides methods of using nucleic acid e.g. an siRNA of the invention or a composition containing nucleic acid e.g. an siRNA of the invention to reduce or inhibit gene expression in a cell or reduce expression or function of a target. The methods include contacting the cell with a nucleic acid e.g. dsiRNA of the invention and maintaining the cell for a time sufficient to obtain degradation of the mRNA transcript of a gene, thereby inhibiting expression of the gene in the cell. Reduction in gene expression or function of a target can be assessed by any methods known in the art. In a preferred embodiment, the gene is NR3C2. The present invention also provides methods of using nucleic acid e.g. an siRNA of the invention or a composition containing nucleic acid e.g. an siRNA of the invention to reduce or inhibit NR3C2 gene expression in a cell. In the methods of the invention the cell may be contacted in vitro or in vivo, i.e., the cell may be within a subject. A cell suitable for treatment using the methods of the invention may be any cell that expresses a gene of interest or target of interest associated with disease. A cell suitable for treatment using the methods of the invention may be any cell that expresses a gene of interest associated with ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof. The in vivo methods of the invention may include administering to a subject a composition containing a nucleic acid of the invention e.g. an iRNA, where the nucleic acid e.g. siRNA includes a nucleoside sequence that is complementary to at least a part of an RNA transcript of the gene of the mammal to be treated, or complementary to another nucleic acid the expression and / or function of which is associated with diseases. The present invention further provides methods of treatment of a subject in need thereof. The treatment methods of the invention include administering a nucleic acid such as an siRNA of the invention to a subject, e.g., a subject that would benefit from a reduction or inhibition of the expression of a gene and / or expression and / or function of a target, in a therapeutically effective amount e.g. a nucleic acid such as an siRNA targeting a gene or a pharmaceutical composition comprising the nucleic acid targeting a gene. The present invention further provides methods of treatment of a subject in need thereof. The treatment methods of the invention include administering a nucleic acid such as an siRNA of the invention to a subject, e.g., a subject that would benefit from a reduction or inhibition of the expression of NR3C2 gene, in a therapeutically effective amount e.g. a nucleic acid such as an siRNA targeting NR3C2 or a pharmaceutical composition comprising the nucleic acid targeting NR3C2. The disease to be treated is related to ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof. That is, the nucleic acid according to the invention may be used in the prevention and / or treatment of an ischaemic heart disease. The term, "ischaemic heart disease," as used herein, means any disorder resulting from an imbalance between the myocardial need for oxygen and the adequacy of the oxygen supply. Most cases of ischemic heart disease result from narrowing of the coronary arteries, as occurs in atherosclerosis or other vascular disorders. The nucleic acid of the invention additionally may be useful for treating ischaemic damage to other organs. Non-limiting examples of ischemic heart diseases include ischemic cardiomyopathy, myocardial infarction or ischemic heart failure and chronic ischemic heart disease. The patient to be treated may be a patient that already has an ischaemic heart disease or that is at risk of developing an ischaemic heart disease. That is, in certain embodiments, the nucleic acid of the present invention may be used in the treatment of an existing ischaemic heart disease. Treatment of an existing ischaemic heart disease with the nucleic acid of the present invention may prevent worsening of the ischaemic heart disease and / or ischaemic heart disease. In some instances, treatment of an existing ischaemic heart disease with the nucleic acid of the present invention may even cure the ischaemic heart disease. In certain embodiments, the nucleic acid of the present invention may be used to prevent manifestation of an ischaemic heart disease in a patient that is at risk of developing an ischaemic heart disease. The skilled person is capable of diagnosing whether a patient has an ischaemic heart disease or is at risk of developing an ischaemic heart disease. Diagnosing an ischaemic heart disease may include medical history analysis, physical examination, imaging tests (such as ECG or stress test), blood tests (e.g., cardiac enzymes), and / or coronary angiography. In certain embodiments, the ischaemic heart disease is myocardial infarction. The term "myocardial infarction," as used herein, means a process by which ischemic disease results in a region of the myocardium being replaced by scar tissue. In certain embodiments, the nucleic acid of the invention may be administered to a patient that is at risk of myocardial infarction. Risk factors for myocardial infarction include, without limitation, age, tobacco use, high blood pressure, high cholesterol or triglycerides, obesity, diabetes, metabolic syndrome, family history or heart attacks, lack of exercise, unhealthy diet, stress, drug use, history of preeclampsia and autoimmune conditions. In certain embodiments, the nucleic acid of the invention may be administered to a patient after myocardial infarction. That is, the patient to be treated may be a patient that had a history of one or more myocardial infarctions. In such patients, the nucleic acid of the invention may be administered to prevent the occurrence of further myocardial infarctions. A person skilled in the art, such as a physician is capable of determining whether a patient is at risk of developing an ischaemic heart disease, in particular a myocardial infarction, or whether a person already had an ischaemic heart disease, in particular a myocardial infarction. A nucleic acid e.g. siRNA of the invention may be administered as a "free” nucleic acid or “free” siRNA, administered in the absence of a pharmaceutical composition. The naked nucleic acid may be in a suitable buffer solution. The buffer solution may comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS). The pH and osmolarity of the buffer solution can be adjusted such that it is suitable for administering to a subject. Alternatively, a nucleic acid e.g. siRNA of the invention may be administered as a pharmaceutical composition, such as a dsiRNA liposomal formulation. In one embodiment, the method includes administering a composition featured herein such that expression of the target gene is decreased, such as for about 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 18, 24 hours, 28, 32, or about 36 hours. In one embodiment, expression of the target gene is decreased for an extended duration, e.g., at least about two, three, four days or more, e.g., about one week, two weeks, three weeks, or four weeks or longer, e.g., about 1 month, 2 months, or 3 months. Subjects can be administered a therapeutic amount of nucleic acid e.g. siRNA, such as about 0.01 mg / kg to about 200 mg / kg. Subjects can be administered a therapeutic amount of nucleic acid e.g. siRNA, such as about 0.01 mg / kg to about 200 mg / kg, so as to prevent and / or treat an ischaemic heart disease, in particular myocardial infarction and / or symptoms thereof. The nucleic acid e.g. siRNA can be administered by intravenous infusion over a period of time, on a regular basis. In certain embodiments, after an initial treatment regimen, the treatments can be administered on a less frequent basis. Administration of the siRNA can reduce gene product levels of a target gene , e.g., in a cell or tissue of the patient by at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or below the level of detection of the assay method used. In certain embodiments, administration results in clinical stabilization or preferably clinically relevant reduction of at least one sign or symptom of a gene- associated disorder. Alternatively, the nucleic acid e.g. siRNA can be administered subcutaneously, i.e., by subcutaneous injection. One or more injections may be used to deliver the desired daily dose of nucleic acid e.g. s iRNA to a subject. The injections may be repeated over a period of time. The administration may be repeated on a regular basis. In certain embodiments, after an initial treatment regimen, the treatments can be administered on a less frequent basis. A repeat-dose regimen may include administration of a therapeutic amount of nucleic acid on a regular basis, such as every other day or to once a year. In certain embodiments, the nucleic acid is administered about once per month to about once per quarter (i.e., about once every three months). In one aspect the present invention may be applied in the compounds, processes, compositions or uses of the following Sentences numbered 1-101 (wherein reference to any Formula in the Sentences 1-101 refers only to those Formulas that are defined within Sentences 1-101. These formulae are reproduced in Figure 5). Specifically, an oligonucleoside moiety as represented by Z in any of the following sentences can comprise a nucleic acid for inhibiting expression of NR3C2 as defined in any of the claims hereinafter. 1. A compound comprising the following structure: Formula (I) wherein: R1at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; R2 is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X1 and X2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; m is an integer of from 1 to 6; n is an integer of from 1 to 10; q, r, s, t, v are independently integers from 0 to 4, with the proviso that: (i) q and r cannot both be 0 at the same time; and (ii) s, t and v cannot all be 0 at the same time; Z is an oligonucleoside moiety. 2. A compound according to Sentence 1, wherein R1 is hydrogen at each occurrence. 3. A compound according to Sentence 1, wherein R1 is methyl. 4. A compound according to Sentence 1, wherein R1 is ethyl. 5. A compound according to any of Sentences 1 to 4, wherein R2 is hydroxy. A compound according to any of Sentences 1 to 4, wherein R2 is halo. A compound according to Sentence 6, wherein R2 is fluoro. A compound according to Sentence 6, wherein R2 is chloro. A compound according to Sentence 6, wherein R2 is bromo. A compound according to Sentence 6, wherein R2 is iodo. A compound according to Sentence 6, wherein R2is nitro. A compound according to any of Sentences 1 to 11, wherein X1 is methylene. A compound according to any of Sentences 1 to 11, wherein X1 is oxygen. A compound according to any of Sentences 1 to 11, wherein X1 is sulfur. A compound according to any of Sentences 1 to 14, wherein X2 is methylene. A compound according to any of Sentences 1 to 15, wherein X2 is oxygen. A compound according to any of Sentences 1 to 16, wherein X2is sulfur. A compound according to any of Sentences 1 to 17, wherein m = 3. A compound according to any of Sentences 1 to 18, wherein n = 6. A compound according to Sentences 13 and 15, wherein X1is oxygen and X2is methylene, and preferably wherein: q = 1, r = 2, s = 1, t = 1, v = 1. A compound according to Sentences 12 and 15, wherein both X1and X2are methylene, and preferably wherein: q = 1, r = 3, s = 1, t = 1, v = 1. 22. A compound according to any of Sentences 1 to 21, wherein Z is: wherein: Z1, Z2, Z3, Z4 are independently at each occurrence oxygen or sulfur; and one the bonds between P and Z2, and P and Z3 is a single bond and the other bond is a double bond. 23. A compound according to Sentence 22, wherein said oligonucleoside is an RNA compound capable of modulating, preferably inhibiting, expression of a target gene. 24. A compound according to Sentence 23, wherein said RNA compound comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends. 25. A compound according to Sentence 24, wherein the RNA compound is attached at the 5’ end of its second strand to the adjacent phosphate. 26. A compound according to Sentence 24, wherein the RNA compound is attached at the 3’ end of its second strand to the adjacent phosphate. 27. A compound of Formula (II): Formula (II) 28. A compound of Formula (III): Formula (III) 29. A compound according to Sentence 27 or 28, wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 5’ end of its second strand to the adjacent phosphate. 30. A composition comprising a compound of Formula (II) as defined in Sentence 27, and a compound of Formula (III) as defined in Sentence 28, optionally dependent on Sentence 29. 31. A composition according to Sentence 30, wherein said compound of Formula (III) as defined in Sentence 28 is present in an amount in the range of 10 to 15% by weight of said composition. 32. A compound of Formula (IV): Formula (IV) 33. A compound of Formula (V): Formula (V) 34. A compound according to Sentence 32 or 33, wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 3’ end of its second strand to the adjacent phosphate. 35. A composition comprising a compound of Formula (IV) as defined in Sentence 32, and a compound of Formula (V) as defined in Sentence 33, optionally dependent on Sentence 34. 36. A composition according to Sentence 35, wherein said compound of Formula (V) as defined in Sentence 33 is present in an amount in the range of 10 to 15% by weight of said composition. 37. A compound as defined in any of Sentences 1 to 29, or 32 to 34, wherein the oligonucleoside comprises an RNA duplex which further comprises one or more riboses modified at the 2’ position, preferably a plurality of riboses modified at the 2’ position. 38. A compound according to Sentence 37, wherein the modifications are chosen from 2’-O- methyl, 2’-deoxy-fluoro, and 2’-deoxy. 39. A compound according to any of Sentences 1 to 29, or 32 to 34, or 37 to 38, wherein the oligonucleoside further comprises one or more degradation protective moieties at one or more ends. 40. A compound according to Sentence 39, wherein said one or more degradation protective moieties are not present at the end of the oligonucleoside strand that carries the ligand moieties, and / or wherein said one or more degradation protective moieties is selected from phosphorothioate internucleoside linkages, phosphorodithioate internucleoside linkages and inverted abasic nucleosides, wherein said inverted abasic nucleosides are present at the distal end of the strand that carries the ligand moieties. 41. A compound according to any of Sentences 1 to 29, or 32 to 34, or 37 to 40, wherein said ligand moiety as depicted in Formula (I) in Sentence 1 comprises one or more ligands. 42. A compound according to Sentence 41, wherein said ligand moiety as depicted in Formula (I) in Sentence 1 comprises one or more carbohydrate ligands. 43. A compound according to Sentence 42, wherein said one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide. 44. A compound according to Sentence 43, wherein said one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N- AcetylGalactosamine moieties, and / or one or more mannose moieties. 45. A compound according to Sentence 44, wherein said one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties. 46. A compound according to Sentence 45, which comprises two or three N- AcetylGalactosamine moieties. 47. A compound according to any of Sentences 41 to 46, wherein said one or more ligands are attached in a linear configuration, or in a branched configuration. 48. A compound according to Sentence 47, wherein said one or more ligands are attached as a biantennary or triantennary branched configuration. 49. A compound according to Sentences 46 to 48, wherein said moiety: as depicted in Formula (I) in Sentence 1 is any of Formulae (VIa), (VIb) or (VIc), preferably Formula (VIa): Formula (VIa) wherein: AIis hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and b is an integer of 2 to 5; or Formula (VIb) wherein: AIis hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and c and d are independently integers of 1 to 6; or

[0008] Formula (VIc) wherein: AI is hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and e is an integer of 2 to 10. 50. A compound according to Sentences 46 to 48, wherein said moiety: as depicted in Formula (I) in Sentence 1 is Formula (VII): Formula (VII) wherein: AIis hydrogen; a is an integer of 2 or 3. 51. A compound according to Sentence 49 or 50, wherein a = 2. 52. A compound according to Sentence 49 or 50, wherein a = 3. 53. A compound according to Sentence 49, wherein b = 3. 54. A compound of Formula (VIII): Formula (VIII) 55. A compound of Formula (IX):

[0009] Formula (IX) 56. A compound according to Sentence 54 or 55, wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 5’ end of its second strand to the adjacent phosphate. 57. A composition comprising a compound of Formula (VIII) as defined in Sentence 54, and a compound of Formula (IX) as defined in Sentence 55, optionally dependent on Sentence 56. 58. A composition according to Sentence 57, wherein said compound of Formula (IX) as defined in Sentence 55 is present in an amount in the range of 10 to 15% by weight of said composition. 59. A compound of Formula (X):

[0010] Formula (X) 60. A compound of Formula (XI): Formula (XI) 61. A compound according to Sentence 59 or 60, wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 3’ end of its second strand to the adjacent phosphate. A composition comprising a compound of Formula (X) as defined in Sentence 59, and a compound of Formula (XI) as defined in Sentence 60, optionally dependent on Sentence 61. A composition according to Sentence 62, wherein said compound of Formula (XI) as defined in Sentence 60 is present in an amount in the range of 10 to 15% by weight of said composition. A compound as defined in any of Sentences 54 to 63, wherein the oligonucleoside comprises an RNA duplex which further comprises one or more riboses modified at the 2’ position, preferably a plurality of riboses modified at the 2’ position. A compound according to Sentence 64, wherein the modifications are chosen from 2’-O- methyl, 2’-deoxy-fluoro, and 2’-deoxy. A compound according to any of Sentences 54 to 65, wherein the oligonucleoside further comprises one or more degradation protective moieties at one or more ends. A compound according to Sentence 66, wherein said one or more degradation protective moieties are not present at the end of the oligonucleoside strand that carries the ligand moieties, and / or wherein said one or more degradation protective moieties is selected from phosphorothioate internucleoside linkages, phosphorodithioate internucleoside linkages and inverted abasic nucleosides, wherein said inverted abasic nucleosides are present at the distal end of the strand that carries the ligand moieties, as shown in any of Formulae (VIII), (IX), (X) or (XI) in any of Sentences 54, 55, 59 or 60. A process of preparing a compound according to any of Sentences 1 to 29, 32 to 34, 37 to 56, 59 to 61, and 64 to 67, and / or a composition according to any of Sentences 30, 31, 35, 36, 57, 58, 62, 63, which comprises reacting compounds of Formulae (XII) and (XIII): Formula (XIII) herein: R1at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; R2 is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X1and X2at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; m is an integer of from 1 to 6; n is an integer of from 1 to 10; q, r, s, t, v are independently integers from 0 to 4, with the proviso that: (i) q and r cannot both be 0 at the same time; and (ii) s, t and v cannot all be 0 at the same time; Z is an oligonucleoside moiety; and where appropriate carrying out deprotection of the ligand and / or annealing of a second strand for the oligonucleoside moiety. 69. A process according to Sentence 68, wherein a compound of Formula (XII) is prepared by reacting compounds of Formulae (XIV) and (XV): Formula (XV) R1 at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; R2is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X1 and X2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; q, r, s, t, v are independently integers from 0 to 4, with the proviso that: (i) q and r cannot both be 0 at the same time; and (ii) s, t and v cannot all be 0 at the same time; Z is an oligonucleoside moiety. 70. A process according to Sentence 68, to prepare a compound according to any of Sentences 20, 25, 27, 29, 54, 56, and / or a composition according to any of Sentences 30, 31, 57, 58, wherein: compound of Formula (XII) is Formula (XIIa): Formula (XIIa) and compound of Formula (XIII) is Formula (XIIIa): Formula (XIIIa) wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 5’ end of its second strand to the adjacent phosphate. 71. A process according to Sentence 68, to prepare a compound according to any of Sentences 20, 25, 28, 29, 55, 56, and / or a composition according to any of Sentences 30, 31, 57, 58, wherein: compound of Formula (XII) is Formula (XIIb): Formula (XIIb) and compound of Formula (XIII) is Formula (XIIIa): Formula (XIIIa) wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 5’ end of its second strand to the adjacent phosphate. 72. A process according to Sentence 68, to prepare a compound according to any of Sentences 21, 26, 32, 34, 59, 61, and / or a composition according to any of Sentences 35, 36, 62, 63, wherein: compound of Formula (XII) is Formula (XIIc): Formula (XIIc) and compound of Formula (XIII) is Formula (XIIIa): Formula (XIIIa) wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 3’ end of its second strand to the adjacent phosphate. 73. A process according to Sentence 68, to prepare a compound according to any of Sentences 21, 26, 33, 34, 60, 61, and / or a composition according to any of Sentences 35, 36, 62, 63, wherein: compound of Formula (XII) is Formula (XIId): Formula (XIId) and compound of Formula (XIII) is Formula (XIIIa): Formula (XIIIa) wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 3’ end of its second strand to the adjacent phosphate. 74. A process according to any of Sentences 70 to 73, wherein: compound of Formula (XIIIa) is Formula (XIIIb):

[0011] Formula (XIIIb) 75. A process according to Sentences 69, as dependent on Sentences 70 to 73, wherein: compound of Formula (XIV) is either Formula (XIVa) or Formula (XIVb): Formula (XIVb) and compound of Formula (XV) is either Formula (XVa) or Formula (XIVb): Formula (XVa) Formula (XVb) wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein (i) said RNA duplex is attached at the 5’ end of its second strand to the adjacent phosphate in Formula (XVa), or (ii) said RNA duplex is attached at the 3’ end of its second strand to the adjacent phosphate in Formula (XVb). 76. A compound of Formula (XII): Formula (XII) wherein: R1at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; R2is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X1 and X2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; q, r, s, t, v are independently integers from 0 to 4, with the proviso that: (i) q and r cannot both be 0 at the same time; and (ii) s, t and v cannot all be 0 at the same time; Z is an oligonucleoside moiety. 77. A compound of Formula (XIIa): Formula (XIIa) 78. A compound of Formula (XIIb): Formula (XIIb) 79. A compound of Formula (XIIc): Formula (XIIc) 80. compound of Formula (XIId): Formula (XIId) 81. A compound of Formula (XIII): Formula (XIII) wherein: R1 at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; m is an integer of from 1 to 6; n is an integer of from 1 to 10. 82. A compound of Formula (XIIIa): Formula (XIIIa) 83. A compound of Formula (XIIIb):

[0012] Formula (XIIIb) 84. A compound of Formula (XIV): Formula (XIV) wherein: R1is selected from the group consisting of hydrogen, methyl and ethyl; R2 is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X2is selected from the group consisting of methylene, oxygen and sulfur; s, t, v are independently integers from 0 to 4, with the proviso that s, t and v cannot all be 0 at the same time. 85. A compound of Formula (XIVa): Formula (XIVa) 86. A compound of Formula (XIVb): Formula (XIVb) 87. A compound of Formula (XV): Formula (XV) wherein: R1 at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; X1 is selected from the group consisting of methylene, oxygen and sulfur; q and r are independently integers from 0 to 4, with the proviso that q and r cannot both be 0 at the same time; Z is an oligonucleoside moiety. 88. A compound of Formula (XVa): Formula (XVa) 89. A compound of Formula (XVb): Formula (XVb) 90. Use of a compound according to any of Sentences 76, 81 to 84, 87, for the preparation of a compound according to any of Sentences 1 to 29, 32 to 34, 37 to 56, 59 to 61, and 64 to 67, and / or a composition according to any of Sentences 30, 31, 35, 36, 57, 58, 62 and 63. 91. Use of a compound according to Sentence 85, for the preparation of a compound according to any of Sentences 1 to 29, 32 to 34, 37 to 56, 59 to 61, and 64 to 67, and / or a composition according to any of Sentences 30, 31, 35, 36, 57, 58, 62 and 63, wherein R2 = F. 92. Use of a compound according to Sentence 86, for the preparation of a compound according to any of Sentences 1 to 29, 32 to 34, 37 to 56, 59 to 61, and 64 to 67, and / or a composition according to any of Sentences 30, 31, 35, 36, 57, 58, 62 and 63, wherein R2 = OH. 93. Use of a compound according to Sentence 77, for the preparation of a compound according to any of Sentences 20, 25, 27, 29, 54, 56, and / or a composition according to any of Sentences 30, 31, 57, 58. 94. Use of a compound according to Sentence 78, for the preparation of a compound according to any of Sentences 20, 25, 28, 29, 55, 56, and / or a composition according to any of Sentences 30, 31, 57, 58. 95. Use of a compound according to Sentence 79, for the preparation of a compound according to any of Sentences 21, 26, 32, 34, 59, 61, and / or a composition according to any of Sentences 35, 36, 62, 63. 96. Use of a compound according to Sentence 80, for the preparation of a compound according to any of Sentences 21, 26, 33, 34, 60, 61, and / or a composition according to any of Sentences 35, 36, 62, 63. 97. Use of a compound according to Sentence 88, for the preparation of a compound according to any of Sentences 20, 25, 27 to 29, 54 to 56, and / or a composition according to any of Sentences 30, 31, 57, 58. 98. Use of a compound according to Sentence 89, for the preparation of a compound according to any of Sentences 21, 26, 32 to 34, 59 to 61, and / or a composition according to any of Sentences 35, 36, 62, 63. 99. A compound or composition obtained, or obtainable by a process according to any of Sentences 68 to 75. 100. A pharmaceutical composition comprising of a compound according to any of Sentences 1 to 29, 32 to 34, 37 to 56, 59 to 61, and 64 to 67, and / or a composition according to any of Sentences 30, 31, 35, 36, 57, 58, 62 and 63, together with a pharmaceutically acceptable carrier, diluent or excipient. 101. A compound according to any of Sentences 1 to 29, 32 to 34, 37 to 56, 59 to 61, and 64 to 67, and / or a composition according to any of Sentences 30, 31, 35, 36, 57, 58, 62 and 63, for use in therapy. In another aspect the present invention may be applied in the compounds, processes, compositions or uses of the following Clauses numbered 1-56 (wherein reference to any Formula in the Clauses refers only to those Formulas that are defined within Clause 1-56. These formulae are reproduced in Figure 6). Specifically, an oligonucleoside moiety as represented by Z in any of the following clauses can comprise a nucleic acid for inhibiting expression of NR3C2 as defined in any of the claims hereinafter. 1. A compound comprising the following structure: Formula (I*) wherein: r and s are independently an integer selected from 1 to 16; and Z is an oligonucleoside moiety. 2. A compound according to Clause 1, wherein s is an integer selected from 4 to 12. 3. A compound according to Clause 2, wherein s is 6. 4. A compound according to any of Clauses 1 to 3, wherein r is an integer selected from 4 to 14. 5. A compound according to Clause 4, wherein r is 6. 6. A compound according to Clause 4, wherein r is 12. 7. A compound according to Clause 5, which is dependent on Clause 3. 8. A compound according to Clause 6, which is dependent on Clause 3. 9. A compound according to any of Clauses 1 to 8, wherein Z is: wherein: Z1, Z2, Z3, Z4are independently at each occurrence oxygen or sulfur; and one the bonds between P and Z2, and P and Z3 is a single bond and the other bond is a double bond. 10. A compound according to any of Clauses 1 to 9, wherein said oligonucleoside is an RNA compound capable of modulating, preferably inhibiting, expression of a target gene. 11. A compound according to any of Clause 10, wherein said RNA compound comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends. 12. A compound according to Clause 11, preferably also dependent on Clauses 3 and 6, wherein the RNA compound is attached at the 5’ end of its second strand to the adjacent phosphate. 13. A compound according to Clause 11, preferably also dependent on Clauses 3 and 5, wherein the RNA compound is attached at the 3’ end of its second strand to the adjacent phosphate. 14. A compound of Formula (II*), preferably dependent on Clause 12: Formula (II*) 15. A compound of Formula (III), preferably dependent on Clause 13: Formula (III*) 16. A compound as defined in any of Clauses 1 to 15, wherein the oligonucleoside comprises an RNA duplex which further comprises one or more riboses modified at the 2’ position, preferably a plurality of riboses modified at the 2’ position. 17. A compound according to Clause 16, wherein the modifications are chosen from 2’-O- methyl, 2’-deoxy-fluoro, and 2’-deoxy. A compound according to any of Clauses 1 to 17, wherein the oligonucleoside further comprises one or more degradation protective moieties at one or more ends. A compound according to Clause 18, wherein said one or more degradation protective moieties are not present at the end of the oligonucleoside strand that carries the linker / ligand moieties, and / or wherein said one or more degradation protective moieties is selected from phosphorothioate internucleoside linkages, phosphorodithioate internucleoside linkages and inverted abasic nucleosides, wherein said inverted abasic nucleosides are present at the distal end of the same strand to the end that carries the linker / ligand moieties. A compound according to any of Clauses 1 to 19, wherein said ligand moiety as depicted in Formula (I*) in Clause 1 comprises one or more ligands. A compound according to Clause 20, wherein said ligand moiety as depicted in Formula (I*) in Clause 1 comprises one or more carbohydrate ligands. A compound according to Clause 21, wherein said one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide. A compound according to Clause 22, wherein said one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N- AcetylGalactosamine moieties, and / or one or more mannose moieties. A compound according to Clause 23, wherein said one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties. A compound according to Clause 24, which comprises two or three N- AcetylGalactosamine moieties. A compound according to any of the preceding Clauses, wherein said one or more ligands are attached in a linear configuration, or in a branched configuration. A compound according to Clause 26, wherein said one or more ligands are attached as a biantennary or triantennary branched configuration. A compound according to Clauses 20 to 27, wherein said moiety: as depicted in Formula (I*) in Clause 1 is any of Formulae (IV*), (V*) or (VI*), preferably Formula (IV*): Formula (IV*) wherein: AIis hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and b is an integer of 2 to 5; or Formula (V*) wherein: AIis hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and c and d are independently integers of 1 to 6; or Formula (VI*) wherein: AIis hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and e is an integer of 2 to 10. 29. A compound according to any of Clauses 1 to 28, wherein said moiety: as depicted in Formula (I*) in Clause 1 is Formula (VII*): Formula (VII*) wherein: AI is hydrogen; a is an integer of 2 or 3. 30. A compound according to Clause 28 or 29, wherein a = 2. 31. A compound according to Clause 28 or 29, wherein a = 3. 32. A compound according to Clause 28, wherein b = 3. 33. A compound of Formula (VIII*): Formula (VIII*) 34. A compound of Formula (IX*): Formula (IX*) 35. A compound according to Clause 33 or 34, wherein the oligonucleoside comprises an RNA duplex which further comprises one or more riboses modified at the 2’ position, preferably a plurality of riboses modified at the 2’ position. 36. A compound according to Clause 35, wherein the modifications are chosen from 2’-O- methyl, 2’-deoxy-fluoro, and 2’-deoxy. 37. A compound according to any of Clauses 33 to 36, wherein the oligonucleoside further comprises one or more degradation protective moieties at one or more ends. 38. A compound according to Clause 37, wherein said one or more degradation protective moieties are not present at the end of the oligonucleoside strand that carries the linker / ligand moieties, and / or wherein said one or more degradation protective moieties is selected from phosphorothioate internucleoside linkages, phosphorodithioate internucleoside linkages and inverted abasic nucleosides, wherein said inverted abasic nucleosides are present at the distal end of the same strand to the end that carries the linker / ligand moieties. 39. A compound according to Clause 33, wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 5’ end of its second strand to the adjacent phosphate. 40. A compound according to Clause 34, wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 3’ end of its second strand to the adjacent phosphate. 41. A process of preparing a compound according to any of Clauses 1 to 40, which comprises reacting compounds of Formulae (X*) and (XI*): Formula (XI*) wherein: r and s are independently an integer selected from 1 to 16; and Z is an oligonucleoside moiety; and where appropriate carrying out deprotection of the ligand and / or annealing of a second strand for the oligonucleoside. 42. A process according to Clause 41, to prepare a compound according to any of Clauses 6, 8 to 14, 16 to 33, and 35 to 40, wherein: compound of Formula (X*) is Formula (Xa*): Formula (Xa*) and compound of Formula (XI*) is Formula (Xia*): Formula (Xia*) wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 5’ end of its second strand to the adjacent phosphate. 43. A process according to Clause 41, to prepare a compound according to any of Clauses 5, 7, 9 to 13, 15 to 32, and 34 to 40, wherein: compound of Formula (X*) is Formula (Xb*): Formula (Xb*) and compound of Formula (XI*) is Formula (Xia*): Formula (Xia*) wherein the oligonucleoside comprises an RNA duplex comprising first and second strands, wherein the first strand is at least partially complementary to an RNA sequence of a target gene, and the second strand is at least partially complementary to said first strand, and wherein each of the first and second strands have 5’ and 3’ ends, and wherein said RNA duplex is attached at the 3’ end of its second strand to the adjacent phosphate. 44. A process according to Clauses 42 or 43, wherein: compound of Formula (Xia*) is Formula (XIb*): Formula (XIb*) 45. A compound of Formula (X*): Formula (X*) wherein: r is independently an integer selected from 1 to 16; and Z is an oligonucleoside moiety. 46. A compound of Formula (Xa*): Formula (Xa*) 47. A compound of Formula (Xb*): Formula (Xb*) 48. A compound of Formula (XI*): Formula (XI*) wherein: s is independently an integer selected from 1 to 16; and Z is an oligonucleoside moiety. 49. A compound of Formula (Xia*): Formula (Xia*) 50. A compound of Formula (XIb*): Formula (XIb*) 51. Use of a compound according to any of Clauses 45 and 48 to 50, for the preparation of a compound according to any of Clauses 1 to 40. 52. Use of a compound according to Clause 46, for the preparation of a compound according to any of Clauses 6, 8 to 14, 16 to 33, and 35 to 40. 53. Use of a compound according to Clause 47, for the preparation of a compound according to any of Clauses 5, 7, 9 to 13, 15 to 32, and 34 to 40. 54. A compound or composition obtained, or obtainable by a process according to any of Clauses 41 to 44. 55. A pharmaceutical composition comprising of a compound according to any of Clauses 1 to 40, together with a pharmaceutically acceptable carrier, diluent or excipient. 56. A compound according to any of Clauses 1 to 40, for use in therapy. EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. EXAMPLE 1: SYNTHESIS OF TETHER 1 General Experimental conditions: Thin layer chromatography (TLC) was performed on silica-coated aluminium plates with fluorescence indicator 254 nm from Macherey-Nagel. Compounds were visualized under UV light (254 nm), or after spraying with the 5% H2SO4in methanol (MeOH) or ninhydrin reagent according to Stahl (from Sigma-Aldrich), followed by heating. Flash chromatography was performed with a Biotage Isolera One flash chromatography instrument equipped with a dual variable UV wavelength detector (200-400 nm) using Biotage Sfär Silica 10, 25, 50 or 100 g columns (Uppsala, Sweden). All moisture-sensitive reactions were carried out under anhydrous conditions using dry glassware, anhydrous solvents, and argon atmosphere. All commercially available reagents were purchased from Sigma-Aldrich and solvents from Carl Roth GmbH + Co. KG. D-Galactosamine pentaacetate was purchased from AK scientific. HPLC / ESI-MS was performed on a Dionex UltiMate 3000 RS UHPLC system and Thermo Scientific MSQ Plus Mass spectrometer using an Acquity UPLC Protein BEH C4 column from Waters (300Å, 1.7 µm, 2.1 x 100 mm) at 60 °C. The solvent system consisted of solvent A with H2O containing 0.1% formic acid and solvent B with acetonitrile (ACN) containing 0.1% formic acid. A gradient from 5-100% of B over 15 min with a flow rate of 0.4 mL / min was employed. Detector and conditions: Corona ultra-charged aerosol detection (from esa). Nebulizer Temp.: 25 °C. N2 pressure: 35.1 psi. Filter: Corona. 1H and 13C NMR spectra were recorded at room temperature on a Varian spectrometer at 500 MHz (1H NMR) and 125 MHz (13C NMR). Chemical shifts are given in ppm referenced to the solvent residual peak (CDCl3 – 1H NMR: δ at 7.26 ppm and 13C NMR δ at 77.2 ppm; DMSO-d6 – 1H NMR: δ at 2.50 ppm and 13C NMR δ at 39.5 ppm). Coupling constants are given in Hertz. Signal splitting patterns are described as singlet (s), doublet (d), triplet (t) or multiplet (m). Synthesis route for the conjugate building block TriGalNAc _Tether1: Preparation of compound 2: D-Galactosamine pentaacetate (3.00 g, 7.71 mmol, 1.0 eq.) was dissolved in anhydrous dichloromethane (DCM) (30 mL) under argon and trimethylsilyl trifluoromethanesulfonate (TMSOTf, 4.28 g, 19.27 mmol, 2.5 eq.) was added. The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (50 mL) and washed with cold saturated aq. NaHCO3 (100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4and concentrated to afford the title compound as yellow oil, which was purified by flash chromatography (gradient elution: 0-10% MeOH in DCM in 10 CV). The product was obtained as colourless oil (2.5 g, 98%, rf= 0.45 (2% MeOH in DCM)). Preparation of compound 4: Compound 2 (2.30 g, 6.98 mmol, 1.0 eq.) and azido-PEG3-OH (1.83 g, 10.5 mmol, 1.5 eq.) were dissolved in anhydrous DCM (40 mL) under argon and molecular sieves 3 Å (5 g) were added to the solution. The mixture was stirred at room temperature for 1 h. TMSOTf (0.77 g, 3.49 mmol, 0.5 eq.) was then added to the mixture and the reaction was stirred overnight. The molecular sieves were filtered, the filtrate was diluted with DCM (100 mL) and washed with cold saturated aq. NaHCO3(100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (gradient elution: 0-3% MeOH in DCM in 10 CV) to afford the title product as light yellow oil (3.10 g, 88%, rf = 0.25 (2% MeOH in DCM)). MS: calculated for C20H32N4O11, 504.21. Found 505.4.1H NMR (500 MHz, CDCl3) ^ 6.21-6.14 (m, 1H), 5.30 (dd, J = 3.4, 1.1 Hz, 1H), 5.04 (dd, J = 11.2, 3.4 Hz,1H), 4.76 (d, J = 8.6 Hz, 1H), 4.23- 4.08 (m, 3H), 3.91-3.80 (m, 3H), 3.74-3.59 (m, 9H), 3.49-3.41 (m, 2H), 2.14 (s, 3H), 2.02 (s, 3H), 1.97 (d, J = 4.2 Hz, 6H).13C NMR (125 MHz, CDCl3) ^ 170.6 (C), 170.5 (C), 170.4 (C), 170.3 (C), 102.1 (CH), 71.6 (CH), 70.8 (CH), 70.6 (CH), 70.5 (CH), 70.3 (CH2), 69.7 (CH2), 68.5 (CH2), 66.6 (CH2), 61.5 (CH2), 23.1 (CH3), 20.7 (3xCH3). Preparation of compound 5: Compound 4 (1.00 g, 1.98 mmol, 1.0 eq.) was dissolved in a mixture of ethyl acetate (EtOAc) and MeOH (30 mL 1:1 v / v) and Pd / C (100 mg) was added. The reaction mixture was degassed using vacuum / argon cycles (3x) and hydrogenated under balloon pressure overnight. The reaction mixture was filtered through celite and washed with EtOAc (30 mL). The solvent was removed under reduced pressure to afford the title compound as colourless oil (0.95 g, quantitative yield, rf = 0.25 (10% MeOH in DCM)). The compound was used without further purification. MS: calculated for C20H34N2O11, 478.2. Found 479.4. Preparation of compound 7: Tris{[2-(tert-butoxycarbonyl)ethoxy]methyl}-methylamine 6 (3.37 g, 6.67 mmol, 1.0 eq.) was dissolved in a mixture of DCM / water (40 mL 1:1 v / v) and Na2CO3 (0.18 g, 1.7 mmol, 0.25 eq.) was added while stirring vigorously. Benzyl chloroformate (2.94 mL, 20.7 mmol, 3.10 eq.) was added dropwise to the previous mixture and the reaction was stirred at room temperature for 24 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with water (100 mL). The organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting crude material was purified by flash chromatography (gradient elution: 0-10% EtOAc in cyclohexane in 12 CV) to afford the title compound as pale yellowish oil (3.9 g, 91%, rf = 0.56 (10% EtOAc in cyclohexane)). MS: calculated for C33H53NO11, 639.3. Found 640.9.1H NMR (500 MHz, DMSO-d6) ^ 7.38-7.26 (m, 5H), 4.97 (s, 2H), 3.54 (t, 6H), 3.50 (s, 6H), 2.38 (t, 6H), 1.39 (s, 27H). 13C NMR (125 MHz, DMSO-d6) ^ 170.3 (3xC), 154.5 (C), 137.1 (C), 128.2 (2xCH), 127.7 (CH), 127.6 (2xCH), 79.7 (3xC), 68.4 (3xCH2), 66.8 (3xCH2), 64.9 (C), 58.7 (CH2), 35.8 (3xCH2), 27.7 (9xCH3). Preparation of compound 8: Cbz-NH-tris-Boc-ester 7 (0.20 g, 0.39 mmol, 1.0 eq.) was dissolved in CH2Cl2 (1 mL) under argon, trifluoroacetic acid (TFA, 1 mL) was added and the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, the residue was co-evaporated 3 times with toluene (5 mL) and dried under high vacuum to get the compound as its TFA salt (0.183 g, 98%). The compound was used without further purification. MS: calculated for C21H29NO11, 471.6. Found 472.4. Preparation of compound 9: CbzNH-tris-COOH 8 (0.72 g, 1.49 mmol, 1.0 eq.) and GalNAc- PEG3-NH25 (3.56 g, 7.44 mmol, 5.0 eq.) were dissolved in N,N-dimethylformamide (DMF) (25 mL). Then N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (2.78 g, 7.44 mmol, 5.0 eq.), 1-hydroxybenzotriazole hydrate (HOBt) (1.05 g, 7.44 mmol, 5.0 eq.) and N,N-diisopropylethylamine (DIPEA) (2.07 mL, 11.9 mmol, 8.0 eq.) were added to the solution and the reaction was stirred for 72 h. The solvent was removed under reduced pressure, the residue was dissolved in DCM (100 mL) and washed with saturated aq. NaHCO3 (100 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the crude material was purified by flash chromatography (gradient elution: 0-5% MeOH in DCM in 14 CV). The product was obtained as pale yellowish oil (1.2 g, 43%, rf = 0.20 (5% MeOH in DCM)). MS: calculated for C81H125N7O41, 1852.9. Found 1854.7. 1H NMR (500 MHz, DMSO-d6) ^ 7.90-7.80 (m, 10H), 7.65-7.62 (m, 4H), 7.47-7.43 (m, 3H), 7.38-7.32 (m, 8H), 5.24-5.22 (m, 3H), 5.02-4.97 (m, 4H), 4.60-4.57 (m, 3 H), 4.07-3.90 (m 10H), 3.67-3.36 (m, 70H), 3.23-3.07 (m, 25H), 2.18 (s, 10H), 2.00 (s, 13H), 1.89 (s, 11H), 1.80-1.78 (m, 17H). 13C NMR (125 MHz, DMSO-d6) ^ 170.1 (C), 169.8 (C), 169.7 (C), 169.4 (C), 169.2 (C), 169.1 (C), 142.7 (C), 126.3 (CH), 123.9 (CH), 118.7 (CH), 109.7 (CH), 100.8 (CH), 70.5 (CH), 69.8 (CH), 69.6 (CH), 69.5 (CH), 69.3 (CH2), 69.0 (CH2), 68.2 (CH2), 67.2 (CH2), 66.7 (CH2), 61.4 (CH2), 22.6 (CH2), 22.4 (3xCH3), 20.7 (9xCH3). O O O O O O O O O O O OOO NH O O H O O O O NOONH O HN OOOO O O O O O Pd / C, H O O O O O O O OOON O O O NHOOH NCbzMeOH,drops of AcOHO O O HOO NHON O O O O H NH O O O O O O O O O OON O O O HN H O O OON O HN H O 9 O10Preparation of compound 10: Triantennary GalNAc compound 9 (0.27 g, 0.14 mmol, 1.0 eq.) was dissolved in MeOH (15 mL), 3 drops of acetic acid (AcOH) and Pd / C (30 mg) was added. The reaction mixture was degassed using vacuum / argon cycles (3x) and hydrogenated under balloon pressure overnight. The completion of the reaction was followed by mass spectrometry and the resulting mixture was filtered through a thin pad of celite. The solvent was evaporated and the residue obtained was dried under high vacuum and used for the next step without further purification. The product was obtained as pale yellowish oil (0.24 g, quantitative yield). MS: calculated for C73H119N7O39, 1718.8. Found 1719.3. Preparation of compound 11: Commercially available suberic acid bis(N-hydroxysuccinimide ester) (3.67 g, 9.9 mmol, 1.0 eq.) was dissolved in DMF (5 mL) and triethylamine (1.2 mL) was added. To this solution was added dropwise a solution of 3-azido-1-propylamine (1.0 g, 9.9 mmol, 1.0 eq.) in DMF (5 mL). The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was separated, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (gradient elution: 0-5% MeOH in DCM in 16 CV). The product was obtained as white solid (1.54 g, 43%, rf = 0.71 (5% MeOH in DCM)). MS: calculated for C15H23N5O5, 353.4. Found 354.3. O O OOO O O O O O O O O O O O O OOHNONH OONH O HN O O O O O O O O O O O O O O O O O OON O O O O O O O NH O O H NHOON O CH C O NH H NH O l , Et N O O N N O O O H O O O O O O O OON O O O O O O HN HON O HN H O 10 O + 12 O O O N N N O H O 11 Preparation of TriGalNAc (12): Triantennary GalNAc compound 10 (0.35 g, 0.24 mmol, 1.0 eq.) and compound 11 (0.11 g, 0.31 mmol, 1.5 eq.) were dissolved in DCM (5 mL) under argon and triethylamine (0.1 mL, 0.61 mmol, 3.0 eq.) was added. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (100 mL) and washed with water (100 mL). The organic layer was separated and dried over Na2SO4. The solvent was evaporated and the resulting crude material was purified by flash chromatography (elution gradient: 0-10% MeOH in DCM in 20 CV) to afford the title compound as white fluffy solid (0.27 g, 67%, rf = 0.5 (10% MeOH in DCM)). MS: calculated for C84H137N11O41, 1957.1. Found 1959.6. Conjugation of Tether 1 to a siRNA strand: Monofluoro cyclooctyne (MFCO) conjugation at 5’- or 3’-end 5‘-end MFCO conjugation 3‘-end MFCO conjugation General conditions for MFCO conjugation: Amine-modified single strand was dissolved at 700 OD / mL in 50 mM carbonate / bicarbonate buffer pH 9.6 / dimethyl sulfoxide (DMSO) 4:6 (v / v) and to this solution was added one molar equivalent of a 35 mM solution of MFCO-C6-NHS ester (Berry&Associates, Cat. # LK 4300) in DMF. The reaction was carried out at room temperature and after 1 h another molar equivalent of the MFCO solution was added. The reaction was allowed to proceed for an additional hour and was monitored by LC / MS. At least two molar equivalent excess of the MFCO NHS ester reagent relative to the amino modified oligonucleotide were needed to achieve quantitative consumption of the starting material. The reaction mixture was diluted 15-fold with water, filtered through a 1.2 µm filter from Sartorius and then purified by reserve phase (RP HPLC) on an Äkta Pure instrument (GE Healthcare). Purification was performed using a XBridge C18 Prep 19 x 50 mm column from Waters. Buffer A was 100 mM TEAAc pH 7 and buffer B contained 95% acetonitrile in buffer A. A flow rate of 10 mL / min and a temperature of 60°C were employed. UV traces at 280 nm were recorded. A gradient of 0-100% B within 60 column volumes was employed. Fractions containing full length conjugated oligonucleotide were pooled, precipitated in the freezer with 3 M NaOAc, pH 5.2 and 85% ethanol and the collected pellet was dissolved in water. Samples were desalted by size exclusion chromatography and concentrated using a speed-vac concentrator to yield the conjugated oligonucleotide in an isolated yield of 40–80%. TriGalNAc (GalNAc-T1) conjugation at 5’- or 3’-end 5’-GalNAc-T1 conjugates 3’-GalNAc-T1 conjugates

[0013] 5’-GalNAc-T1 conjugates General procedure for TriGalNAc conjugation: MFCO-modified single strand was dissolved at 2000 OD / mL in water and to this solution was added one equivalent solution of compound 12 (10 mM) in DMF. The reaction was carried out at room temperature and after 3 h 0.7 molar equivalent of the compound 12 solution was added. The reaction was allowed to proceed overnight and completion was monitored by LCMS. The conjugate was diluted 15-fold in water, filtered through a 1.2 µm filter from Sartorius and then purified by RP HPLC on an Äkta Pure instrument (GE Healthcare). RP HPLC purification was performed using a XBridge C18 Prep 19 x 50 mm column from Waters. Buffer A was 100 mM triethylammonium acetate pH 7 and buffer B contained 95% acetonitrile in buffer A. A flow rate of 10 mL / min and a temperature of 60°C were employed. UV traces at 280 nm were recorded. A gradient of 0-100% B within 60 column volumes was employed. Fractions containing full-length conjugated oligonucleotide were pooled, precipitated in the freezer with 3 M NaOAc, pH 5.2 and 85% ethanol and the collected pellet was dissolved in water to give an oligonucleotide solution of about 1000 OD / mL. The O-acetates were removed by adding 20% aqueous ammonia. Quantitative removal of these protecting groups was verified by LC-MS. The conjugates were desalted by size exclusion chromatography using Sephadex G25 Fine resin (GE Healthcare) on an Äkta Pure (GE Healthcare) instrument to yield the conjugated oligonucleotides in an isolated yield of 50–70%. The following schemes further set out the routes of synthesis:

[0014] Scheme 1:

[0015] Scheme 2: ı35 Scheme 3: ı36 Scheme 4: ıij7 Scheme 5: ıij8 EXAMPLE 2: DUPLEX ANNEALING To generate the desired siRNA duplex, the two complementary strands were annealed by combining equimolar aqueous solutions of both strands. The mixtures were placed into a water bath at 70°C for 5 minutes and subsequently allowed to cool to ambient temperature within 2 h. The duplexes were lyophilized for 2 days and stored at -20°C. The duplexes were analyzed by analytical SEC HPLC on Superdex™ 75 Increase 5 / 150 GL column 5 x 153-158 mm (Cytiva) on a Dionex Ultimate 3000 (Thermo Fisher Scientific) HPLC system. Mobile phase consisted of 1x PBS containing 10% acetonitrile. An isocratic gradient was run in 10 min at a flow rate of 1.5 mL / min at room temperature. UV traces at 260 and 280 nm were recorded. Water (LC-MS grade) was purchased from Sigma-Aldrich and Phosphate-buffered saline (PBS; 10x, pH 7.4) was purchased from GIBCO (Thermo Fisher Scientific). EXAMPLE 3: SYNTHESIS OF TETHER 2 General Experimental conditions: Thin layer chromatography (TLC) was performed on silica-coated aluminium plates with fluorescence indicator 254 nm from Macherey-Nagel. Compounds were visualized under UV light (254 nm), or after spraying with the 5% H2SO4 in methanol (MeOH) or ninhydrin reagent according to Stahl (from Sigma-Aldrich), followed by heating. Flash chromatography was performed with a Biotage Isolera One flash chromatography instrument equipped with a dual variable UV wavelength detector (200-400 nm) using Biotage Sfär Silica 10, 25, 50 or 100 g columns (Uppsala, Sweden). All moisture-sensitive reactions were carried out under anhydrous conditions using dry glassware, anhydrous solvents, and argon atmosphere. All commercially available reagents were purchased from Sigma-Aldrich and solvents from Carl Roth GmbH + Co. KG. D-Galactosamine pentaacetate was purchased from AK scientific. HPLC / ESI-MS was performed on a Dionex UltiMate 3000 RS UHPLC system and Thermo Scientific MSQ Plus Mass spectrometer using an Acquity UPLC Protein BEH C4 column from Waters (300Å, 1.7 µm, 2.1 x 100 mm) at 60 °C. The solvent system consisted of solvent A with H2O containing 0.1% formic acid and solvent B with acetonitrile (ACN) containing 0.1% formic acid. A gradient from 5-100% of B over 15 min with a flow rate of 0.4 mL / min was employed. Detector and conditions: Corona ultra-charged aerosol detection (from esa). Nebulizer Temp.: 25 °C. N2pressure: 35.1 psi. Filter: Corona. 1H and 13C NMR spectra were recorded at room temperature on a Varian spectrometer at 500 MHz (1H NMR) and 125 MHz (13C NMR). Chemical shifts are given in ppm referenced to the solvent residual peak (CDCl3–1H NMR: δ at 7.26 ppm and13C NMR δ at 77.2 ppm; DMSO-d6 –1H NMR: δ at 2.50 ppm and13C NMR δ at 39.5 ppm). Coupling constants are given in Hertz. Signal splitting patterns are described as singlet (s), doublet (d), triplet (t) or multiplet (m). Synthesis route for the conjugate building block TriGalNAc _Tether2: Preparation of compound 2: D-Galactosamine pentaacetate (3.00 g, 7.71 mmol, 1.0 eq.) was dissolved in anhydrous dichloromethane (DCM) (30 mL) under argon and trimethylsilyl trifluoromethanesulfonate (TMSOTf, 4.28 g, 19.27 mmol, 2.5 eq.) was added. The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (50 mL) and washed with cold saturated aq. NaHCO3(100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated to afford the title compound as yellow oil, which was purified by flash chromatography (gradient elution: 0-10% MeOH in DCM in 10 CV). The product was obtained as colourless oil (2.5 g, 98%, rf= 0.45 (2% MeOH in DCM)). Preparation of compound 4: Compound 2 (2.30 g, 6.98 mmol, 1.0 eq.) and azido-PEG3-OH (1.83 g, 10.5 mmol, 1.5 eq.) were dissolved in anhydrous DCM (40 mL) under argon and molecular sieves 3 Å (5 g) were added to the solution. The mixture was stirred at room temperature for 1 h. TMSOTf (0.77 g, 3.49 mmol, 0.5 eq.) was then added to the mixture and the reaction was stirred overnight. The molecular sieves were filtered, the filtrate was diluted with DCM (100 mL) and washed with cold saturated aq. NaHCO3 (100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (gradient elution: 0-3% MeOH in DCM in 10 CV) to afford the title product as light-yellow oil (3.10 g, 88%, rf = 0.25 (2% MeOH in DCM)). MS: calculated for C20H32N4O11, 504.21. Found 505.4.1H NMR (500 MHz, CDCl3) ^ 6.21-6.14 (m, 1H), 5.30 (dd, J = 3.4, 1.1 Hz, 1H), 5.04 (dd, J = 11.2, 3.4 Hz,1H), 4.76 (d, J = 8.6 Hz, 1H), 4.23- 4.08 (m, 3H), 3.91-3.80 (m, 3H), 3.74-3.59 (m, 9H), 3.49-3.41 (m, 2H), 2.14 (s, 3H), 2.02 (s, 3H), 1.97 (d, J = 4.2 Hz, 6H).13C NMR (125 MHz, CDCl3) ^ 170.6 (C), 170.5 (C), 170.4 (C), 170.3 (C), 102.1 (CH), 71.6 (CH), 70.8 (CH), 70.6 (CH), 70.5 (CH), 70.3 (CH2), 69.7 (CH2), 68.5 (CH2), 66.6 (CH2), 61.5 (CH2), 23.1 (CH3), 20.7 (3xCH3). Preparation of compound 5: Compound 4 (1.00 g, 1.98 mmol, 1.0 eq.) was dissolved in a mixture of ethyl acetate (EtOAc) and MeOH (30 mL 1:1 v / v) and Pd / C (100 mg) was added. The reaction mixture was degassed using vacuum / argon cycles (3x) and hydrogenated under balloon pressure overnight. The reaction mixture was filtered through celite and washed with EtOAc (30 mL). The solvent was removed under reduced pressure to afford the title compound as colourless oil (0.95 g, quantitative yield, rf = 0.25 (10% MeOH in DCM)). The compound was used without further purification. MS: calculated for C20H34N2O11, 478.2. Found 479.4. Preparation of compound 7: Tris{[2-(tert-butoxycarbonyl)ethoxy]methyl}-methylamine 6 (3.37 g, 6.67 mmol, 1.0 eq.) was dissolved in a mixture of DCM / water (40 mL 1:1 v / v) and Na2CO3 (0.18 g, 1.7 mmol, 0.25 eq.) was added while stirring vigorously. Benzyl chloroformate (2.94 mL, 20.7 mmol, 3.10 eq.) was added dropwise to the previous mixture and the reaction was stirred at room temperature for 24 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with water (100 mL). The organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting crude material was purified by flash chromatography (gradient elution: 0-10% EtOAc in cyclohexane in 12 CV) to afford the title compound as pale yellowish oil (3.9 g, 91%, rf = 0.56 (10% EtOAc in cyclohexane)). MS: calculated for C33H53NO11, 639.3. Found 640.9.1H NMR (500 MHz, DMSO-d6) ^ 7.38-7.26 (m, 5H), 4.97 (s, 2H), 3.54 (t, 6H), 3.50 (s, 6H), 2.38 (t, 6H), 1.39 (s, 27H). 13C NMR (125 MHz, DMSO-d6) ^ 170.3 (3xC), 154.5 (C), 137.1 (C), 128.2 (2xCH), 127.7 (CH), 127.6 (2xCH), 79.7 (3xC), 68.4 (3xCH2), 66.8 (3xCH2), 64.9 (C), 58.7 (CH2), 35.8 (3xCH2), 27.7 (9xCH3). Preparation of compound 8: Cbz-NH-tris-Boc-ester 7 (0.20 g, 0.39 mmol, 1.0 eq.) was dissolved in CH2Cl2 (1 mL) under argon, trifluoroacetic acid (TFA, 1 mL) was added and the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, the residue was co-evaporated 3 times with toluene (5 mL) and dried under high vacuum to get the compound as its TFA salt (0.183 g, 98%). The compound was used without further purification. MS: calculated for C21H29NO11, 471.6. Found 472.4. Preparation of compound 9: CbzNH-tris-COOH 8 (0.72 g, 1.49 mmol, 1.0 eq.) and GalNAc- PEG3-NH25 (3.56 g, 7.44 mmol, 5.0 eq.) were dissolved in N,N-dimethylformamide (DMF) (25 mL). Then N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (2.78 g, 7.44 mmol, 5.0 eq.), 1-hydroxybenzotriazole hydrate (HOBt) (1.05 g, 7.44 mmol, 5.0 eq.) and N,N-diisopropylethylamine (DIPEA) (2.07 mL, 11.9 mmol, 8.0 eq.) were added to the solution and the reaction was stirred for 72 h. The solvent was removed under reduced pressure, the residue was dissolved in DCM (100 mL) and washed with saturated aq. NaHCO3 (100 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the crude material was purified by flash chromatography (gradient elution: 0-5% MeOH in DCM in 14 CV). The product was obtained as pale yellowish oil (1.2 g, 43%, rf = 0.20 (5% MeOH in DCM)). MS: calculated for C81H125N7O41, 1852.9. Found 1854.7.1H NMR (500 MHz, DMSO-d6) ^ 7.90-7.80 (m, 10H), 7.65-7.62 (m, 4H), 7.47-7.43 (m, 3H), 7.38-7.32 (m, 8H), 5.24-5.22 (m, 3H), 5.02-4.97 (m, 4H), 4.60-4.57 (m, 3 H), 4.07-3.90 (m 10H), 3.67-3.36 (m, 70H), 3.23-3.07 (m, 25H), 2.18 (s, 10H), 2.00 (s, 13H), 1.89 (s, 11H), 1.80-1.78 (m, 17H).13C NMR (125 MHz, DMSO-d6) ^ 170.1 (C), 169.8 (C), 169.7 (C), 169.4 (C), 169.2 (C), 169.1 (C), 142.7 (C), 126.3 (CH), 123.9 (CH), 118.7 (CH), 109.7 (CH), 100.8 (CH), 70.5 (CH), 69.8 (CH), 69.6 (CH), 69.5 (CH), 69.3 (CH2), 69.0 (CH2), 68.2 (CH2), 67.2 (CH2), 66.7 (CH2), 61.4 (CH2), 22.6 (CH2), 22.4 (3xCH3), 20.7 (9xCH3). Preparation of compound 10: Triantennary GalNAc compound 9 (0.27 g, 0.14 mmol, 1.0 eq.) was dissolved in MeOH (15 mL), 3 drops of acetic acid (AcOH) and Pd / C (30 mg) was added. The reaction mixture was degassed using vacuum / argon cycles (3x) and hydrogenated under balloon pressure overnight. The completion of the reaction was followed by mass spectrometry and the resulting mixture was filtered through a thin pad of celite. The solvent was evaporated, and the residue obtained was dried under high vacuum and used for the next step without further purification. The product was obtained as pale yellowish oil (0.24 g, quantitative yield). MS: calculated for C73H119N7O39, 1718.8. Found 1719.3.

[0016] Preparation of compound 14: Triantennary GalNAc compound 10 (0.45 g, 0.26 mmol, 1.0 eq.), HBTU (0.19 g, 0.53 mmol, 2.0 eq.) and DIPEA (0.23 mL, 1.3 mmol, 5.0 eq.) were dissolved in DCM (10 mL) under argon. To this mixture, it was added dropwise a solution of compound 13 (0.14 g, 0.53 mmol, 2.0 eq.) in DCM (5 mL). The reaction was stirred at room temperature overnight. The solvent was removed, and the residue was dissolved in EtOAc (50 mL), washed with water (50 mL) and dried over Na2SO4. The solvent was evaporated, and the crude material was purified by flash chromatography (gradient elution: 0-5% MeOH in DCM in 20 CV). The product was obtained as white fluffy solid (0.25 g, 48%, rf = 0.4 (10% MeOH in DCM)). MS: calculated for C88H137N7O42, 1965.1. Found 1965.6. Preparation of TriGalNAc (15): Triantennary GalNAc compound 14 (0.31 g, 0.15 mmol, 1.0 eq.) was dissolved in EtOAc (15 mL) and Pd / C (40 mg) was added. The reaction mixture was degassed by using vacuum / argon cycles (3x) and hydrogenated under balloon pressure overnight. The completion of the reaction was monitored by mass spectrometry and the resulting mixture was filtered through a thin pad of celite. The solvent was removed under reduced pressure and the resulting residue was dried under high vacuum overnight. The residue was used for conjugations to oligonucleosides without further purification (0.28 g, quantitative yield). MS: calculated for C81H131N7O42, 1874.9. Found 1875.3. Conjugation of Tether 2 to a siRNA strand: TriGalNAc tether 2 (GalNAc-T2) conjugation at 5’- end or 3’-end 5’-GalNAc-T2 conjugates 5’-GalNAc-T2 conjugates 3’-GalNAc-T2 conjugates Preparation of TriGalNAc tether 2 NHS ester: To a solution of carboxylic acid tether 2 (compound 15, 227 mg, 121 µmol) in DMF (2.1 mL), N-hydroxysuccinimide (NHS) (15.3 mg, 133 µmol) and N,N′-diisopropylcarbodiimide (DIC) (19.7 µL, 127 µmol) were added. The solution was stirred at room temperature for 18 h and used without purification for the subsequent conjugation reactions. General procedure for triGalNAc tether 2 conjugation: Amine-modified single strand was dissolved at 700 OD / mL in 50 mM carbonate / bicarbonate buffer pH 9.6 / DMSO 4:6 (v / v) and to this solution was added one molar equivalent of Tether 2 NHS ester (57 mM) solution in DMF. The reaction was carried out at room temperature and after 1 h another molar equivalent of the NHS ester solution was added. The reaction was allowed to proceed for one more hour and reaction progress was monitored by LCMS. At least two molar equivalent excess of the NHS ester reagent relative to the amino modified oligonucleoside were needed to achieve quantitative consumption of the starting material. The reaction mixture was diluted 15-fold with water, filtered once through 1.2 µm filter from Sartorius and then purified by reserve phase (RP HPLC) on an Äkta Pure (GE Healthcare) instrument. The purification was performed using a XBridge C18 Prep 19 x 50 mm column from Waters. Buffer A was 100 mM TEAA pH 7 and buffer B contained 95% acetonitrile in buffer A. A flow rate of 10 mL / min and a temperature of 60°C were employed. UV traces at 280 nm were recorded. A gradient of 0–100% B within 60 column volumes was employed. Fractions containing full-length conjugated oligonucleosides were pooled together, precipitated in the freezer with 3 M NaOAc, pH 5.2 and 85% ethanol and then dissolved at 1000 OD / mL in water. The O-acetates were removed with 20% ammonium hydroxide in water until completion (monitored by LC-MS). The conjugates were desalted by size exclusion chromatography using Sephadex G25 Fine resin (GE Healthcare) on an Äkta Pure (GE Healthcare) instrument to yield the conjugated oligonucleotides in an isolated yield of 60–80%. The conjugates were characterized by HPLC–MS analysis with a 2.1 x 50 mm XBridge C18 column (Waters) on a Dionex Ultimate 3000 (Thermo Fisher Scientific) HPLC system equipped with a Compact ESI-Qq-TOF mass spectrometer (Bruker Daltonics). Buffer A was 16.3 mM triethylamine, 100 mM HFIP in 1% MeOH in H2O and buffer B contained 95% MeOH in buffer A. A flow rate of 250 µL / min and a temperature of 60°C were employed. UV traces at 260 and 280 nm were recorded. A gradient of 1-100% B within 31 min was employed. The following schemes further set out the routes of synthesis:

[0017] Scheme 6: ıĴ8 Scheme 7: ıĴ9 Scheme 8:

[0018] Scheme 9:

[0019] EXAMPLE 4: DUPLEX ANNEALING To generate the desired siRNA duplex, the two complementary strands were annealed by combining equimolar aqueous solutions of both strands. The mixtures were placed into a water bath at 70°C for 5 minutes and subsequently allowed to cool to ambient temperature within 2 h. The duplexes were lyophilized for 2 days and stored at -20°C. The duplexes were analyzed by analytical SEC HPLC on Superdex™ 75 Increase 5 / 150 GL column 5 x 153-158 mm (Cytiva) on a Dionex Ultimate 3000 (Thermo Fisher Scientific) HPLC system. Mobile phase consisted of 1x PBS containing 10% acetonitrile. An isocratic gradient was run in 10 min at a flow rate of 1.5 mL / min at room temperature. UV traces at 260 and 280 nm were recorded. Water (LC-MS grade) was purchased from Sigma-Aldrich and Phosphate-buffered saline (PBS; 10x, pH 7.4) was purchased from GIBCO (Thermo Fisher Scientific). EXAMPLE 5: ALTERNATIVE SYNTHESIS ROUTE FOR THE CONJUGATE BUILDING BLOCK TRIGALNAC _TETHER2: O

[0020] ı53 Conjugation of Tether 2 to a siRNA strand: TriGalNAc tether 2 (GalNAc-T2) conjugation at 5’- end or 3’-end Conjugation conditions Pre-activation: To a solution of compound 15 (16 umol, 4 eq.) in DMF (160 μL) was added TFA- O-PFP (15 μl, 21 eq.) followed by DIPEA (23 μl, 32 eq.) at 25°C. The tube was shaken for 2 h at 25°C. The reaction was quenched with H2O (10 μL). Coupling: The resulting mixture was diluted with DMF (400 μl), followed by addition of oligo- amine solution (4.0 μmol in 10 x PBS, pH 7.4, 500 μL; final oligo concentration in organic and aqueous solution: 4 µmol / ml = 4 mM). The tube was shaken at 25°C for 16 h and the reaction was analysed by LCMS. The resulting mixture was treated with 28% NH4OH (4.5 ml) and shaken for 2 h at 25°C. The mixture was analysed by LCMS, concentrated, and purified by IP-RP HPLC to produce the oligonucleotides conjugated to tether 2 GalNAc. 5’-GalNAc-T2 conjugates 3’-GalNAc-T2 conjugates

[0021] 5’ 3’ EXAMPLE 6: SOLID PHASE SYNTHESIS METHOD: SCALE ≤1µMOL Syntheses of siRNA sense and antisense strands were performed on a MerMade192X synthesiser with commercially available solid supports made of controlled pore glass with universal linker (Universal CPG, with a loading of 40 μmol / g; LGC Biosearch or Glen Research). RNA phosphoramidites were purchased from ChemGenes or Hongene. The 2'-O-Methyl phosphoramidites used were the following: 5'-(4,4'-dimethoxytrityl)-N-benzoyl- adenosine 2'-O-methyl-3'- [(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'- dimethoxytrityl)-N-acetyl-cytidine 2'-O-methyl-3'- [(2-cyanoethyl)-(N,N-diisopropyl)]- phosphoramidite, 5'-(4,4'-dimethoxytrityl)-N-isobutyryl-guanosine 2'-O-methyl-3'-[(2- cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'-dimethoxytrityl)-uridine 2'-O-methyl- 3'-[(2-cyanoethyl)- (N,N-diisopropyl)]-phosphoramidite. The 2’-F phosphoramidites used were the following: 5'-dimethoxytrityl-N-benzoyl- deoxyadenosine 2'-fluoro-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'- dimethoxytrityl-N-acetyl-deoxycytidine 2'-fluoro-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]- phosphoramidite, 5'-dimethoxytrityl-N-isobutyryl-deoxyguanosine 2'-fluoro-3'- [(2-cyanoethyl)- (N,N-diisopropyl)]-phosphoramidite and 5'-dimethoxytrityl-deoxyuridine 2'-fluoro-3'-[(2- cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. All phosphoramidites were dissolved in anhydrous acetonitrile (Honeywell Research Chemicals) at a concentration of 0.05M, except 2’-O-methyl-uridine phosphoramidite which was dissolved in DMF / MeCN (1:4, v / v). Iodine at 0.02M in acetonitrile / Pyridine / H2O (DNAchem) was used as oxidizing reagent. Thiolation for phosphorothioate linkages was performed with 0.2 M PADS (TCI) in acetonitrile / pyridine 1:1 v / v.5-Ethyl thiotetrazole (ETT), 0.25M mM in acetonitrile was used as activator solution. Inverted abasic phosphoramidite, 3-O-Dimethoxytrityl-2-deoxyribose-5-[(2-cyanoethyl)-(N, N- diisopropyl)]-phosphoramidite were purchased from Chemgenes (ANP-1422) or Hongene (OP- 040). At each cycle, the DMT was removed by deblock solution, 3% TCA in DCM (DNAchem). The coupling time was 180 seconds. The oxidizer contact time was set to 80 seconds and thiolation time was 2*100 seconds. At the end of the synthesis, the oligonucleotides were cleaved from the solid support using a NH4OH:EtOH solution 4:1 (v / v) for 20 hours at 45°C (TCI). The solid support was then filtered off, the filter was thoroughly washed with H2O and the volume of the combined solution was reduced by evaporation under reduced pressure. Oligonucleotide were treated to form the sodium salt by ultracentrifugation using Amicon Ultra-2 Centrifugal Filter Unit; PBS buffer (10x, Teknova, pH 7.4, Sterile) or by EtOH precipitation from 1M sodium acetate. The single strands identity were assessed by MS ESI- and then, were annealed in water to form the final duplex siRNA and duplex purity were assessed by size exclusion chromatography. EXAMPLE 7: SOLID PHASE SYNTHESIS METHOD: SCALE ≥5 µMOL Syntheses of siRNA sense and antisense strands were performed on a MerMade12 synthesiser with commercially available solid supports made of controlled pore glass with universal linker (Universal CPG, with a loading of 40 μmol / g; LGC Biosearch or Glen Research) at 5 µmol scale. Sense strand destined to 3' conjugation were sytnthesised at 12 µmol on 3'-PT-Amino-Modifier C6 CPG 500 Å solid support with a loading of 86 µmol / g (LGC). RNA phosphoramidites were purchased from ChemGenes or Hongene. The 2'-O-Methyl phosphoramidites used were the following: 5'-(4,4'-dimethoxytrityl)-N-benzoyl- adenosine 2'-O-methyl-3'- [(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'- dimethoxytrityl)-N-acetyl-cytidine 2'-O-methyl-3'- [(2-cyanoethyl)-(N,N-diisopropyl)]- phosphoramidite, 5'-(4,4'-dimethoxytrityl)-N-isobutyryl-guanosine 2'-O-methyl-3'-[(2- cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'-dimethoxytrityl)-uridine 2'-O-methyl- 3'-[(2-cyanoethyl)- (N,N-diisopropyl)]-phosphoramidite. The 2’-F phosphoramidites used were the following: 5'-dimethoxytrityl-N-benzoyl- deoxyadenosine 2'-fluoro-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'- dimethoxytrityl-N-acetyl-deoxycytidine 2'-fluoro-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]- phosphoramidite, 5'-dimethoxytrityl-N-isobutyryl-deoxyguanosine 2'-fluoro-3'- [(2-cyanoethyl)- (N,N-diisopropyl)]-phosphoramidite and 5'-dimethoxytrityl-deoxyuridine 2'-fluoro-3'-[(2- cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. Inverted abasic phosphoramidite, 3-O-Dimethoxytrityl-2-deoxyribose-5-[(2-cyanoethyl)-(N, N- diisopropyl)]-phosphoramidite were purchased from Chemgenes (ANP-1422) or Hongene (OP- 040). All phosphoramidites were dissolved in anhydrous acetonitrile (Honeywell Research Chemicals) at a concentration of 0.05M, except 2’-O-methyl-uridine phosphoramidite which was dissolved in DMF / MeCN (1:4, v / v). Iodine at 0.02M in acetonitrile / Pyridine / H2O (DNAchem) was used as oxidizing reagent. Thiolation for phosphorothioate linkages was performed with 0.2 M PADS (TCI) in acetonitrile / pyridine 1:1 v / v.5-Ethyl thiotetrazole (ETT), 0.25M mM in acetonitrile was used as activator solution. At each cycle, the DMT was removed by deblock solution, 3% TCA in DCM (DNAchem). For strands synthesised on universal CPG the coupling was performed with 8 eq. of amidite for 130 seconds. The oxidation time was 47 seconds, the thiolation time was 210 seconds. For strands synthesised on 3'-PT-Amino-Modifier C6 CPG the coupling was performed with 8 eq. of amidite for 2*150 seconds. The oxidation time was 47 seconds, the thiolation time was 250 seconds. At the end of the synthesis, the oligonucleotides were cleaved from the solid support using a NH4OH:EtOH solution 4:1 (v / v) for 20 hours at 45°C (TCI). The solid support was then filtered off, the filter was thoroughly washed with H2O and the volume of the combined solution was reduced by evaporation under reduced pressure. Oligonucleotide were treated to form the sodium salt by EtOH precipitation from 1M sodium acetate. The single strand oligonucleotides were purified by IP-RP HPLC on Xbridge BEH C185 µm, 130 Å, 19x150 mm (Waters) column with an increasing gradient of B in A. Mobile phase A: 240 mM HFIP, 7 mM TEA and 5% methanol in water; mobile phase B: 240 mM HFIP, 7 mM TEA in methanol. The single strands purity and identity were assessed by UPLC / MS ESI- on Xbridge BEH C182.5 µm, 3x50 mm (Waters) column with an increasing gradient of B in A. Mobile phase A: 100 mM HFIP, 5 mM TEA in water; mobile phase B: 20% mobile phase A: 80% Acetonitrile (v / v). Sense strands were conjugated as per protocol provided in any of Examples 2, 4, 6. Sense and Antisense strands were then annealed in water to form the final duplex siRNA and duplex purity were assessed by size exclusion chromatography. EXAMPLE 8: NUCLEIC ACID SEQUENCES siRNA oligonucleosides according to the present invention target NR3C2. The full DNA sequence of the NR3C2 target gene is SEQ ID NO:1116. Following Table 1 provides oligonucleoside mRNA target sequences of NR3C2, together with the corresponding positions in transcript ENST00000358102.8. It is to be understood that SEQ ID NO: 1 to 223 refer to human (Homo sapiens) mRNA sequences. Table 1 SEQ ID NO Oligonucleoside mRNA target sequence Starting position on 5’ ^ 3’ ENST00000358102.8 SEQ ID NO: 1 UUAUGGAUGAUAAAGACUAUUAU 1636 SEQ ID NO: 2 UAUGGAUGAUAAAGACUAUUAUU 1637 SEQ ID NO: 3 CCUUUAUGGAUGAUAAAGACUAU 1633 SEQ ID NO: 4 GAAUACACCAUCAUGAAAGUUUU 2859 SEQ ID NO: 5 AAGCUCUACUUUACGAAGUGUUU 2012 SEQ ID NO: 6 AGCUCUACUUUACGAAGUGUUUC 2013 SEQ ID NO: 7 GUUUAUAUAUGGAUUCUGUAAGA 574 SEQ ID NO: 8 GUUGAACAGCUGGUGAAAUUUUA 666 SEQ ID NO: 9 UCCUCUCUCAAGUCCGUUAAGUA 1034 SEQ ID NO: 10 UUGAACAGCUGGUGAAAUUUUAC 667 SEQ ID NO: 11 UAUAUAUGGAUUCUGUAAGAGAU 577 SEQ ID NO: 12 AAAUGUAUCAAGCUCUACUUUAC 2003 SEQ ID NO: 13 GUCACUGCAGUGUAAAAUCUCCA 1087 SEQ ID NO: 14 UAGGAGGAAAUAGCAAAAUAAAU 1489 SEQ ID NO: 15 CUGGAAGAAAUGAUUGCAUCAUU 2176 SEQ ID NO: 16 UGCAGUGUAAAAUCUCCAGUCUC 1092 SEQ ID NO: 17 CUUGCAGACUUCAGAAAUGUCUU 2227 SEQ ID NO: 18 CAGUGUAAAAUCUCCAGUCUCCA 1094 SEQ ID NO: 19 CAGCUGCAAAGUUUUCUUCAAAA 2120 SEQ ID NO: 20 GCAGCUGCAAAGUUUUCUUCAAA 2119 SEQ ID NO: 21 AUGAUAAAGACUAUUAUUCCCUA 1642 SEQ ID NO: 22 UCCAGAAAAUGUAUCAAGCUCUA 1997 SEQ ID NO: 23 CAUUCUCAGUACCAAUAAAGCAA 1522 SEQ ID NO: 24 UUGAUAAGAUUCGACGAAAGAAU 2197 SEQ ID NO: 25 UGGGUUUAUAUAUGGAUUCUGUA 571 SEQ ID NO: 26 CUGCUACUAAGCACAAUUCCAAA 2883 SEQ ID NO: 27 CCCUCCAAGUCACUGCAGUGUAA 1079 SEQ ID NO: 28 UGUUGAACAGCUGGUGAAAUUUU 665 SEQ ID NO: 29 AUCAUGAAAGUUUUGCUGCUACU 2868 SEQ ID NO: 30 UUCCAGAAAAUGUAUCAAGCUCU 1996 SEQ ID NO: 31 CAAGUCACUGCAGUGUAAAAUCU 1084 SEQ ID NO: 32 UCUUAGAAUACAUUCCAGAAAAU 1984 SEQ ID NO: 33 GCUGAGUCCAUGGGUUUAUAUAU 561 SEQ ID NO: 34 CGAUCGGCUAGAGACCAAUCUUU 1866 SEQ ID NO: 35 UUUCCUUUAUGGAUGAUAAAGAC 1630 SEQ ID NO: 36 AUGUUGAACAGCUGGUGAAAUUU 664 SEQ ID NO: 37 AAAAUGUAUCAAGCUCUACUUUA 2002 SEQ ID NO: 38 CUUUAUGGAUGAUAAAGACUAUU 1634 SEQ ID NO: 39 AGGAGGAAAUAGCAAAAUAAAUU 1490 SEQ ID NO: 40 AAUGAUUGCAUCAUUGAUAAGAU 2184 SEQ ID NO: 41 CAUCAUGAAAGUUUUGCUGCUAC 2867 SEQ ID NO: 42 UUUAUGUGCUGGAAGAAAUGAUU 2168 SEQ ID NO: 43 UAAGAGAUGCUGACUAUUCCUAU 592 SEQ ID NO: 44 CCUGCUGGAAUUCUGCUUCUACA 3068 SEQ ID NO: 45 CUGUAAGAGAUGCUGACUAUUCC 589 SEQ ID NO: 46 UCUAGGAGGAAAUAGCAAAAUAA 1487 SEQ ID NO: 47 UACACCAUCAUGAAAGUUUUGCU 2862 SEQ ID NO: 48 GGUAUCCGGUCUUAGAAUACAUU 1975 SEQ ID NO: 49 AAGUCCGUUAAGUAGCAUGAAAU 1043 SEQ ID NO: 50 AGUCACUGCAGUGUAAAAUCUCC 1086 SEQ ID NO: 51 UUCUGUAAGAGAUGCUGACUAUU 587 SEQ ID NO: 52 UCCUUUAUGGAUGAUAAAGACUA 1632 SEQ ID NO: 53 AUGGGUUUAUAUAUGGAUUCUGU 570 SEQ ID NO: 54 UCUCUCAAGUCCGUUAAGUAGCA 1037 SEQ ID NO: 55 AGCCCUCUGAACAUGACAUCUUC 843 SEQ ID NO: 56 CUAAGGAACUUUCAGCAACUGUA 538 SEQ ID NO: 57 AUUCUGUAAGAGAUGCUGACUAU 586 SEQ ID NO: 58 CUGGUGAAAUUUUACAAAGGAAA 675 SEQ ID NO: 59 AAUCUAAGGAACUUUCAGCAACU 535 SEQ ID NO: 60 GAAGAAAUGAGGACAAAUUACAU 2934 SEQ ID NO: 61 AGUACCAAUAAAGCAAGAAUCAA 1529 SEQ ID NO: 62 AUGUCUUCAAGCUGGAAUGAAUU 2243 SEQ ID NO: 63 CAGCUUAAUAUUGUCCAGUACAU 1428 SEQ ID NO: 64 GGGUUUAUAUAUGGAUUCUGUAA 572 SEQ ID NO: 65 CUCCAAGUCACUGCAGUGUAAAA 1081 SEQ ID NO: 66 UGGAUGAUAAAGACUAUUAUUCC 1639 SEQ ID NO: 67 AUGAUUGCAUCAUUGAUAAGAUU 2185 SEQ ID NO: 68 GCUGGUGAAAUUUUACAAAGGAA 674 SEQ ID NO: 69 AGGACAAAUUACAUCAAAGAACU 2943 SEQ ID NO: 70 GCAGUGUAAAAUCUCCAGUCUCC 1093 SEQ ID NO: 71 CAUGAAAGUUUUGCUGCUACUAA 2870 SEQ ID NO: 72 GAUAUUAAAACUGAGCUGGAAUC 516 SEQ ID NO: 73 UUUUCCUUUAUGGAUGAUAAAGA 1629 SEQ ID NO: 74 GAUUCCCAGUGGGUAUUAAACAA 1720 SEQ ID NO: 75 CACCUCUGCUGGAUCCAGUACAU 1298 SEQ ID NO: 76 UGGAUUCUGUAAGAGAUGCUGAC 583 SEQ ID NO: 77 ACUACAUGGAGAUUGUCAACGUA 379 SEQ ID NO: 78 AAGUCACUGCAGUGUAAAAUCUC 1085 SEQ ID NO: 79 AACAGCUGGUGAAAUUUUACAAA 670 SEQ ID NO: 80 UUUAUGGAUGAUAAAGACUAUUA 1635 SEQ ID NO: 81 CCAGCUAAGAUUUAUCAGAAUGU 645 SEQ ID NO: 82 UAGAAUACAUUCCAGAAAAUGUA 1987 SEQ ID NO: 83 UGAUAAGAUUCGACGAAAGAAUU 2198 SEQ ID NO: 84 UUAAGUAGCAUGAAAUCCUCAAU 1050 SEQ ID NO: 85 CACCUGAGUUCCUUUCCUCCUGU 1893 SEQ ID NO: 86 GGCAGCUGCAAAGUUUUCUUCAA 2118 SEQ ID NO: 87 AGUAGCAUGAAAUCCUCAAUUUC 1053 SEQ ID NO: 88 GUCUAGGAGGAAAUAGCAAAAUA 1486 SEQ ID NO: 89 CUGAUAUUAAAACUGAGCUGGAA 514 SEQ ID NO: 90 CUUAAUAUUGUCCAGUACAUAAA 1431 SEQ ID NO: 91 GCUAAGAUUUAUCAGAAUGUUGA 648 SEQ ID NO: 92 UGGUGAAAUUUUACAAAGGAAAU 676 SEQ ID NO: 93 CGUUAAGUAGCAUGAAAUCCUCA 1048 SEQ ID NO: 94 CUGCAGUGUAAAAUCUCCAGUCU 1091 SEQ ID NO: 95 UCAUGAAAGUUUUGCUGCUACUA 2869 SEQ ID NO: 96 UGAUAUUAAAACUGAGCUGGAAU 515 SEQ ID NO: 97 UCCGUUAAGUAGCAUGAAAUCCU 1046 SEQ ID NO: 98 UUGCAGACUUCAGAAAUGUCUUC 2228 SEQ ID NO: 99 AGCUUAAUAUUGUCCAGUACAUA 1429 SEQ ID NO: 100 GUCCAGCUAAGAUUUAUCAGAAU 643 SEQ ID NO: 101 CAAGCUCUACUUUACGAAGUGUU 2011 SEQ ID NO: 102 CAGCUAAGAUUUAUCAGAAUGUU 646 SEQ ID NO: 103 CUCAGUACCAAUAAAGCAAGAAU 1526 SEQ ID NO: 104 CUCCUCUCUCAAGUCCGUUAAGU 1033 SEQ ID NO: 105 UGUAUCAAGCUCUACUUUACGAA 2006 SEQ ID NO: 106 GAAUGUUGAACAGCUGGUGAAAU 662 SEQ ID NO: 107 CUAAGAUUUAUCAGAAUGUUGAA 649 SEQ ID NO: 108 AGUCCAUGGGUUUAUAUAUGGAU 565 SEQ ID NO: 109 UUGAAGAAAUGAGGACAAAUUAC 2932 SEQ ID NO: 110 AUUGAUAAGAUUCGACGAAAGAA 2196 SEQ ID NO: 111 GAUGAUAAAGACUAUUAUUCCCU 1641 SEQ ID NO: 112 GUAGCUGAGUCCAUGGGUUUAUA 558 SEQ ID NO: 113 UUUCCUAAGACUGAGGAAGUAGA 1377 SEQ ID NO: 114 CUUUCCAACACCUGAGUUCCUUU 1885 SEQ ID NO: 115 AUCAUUGAUAAGAUUCGACGAAA 2193 SEQ ID NO: 116 UAGCAUGAAAUCCUCAAUUUCCA 1055 SEQ ID NO: 117 AGAAAAUGUAUCAAGCUCUACUU 2000 SEQ ID NO: 118 GCUGCUACUAAGCACAAUUCCAA 2882 SEQ ID NO: 119 CAGUACUGUGGGAUCUAUCUGUA 1238 SEQ ID NO: 120 CUAGGAGGAAAUAGCAAAAUAAA 1488 SEQ ID NO: 121 AAGAAAUGAUUGCAUCAUUGAUA 2180 SEQ ID NO: 122 UCCAAGUCACUGCAGUGUAAAAU 1082 SEQ ID NO: 123 GAGUCCAGCUAAGAUUUAUCAGA 641 SEQ ID NO: 124 AUUGCAUCAUUGAUAAGAUUCGA 2188 SEQ ID NO: 125 CCGUUAAGUAGCAUGAAAUCCUC 1047 SEQ ID NO: 126 ACUAAUAACAGAUCCACGCUUUC 1203 SEQ ID NO: 127 CAGAAAAUGUAUCAAGCUCUACU 1999 SEQ ID NO: 128 GUCCAUGGGUUUAUAUAUGGAUU 566 SEQ ID NO: 129 GAAAAUGUAUCAAGCUCUACUUU 2001 SEQ ID NO: 130 AGUCCGUUAAGUAGCAUGAAAUC 1044 SEQ ID NO: 131 UGAUAAAGACUAUUAUUCCCUAU 1643 SEQ ID NO: 132 AUGAAAGUUUUGCUGCUACUAAG 2871 SEQ ID NO: 133 CUCUCCUCUCUCAAGUCCGUUAA 1031 SEQ ID NO: 134 AGAGGACCGAUGAGAAUAACUAC 361 SEQ ID NO: 135 AAUACACCAUCAUGAAAGUUUUG 2860 SEQ ID NO: 136 AUUUGAAGAAAUGAGGACAAAUU 2930 SEQ ID NO: 137 AUGGAUGAUAAAGACUAUUAUUC 1638 SEQ ID NO: 138 AUUAAAACUGAGCUGGAAUCUAA 519 SEQ ID NO: 139 GAGAAUAACUACAUGGAGAUUGU 372 SEQ ID NO: 140 UGUAAGAGAUGCUGACUAUUCCU 590 SEQ ID NO: 141 ACCAUCAUGAAAGUUUUGCUGCU 2865 SEQ ID NO: 142 AGUACAUAAAACCAGAACCAGAU 1444 SEQ ID NO: 143 UUUUGCUGCUACUAAGCACAAUU 2878 SEQ ID NO: 144 UUCGACUGCAGCUCACCUUUGAA 2836 SEQ ID NO: 145 UAUUAAAACUGAGCUGGAAUCUA 518 SEQ ID NO: 146 UUUAGUGGAGUCAUGGAAAUCAC 1922 SEQ ID NO: 147 AAAGUUUUGCUGCUACUAAGCAC 2874 SEQ ID NO: 148 UUUGAAGAAAUGAGGACAAAUUA 2931 SEQ ID NO: 149 UACUCAAGGAAGCAGCAAAGAAA 434 SEQ ID NO: 150 UUAUAUAUGGAUUCUGUAAGAGA 576 SEQ ID NO: 151 UGGUAACUAAGUGUCCCAACAAU 2974 SEQ ID NO: 152 UAUCAAGCUCUACUUUACGAAGU 2008 SEQ ID NO: 153 GAGAGGACCGAUGAGAAUAACUA 360 SEQ ID NO: 154 GAGCUUUUAGCAGCUCAUGUCUA 1468 SEQ ID NO: 155 AUUUAUCAGAAUGUUGAACAGCU 654 SEQ ID NO: 156 AAUGUAUCAAGCUCUACUUUACG 2004 SEQ ID NO: 157 CUAUUCCAAACAACAGUACUCAA 418 SEQ ID NO: 158 AUAAAGACUAUUAUUCCCUAUCA 1645 SEQ ID NO: 159 UCUGAACAUGACAUCUUCGGUUU 848 SEQ ID NO: 160 AAUGUUGAACAGCUGGUGAAAUU 663 SEQ ID NO: 161 GGAUGAUAAAGACUAUUAUUCCC 1640 SEQ ID NO: 162 CAUUCCAGAAAAUGUAUCAAGCU 1994 SEQ ID NO: 163 GAAAUGAGGACAAAUUACAUCAA 2937 SEQ ID NO: 164 AUGUCUAGGAGGAAAUAGCAAAA 1484 SEQ ID NO: 165 GCUAUUCCAAACAACAGUACUCA 417 SEQ ID NO: 166 GAUUCUGUAAGAGAUGCUGACUA 585 SEQ ID NO: 167 CUGCAGCUCACCUUUGAAGAAUA 2841 SEQ ID NO: 168 UGAGAUCAUUUAUGUCUGACUCU 739 SEQ ID NO: 169 CUCUGAACAUGACAUCUUCGGUU 847 SEQ ID NO: 170 CUCUCAAGUCCGUUAAGUAGCAU 1038 SEQ ID NO: 171 CCAGUACUGUGGGAUCUAUCUGU 1237 SEQ ID NO: 172 UCAAGCUCUACUUUACGAAGUGU 2010 SEQ ID NO: 173 UUAAAACUGAGCUGGAAUCUAAG 520 SEQ ID NO: 174 UCAGUACCAAUAAAGCAAGAAUC 1527 SEQ ID NO: 175 GUCUUAGAAUACAUUCCAGAAAA 1983 SEQ ID NO: 176 AGAAAUGAUUGCAUCAUUGAUAA 2181 SEQ ID NO: 177 AGCUGGUGAAAUUUUACAAAGGA 673 SEQ ID NO: 178 AAAUGAGGACAAAUUACAUCAAA 2938 SEQ ID NO: 179 UUUCCGGUGCUAUUCCAAACAAC 409 SEQ ID NO: 180 CAACUCAAGGUGCUCUGUUUCCA 1169 SEQ ID NO: 181 UGGAAGAAAUGAUUGCAUCAUUG 2177 SEQ ID NO: 182 AAAGCAAGAAUCAACCAAGCAUU 1538 SEQ ID NO: 183 UGAGCUGGAAUCUAAGGAACUUU 527 SEQ ID NO: 184 CCAGCUUAAUAUUGUCCAGUACA 1427 SEQ ID NO: 185 CCAUGGGUUUAUAUAUGGAUUCU 568 SEQ ID NO: 186 UUAAUAUUGUCCAGUACAUAAAA 1432 SEQ ID NO: 187 AUACAUUCCAGAAAAUGUAUCAA 1991 SEQ ID NO: 188 GGCUCUCCUCUCUCAAGUCCGUU 1029 SEQ ID NO: 189 CUACUAAGCACAAUUCCAAAGGA 2886 SEQ ID NO: 190 CUGAGCUGGAAUCUAAGGAACUU 526 SEQ ID NO: 191 CCAAGUCACUGCAGUGUAAAAUC 1083 SEQ ID NO: 192 GUAUCAAGCUCUACUUUACGAAG 2007 SEQ ID NO: 193 CGGUGCUAUUCCAAACAACAGUA 413 SEQ ID NO: 194 UGCUAUUCCAAACAACAGUACUC 416 SEQ ID NO: 195 CAUGAGUCCAGCUAAGAUUUAUC 638 SEQ ID NO: 196 CCUGCUUGCAGACUUCAGAAAUG 2223 SEQ ID NO: 197 AUGUAUCAAGCUCUACUUUACGA 2005 SEQ ID NO: 198 UCCCAGUGGGUAUUAAACAAGAA 1723 SEQ ID NO: 199 AAUGUCUUCAAGCUGGAAUGAAU 2242 SEQ ID NO: 200 UAAGUAGCAUGAAAUCCUCAAUU 1051 SEQ ID NO: 201 UUCCACUACAGGAUUGGUGCUCA 1824 SEQ ID NO: 202 GUAACUAAGUGUCCCAACAAUUC 2976 SEQ ID NO: 203 GAAGAAAUGAUUGCAUCAUUGAU 2179 SEQ ID NO: 204 CUUGAGAUCAUUUAUGUCUGACU 737 SEQ ID NO: 205 UAAUAUUGUCCAGUACAUAAAAC 1433 SEQ ID NO: 206 GAAGCAUGAGUCCAGCUAAGAUU 634 SEQ ID NO: 207 CAUUUGAAGAAAUGAGGACAAAU 2929 SEQ ID NO: 208 CCUCCAAGUCACUGCAGUGUAAA 1080 SEQ ID NO: 209 UUCUCAGUACCAAUAAAGCAAGA 1524 SEQ ID NO: 210 GGACCGAUGAGAAUAACUACAUG 364 SEQ ID NO: 211 CUAUCUGUAGCCCUGUAAACAAU 1252 SEQ ID NO: 212 GUAGCAUGAAAUCCUCAAUUUCC 1054 SEQ ID NO: 213 GGUGCUAUUCCAAACAACAGUAC 414 SEQ ID NO: 214 CACUGCAGUGUAAAAUCUCCAGU 1089 SEQ ID NO: 215 UAAAGACUAUUAUUCCCUAUCAG 1646 SEQ ID NO: 216 UUUGCUGCUACUAAGCACAAUUC 2879 SEQ ID NO: 217 UCCAACACCUGAGUUCCUUUCCU 1888 SEQ ID NO: 218 UCUGUAAGAGAUGCUGACUAUUC 588 SEQ ID NO: 219 GGAUCUAUCUGUAGCCCUGUAAA 1248 SEQ ID NO: 220 CUGCUUGCAGACUUCAGAAAUGU 2224 SEQ ID NO: 221 UACUUUAGUGGAGUCAUGGAAAU 1919 SEQ ID NO: 222 AAUGAGGACAAAUUACAUCAAAG 2939 SEQ ID NO: 223 GUUUCCGGUGCUAUUCCAAACAA 408 Table 2 provides the unmodified first (antisense) and corresponding unmodified second (sense) strand sequences for siRNA oligonucleosides according to the present invention, together with the corresponding positions in the overall gene sequence of SEQ ID NO:1116 as follows. Table 2 SEQ ID First (Antisense) Strand Base SEQ ID Second (Sense) Strand Base Corresponding NO (AS) Sequence NO (SS) Sequence positions on 5’ ^ 3’ 5’ ^ 3’ ENST000003 (Shown as an Unmodified (Shown as an Unmodified 58102.8 Nucleoside Sequence) Nucleoside Sequence) SEQ ID AUAAUAGUCUUUAUCAUCC SEQ ID AUGGAUGAUAAAGACUA 1636-1659 NO: 224 AUAA NO: 447 UUAU SEQ ID AAUAAUAGUCUUUAUCAUC SEQ ID UGGAUGAUAAAGACUAU 1637-1660 NO: 225 CAUA NO: 448 UAUU SEQ ID AUAGUCUUUAUCAUCCAUA SEQ ID UUUAUGGAUGAUAAAGA 1633-1656 NO: 226 AAGG NO: 449 CUAU SEQ ID AAAACUUUCAUGAUGGUGU SEQ ID AUACACCAUCAUGAAAG 2859-2882 NO: 227 AUUC NO: 450 UUUU SEQ ID AAACACUUCGUAAAGUAGA SEQ ID GCUCUACUUUACGAAGU 2012-2035 NO: 228 GCUU NO: 451 GUUU SEQ ID GAAACACUUCGUAAAGUAG SEQ ID CUCUACUUUACGAAGUG 2013-2036 NO: 229 AGCU NO: 452 UUUC SEQ ID UCUUACAGAAUCCAUAUAU SEQ ID UUAUAUAUGGAUUCUGU 574-597 NO: 230 AAAC NO: 453 AAGA SEQ ID UAAAAUUUCACCAGCUGUU SEQ ID UGAACAGCUGGUGAAAU 666-689 NO: 231 CAAC NO: 454 UUUA SEQ ID UACUUAACGGACUUGAGAG SEQ ID CUCUCUCAAGUCCGUUA 1034-1057 NO: 232 AGGA NO: 455 AGUA SEQ ID GUAAAAUUUCACCAGCUGU SEQ ID GAACAGCUGGUGAAAUU 667-690 NO: 233 UCAA NO: 456 UUAC SEQ ID AUCUCUUACAGAAUCCAUA SEQ ID UAUAUGGAUUCUGUAAG 577-600 NO: 234 UAUA NO: 457 AGAU SEQ ID GUAAAGUAGAGCUUGAUAC SEQ ID AUGUAUCAAGCUCUACU 2003-2026 NO: 235 AUUU NO: 458 UUAC SEQ ID UGGAGAUUUUACACUGCAG SEQ ID CACUGCAGUGUAAAAUC 1087-1110 NO: 236 UGAC NO: 459 UCCA SEQ ID AUUUAUUUUGCUAUUUCCU SEQ ID GGAGGAAAUAGCAAAAU 1489-1512 NO: 237 CCUA NO: 460 AAAU SEQ ID AAUGAUGCAAUCAUUUCUU SEQ ID GGAAGAAAUGAUUGCAU 2176-2199 NO: 238 CCAG NO: 461 CAUU SEQ ID GAGACUGGAGAUUUUACAC SEQ ID CAGUGUAAAAUCUCCAG 1092-1115 NO: 239 UGCA NO: 462 UCUC SEQ ID AAGACAUUUCUGAAGUCUG SEQ ID UGCAGACUUCAGAAAUG 2227-2250 NO: 240 CAAG NO: 463 UCUU SEQ ID UGGAGACUGGAGAUUUUAC SEQ ID GUGUAAAAUCUCCAGUC 1094-1117 NO: 241 ACUG NO: 464 UCCA SEQ ID UUUUGAAGAAAACUUUGCA SEQ ID GCUGCAAAGUUUUCUUC 2120-2143 NO: 242 GCUG NO: 465 AAAA SEQ ID UUUGAAGAAAACUUUGCAG SEQ ID AGCUGCAAAGUUUUCUU 2119-2142 NO: 243 CUGC NO: 466 CAAA SEQ ID UAGGGAAUAAUAGUCUUUA SEQ ID GAUAAAGACUAUUAUUC 1642-1665 NO: 244 UCAU NO: 467 CCUA SEQ ID UAGAGCUUGAUACAUUUUC SEQ ID CAGAAAAUGUAUCAAGC 1997-2020 NO: 245 UGGA NO: 468 UCUA SEQ ID UUGCUUUAUUGGUACUGAG SEQ ID UUCUCAGUACCAAUAAA 1522-1545 NO: 246 AAUG NO: 469 GCAA SEQ ID AUUCUUUCGUCGAAUCUUA SEQ ID GAUAAGAUUCGACGAAA 2197-2220 NO: 247 UCAA NO: 470 GAAU SEQ ID UACAGAAUCCAUAUAUAAA SEQ ID GGUUUAUAUAUGGAUUC 571-594 NO: 248 CCCA NO: 471 UGUA SEQ ID UUUGGAAUUGUGCUUAGUA SEQ ID GCUACUAAGCACAAUUC 2883-2906 NO: 249 GCAG NO: 472 CAAA SEQ ID UUACACUGCAGUGACUUGG SEQ ID CUCCAAGUCACUGCAGU 1079-1102 NO: 250 AGGG NO: 473 GUAA SEQ ID AAAAUUUCACCAGCUGUUC SEQ ID UUGAACAGCUGGUGAAA 665-688 NO: 251 AACA NO: 474 UUUU SEQ ID AGUAGCAGCAAAACUUUCA SEQ ID CAUGAAAGUUUUGCUGC 2868-2891 NO: 252 UGAU NO: 475 UACU SEQ ID AGAGCUUGAUACAUUUUCU SEQ ID CCAGAAAAUGUAUCAAG 1996-2019 NO: 253 GGAA NO: 476 CUCU SEQ ID AGAUUUUACACUGCAGUGA SEQ ID AGUCACUGCAGUGUAAA 1084-1107 NO: 254 CUUG NO: 477 AUCU SEQ ID AUUUUCUGGAAUGUAUUCU SEQ ID UUAGAAUACAUUCCAGA 1984-2007 NO: 255 AAGA NO: 478 AAAU SEQ ID AUAUAUAAACCCAUGGACU SEQ ID UGAGUCCAUGGGUUUAU 561-584 NO: 256 CAGC NO: 479 AUAU SEQ ID AAAGAUUGGUCUCUAGCCG SEQ ID AUCGGCUAGAGACCAAU 1866-1889 NO: 257 AUCG NO: 480 CUUU SEQ ID GUCUUUAUCAUCCAUAAAG SEQ ID UCCUUUAUGGAUGAUAA 1630-1653 NO: 258 GAAA NO: 481 AGAC SEQ ID AAAUUUCACCAGCUGUUCA SEQ ID GUUGAACAGCUGGUGAA 664-687 NO: 259 ACAU NO: 482 AUUU SEQ ID UAAAGUAGAGCUUGAUACA SEQ ID AAUGUAUCAAGCUCUAC 2002-2025 NO: 260 UUUU NO: 483 UUUA SEQ ID AAUAGUCUUUAUCAUCCAU SEQ ID UUAUGGAUGAUAAAGAC 1634-1657 NO: 261 AAAG NO: 484 UAUU SEQ ID AAUUUAUUUUGCUAUUUCC SEQ ID GAGGAAAUAGCAAAAUA 1490-1513 NO: 262 UCCU NO: 485 AAUU SEQ ID AUCUUAUCAAUGAUGCAAU SEQ ID UGAUUGCAUCAUUGAUA 2184-2207 NO: 263 CAUU NO: 486 AGAU SEQ ID GUAGCAGCAAAACUUUCAU SEQ ID UCAUGAAAGUUUUGCUG 2867-2890 NO: 264 GAUG NO: 487 CUAC SEQ ID AAUCAUUUCUUCCAGCACA SEQ ID UAUGUGCUGGAAGAAAU 2168-2191 NO: 265 UAAA NO: 488 GAUU SEQ ID AUAGGAAUAGUCAGCAUCU SEQ ID AGAGAUGCUGACUAUUC 592-615 NO: 266 CUUA NO: 489 CUAU SEQ ID UGUAGAAGCAGAAUUCCAG SEQ ID UGCUGGAAUUCUGCUUC 3068-3091 NO: 267 CAGG NO: 490 UACA SEQ ID GGAAUAGUCAGCAUCUCUU SEQ ID GUAAGAGAUGCUGACUA 589-612 NO: 268 ACAG NO: 491 UUCC SEQ ID UUAUUUUGCUAUUUCCUCC SEQ ID UAGGAGGAAAUAGCAAA 1487-1510 NO: 269 UAGA NO: 492 AUAA SEQ ID AGCAAAACUUUCAUGAUGG SEQ ID CACCAUCAUGAAAGUUU 2862-2885 NO: 270 UGUA NO: 493 UGCU SEQ ID AAUGUAUUCUAAGACCGGA SEQ ID UAUCCGGUCUUAGAAUA 1975-1998 NO: 271 UACC NO: 494 CAUU SEQ ID AUUUCAUGCUACUUAACGG SEQ ID GUCCGUUAAGUAGCAUG 1043-1066 NO: 272 ACUU NO: 495 AAAU SEQ ID GGAGAUUUUACACUGCAGU SEQ ID UCACUGCAGUGUAAAAU 1086-1109 NO: 273 GACU NO: 496 CUCC SEQ ID AAUAGUCAGCAUCUCUUAC SEQ ID CUGUAAGAGAUGCUGAC 587-610 NO: 274 AGAA NO: 497 UAUU SEQ ID UAGUCUUUAUCAUCCAUAA SEQ ID CUUUAUGGAUGAUAAAG 1632-1655 NO: 275 AGGA NO: 498 ACUA SEQ ID ACAGAAUCCAUAUAUAAAC SEQ ID GGGUUUAUAUAUGGAUU 570-593 NO: 276 CCAU NO: 499 CUGU SEQ ID UGCUACUUAACGGACUUGA SEQ ID UCUCAAGUCCGUUAAGU 1037-1060 NO: 277 GAGA NO: 500 AGCA SEQ ID GAAGAUGUCAUGUUCAGAG SEQ ID CCCUCUGAACAUGACAU 843-866 NO: 278 GGCU NO: 501 CUUC SEQ ID UACAGUUGCUGAAAGUUCC SEQ ID AAGGAACUUUCAGCAAC 538-561 NO: 279 UUAG NO: 502 UGUA SEQ ID AUAGUCAGCAUCUCUUACA SEQ ID UCUGUAAGAGAUGCUGA 586-609 NO: 280 GAAU NO: 503 CUAU SEQ ID UUUCCUUUGUAAAAUUUCA SEQ ID GGUGAAAUUUUACAAAG 675-698 NO: 281 CCAG NO: 504 GAAA SEQ ID AGUUGCUGAAAGUUCCUUA SEQ ID UCUAAGGAACUUUCAGC 535-558 NO: 282 GAUU NO: 505 AACU SEQ ID AUGUAAUUUGUCCUCAUUU SEQ ID AGAAAUGAGGACAAAUU 2934-2957 NO: 283 CUUC NO: 506 ACAU SEQ ID UUGAUUCUUGCUUUAUUGG SEQ ID UACCAAUAAAGCAAGAA 1529-1552 NO: 284 UACU NO: 507 UCAA SEQ ID AAUUCAUUCCAGCUUGAAG SEQ ID GUCUUCAAGCUGGAAUG 2243-2266 NO: 285 ACAU NO: 508 AAUU SEQ ID AUGUACUGGACAAUAUUAA SEQ ID GCUUAAUAUUGUCCAGU 1428-1451 NO: 286 GCUG NO: 509 ACAU SEQ ID UUACAGAAUCCAUAUAUAA SEQ ID GUUUAUAUAUGGAUUCU 572-595 NO: 287 ACCC NO: 510 GUAA SEQ ID UUUUACACUGCAGUGACUU SEQ ID CCAAGUCACUGCAGUGU 1081-1104 NO: 288 GGAG NO: 511 AAAA SEQ ID GGAAUAAUAGUCUUUAUCA SEQ ID GAUGAUAAAGACUAUUA 1639-1662 NO: 289 UCCA NO: 512 UUCC SEQ ID AAUCUUAUCAAUGAUGCAA SEQ ID GAUUGCAUCAUUGAUAA 2185-2208 NO: 290 UCAU NO: 513 GAUU SEQ ID UUCCUUUGUAAAAUUUCAC SEQ ID UGGUGAAAUUUUACAAA 674-697 NO: 291 CAGC NO: 514 GGAA SEQ ID AGUUCUUUGAUGUAAUUUG SEQ ID GACAAAUUACAUCAAAG 2943-2966 NO: 292 UCCU NO: 515 AACU SEQ ID GGAGACUGGAGAUUUUACA SEQ ID AGUGUAAAAUCUCCAGU 1093-1116 NO: 293 CUGC NO: 516 CUCC SEQ ID UUAGUAGCAGCAAAACUUU SEQ ID UGAAAGUUUUGCUGCUA 2870-2893 NO: 294 CAUG NO: 517 CUAA SEQ ID GAUUCCAGCUCAGUUUUAA SEQ ID UAUUAAAACUGAGCUGG 516-539 NO: 295 UAUC NO: 518 AAUC SEQ ID UCUUUAUCAUCCAUAAAGG SEQ ID UUCCUUUAUGGAUGAUA 1629-1652 NO: 296 AAAA NO: 519 AAGA SEQ ID UUGUUUAAUACCCACUGGG SEQ ID UUCCCAGUGGGUAUUAA 1720-1743 NO: 297 AAUC NO: 520 ACAA SEQ ID AUGUACUGGAUCCAGCAGA SEQ ID CCUCUGCUGGAUCCAGU 1298-1321 NO: 298 GGUG NO: 521 ACAU SEQ ID GUCAGCAUCUCUUACAGAA SEQ ID GAUUCUGUAAGAGAUGC 583-606 NO: 299 UCCA NO: 522 UGAC SEQ ID UACGUUGACAAUCUCCAUG SEQ ID UACAUGGAGAUUGUCAA 379-402 NO: 300 UAGU NO: 523 CGUA SEQ ID GAGAUUUUACACUGCAGUG SEQ ID GUCACUGCAGUGUAAAA 1085-1108 NO: 301 ACUU NO: 524 UCUC SEQ ID UUUGUAAAAUUUCACCAGC SEQ ID CAGCUGGUGAAAUUUUA 670-693 NO: 302 UGUU NO: 525 CAAA SEQ ID UAAUAGUCUUUAUCAUCCA SEQ ID UAUGGAUGAUAAAGACU 1635-1658 NO: 303 UAAA NO: 526 AUUA SEQ ID ACAUUCUGAUAAAUCUUAG SEQ ID AGCUAAGAUUUAUCAGA 645-668 NO: 304 CUGG NO: 527 AUGU SEQ ID UACAUUUUCUGGAAUGUAU SEQ ID GAAUACAUUCCAGAAAA 1987-2010 NO: 305 UCUA NO: 528 UGUA SEQ ID AAUUCUUUCGUCGAAUCUU SEQ ID AUAAGAUUCGACGAAAG 2198-2221 NO: 306 AUCA NO: 529 AAUU SEQ ID AUUGAGGAUUUCAUGCUAC SEQ ID AAGUAGCAUGAAAUCCU 1050-1073 NO: 307 UUAA NO: 530 CAAU SEQ ID ACAGGAGGAAAGGAACUCA SEQ ID CCUGAGUUCCUUUCCUC 1893-1916 NO: 308 GGUG NO: 531 CUGU SEQ ID UUGAAGAAAACUUUGCAGC SEQ ID CAGCUGCAAAGUUUUCU 2118-2141 NO: 309 UGCC NO: 532 UCAA SEQ ID GAAAUUGAGGAUUUCAUGC SEQ ID UAGCAUGAAAUCCUCAA 1053-1076 NO: 310 UACU NO: 533 UUUC SEQ ID UAUUUUGCUAUUUCCUCCU SEQ ID CUAGGAGGAAAUAGCAA 1486-1509 NO: 311 AGAC NO: 534 AAUA SEQ ID UUCCAGCUCAGUUUUAAUA SEQ ID GAUAUUAAAACUGAGCU 514-537 NO: 312 UCAG NO: 535 GGAA SEQ ID UUUAUGUACUGGACAAUAU SEQ ID UAAUAUUGUCCAGUACA 1431-1454 NO: 313 UAAG NO: 536 UAAA SEQ ID UCAACAUUCUGAUAAAUCU SEQ ID UAAGAUUUAUCAGAAUG 648-671 NO: 314 UAGC NO: 537 UUGA SEQ ID AUUUCCUUUGUAAAAUUUC SEQ ID GUGAAAUUUUACAAAGG 676-699 NO: 315 ACCA NO: 538 AAAU SEQ ID UGAGGAUUUCAUGCUACUU SEQ ID UUAAGUAGCAUGAAAUC 1048-1071 NO: 316 AACG NO: 539 CUCA SEQ ID AGACUGGAGAUUUUACACU SEQ ID GCAGUGUAAAAUCUCCA 1091-1114 NO: 317 GCAG NO: 540 GUCU SEQ ID UAGUAGCAGCAAAACUUUC SEQ ID AUGAAAGUUUUGCUGCU 2869-2892 NO: 318 AUGA NO: 541 ACUA SEQ ID AUUCCAGCUCAGUUUUAAU SEQ ID AUAUUAAAACUGAGCUG 515-538 NO: 319 AUCA NO: 542 GAAU SEQ ID AGGAUUUCAUGCUACUUAA SEQ ID CGUUAAGUAGCAUGAAA 1046-1069 NO: 320 CGGA NO: 543 UCCU SEQ ID GAAGACAUUUCUGAAGUCU SEQ ID GCAGACUUCAGAAAUGU 2228-2251 NO: 321 GCAA NO: 544 CUUC SEQ ID UAUGUACUGGACAAUAUUA SEQ ID CUUAAUAUUGUCCAGUA 1429-1452 NO: 322 AGCU NO: 545 CAUA SEQ ID AUUCUGAUAAAUCUUAGCU SEQ ID CCAGCUAAGAUUUAUCA 643-666 NO: 323 GGAC NO: 546 GAAU SEQ ID AACACUUCGUAAAGUAGAG SEQ ID AGCUCUACUUUACGAAG 2011-2034 NO: 324 CUUG NO: 547 UGUU SEQ ID AACAUUCUGAUAAAUCUUA SEQ ID GCUAAGAUUUAUCAGAA 646-669 NO: 325 GCUG NO: 548 UGUU SEQ ID AUUCUUGCUUUAUUGGUAC SEQ ID CAGUACCAAUAAAGCAA 1526-1549 NO: 326 UGAG NO: 549 GAAU SEQ ID ACUUAACGGACUUGAGAGA SEQ ID CCUCUCUCAAGUCCGUU 1033-1056 NO: 327 GGAG NO: 550 AAGU SEQ ID UUCGUAAAGUAGAGCUUGA SEQ ID UAUCAAGCUCUACUUUA 2006-2029 NO: 328 UACA NO: 551 CGAA SEQ ID AUUUCACCAGCUGUUCAAC SEQ ID AUGUUGAACAGCUGGUG 662-685 NO: 329 AUUC NO: 552 AAAU SEQ ID UUCAACAUUCUGAUAAAUC SEQ ID AAGAUUUAUCAGAAUGU 649-672 NO: 330 UUAG NO: 553 UGAA SEQ ID AUCCAUAUAUAAACCCAUG SEQ ID UCCAUGGGUUUAUAUAU 565-588 NO: 331 GACU NO: 554 GGAU SEQ ID GUAAUUUGUCCUCAUUUCU SEQ ID GAAGAAAUGAGGACAAA 2932-2955 NO: 332 UCAA NO: 555 UUAC SEQ ID UUCUUUCGUCGAAUCUUAU SEQ ID UGAUAAGAUUCGACGAA 2196-2219 NO: 333 CAAU NO: 556 AGAA SEQ ID AGGGAAUAAUAGUCUUUAU SEQ ID UGAUAAAGACUAUUAUU 1641-1664 NO: 334 CAUC NO: 557 CCCU SEQ ID UAUAAACCCAUGGACUCAG SEQ ID AGCUGAGUCCAUGGGUU 558-581 NO: 335 CUAC NO: 558 UAUA SEQ ID UCUACUUCCUCAGUCUUAG SEQ ID UCCUAAGACUGAGGAAG 1377-1400 NO: 336 GAAA NO: 559 UAGA SEQ ID AAAGGAACUCAGGUGUUGG SEQ ID UUCCAACACCUGAGUUC 1885-1908 NO: 337 AAAG NO: 560 CUUU SEQ ID UUUCGUCGAAUCUUAUCAA SEQ ID CAUUGAUAAGAUUCGAC 2193-2216 NO: 338 UGAU NO: 561 GAAA SEQ ID UGGAAAUUGAGGAUUUCAU SEQ ID GCAUGAAAUCCUCAAUU 1055-1078 NO: 339 GCUA NO: 562 UCCA SEQ ID AAGUAGAGCUUGAUACAUU SEQ ID AAAAUGUAUCAAGCUCU 2000-2023 NO: 340 UUCU NO: 563 ACUU SEQ ID UUGGAAUUGUGCUUAGUAG SEQ ID UGCUACUAAGCACAAUU 2882-2905 NO: 341 CAGC NO: 564 CCAA SEQ ID UACAGAUAGAUCCCACAGU SEQ ID GUACUGUGGGAUCUAUC 1238-1261 NO: 342 ACUG NO: 565 UGUA SEQ ID UUUAUUUUGCUAUUUCCUC SEQ ID AGGAGGAAAUAGCAAAA 1488-1511 NO: 343 CUAG NO: 566 UAAA SEQ ID UAUCAAUGAUGCAAUCAUU SEQ ID GAAAUGAUUGCAUCAUU 2180-2203 NO: 344 UCUU NO: 567 GAUA SEQ ID AUUUUACACUGCAGUGACU SEQ ID CAAGUCACUGCAGUGUA 1082-1105 NO: 345 UGGA NO: 568 AAAU SEQ ID UCUGAUAAAUCUUAGCUGG SEQ ID GUCCAGCUAAGAUUUAU 641-664 NO: 346 ACUC NO: 569 CAGA SEQ ID UCGAAUCUUAUCAAUGAUG SEQ ID UGCAUCAUUGAUAAGAU 2188-2211 NO: 347 CAAU NO: 570 UCGA SEQ ID GAGGAUUUCAUGCUACUUA SEQ ID GUUAAGUAGCAUGAAAU 1047-1070 NO: 348 ACGG NO: 571 CCUC SEQ ID GAAAGCGUGGAUCUGUUAU SEQ ID UAAUAACAGAUCCACGC 1203-1226 NO: 349 UAGU NO: 572 UUUC SEQ ID AGUAGAGCUUGAUACAUUU SEQ ID GAAAAUGUAUCAAGCUC 1999-2022 NO: 350 UCUG NO: 573 UACU SEQ ID AAUCCAUAUAUAAACCCAU SEQ ID CCAUGGGUUUAUAUAUG 566-589 NO: 351 GGAC NO: 574 GAUU SEQ ID AAAGUAGAGCUUGAUACAU SEQ ID AAAUGUAUCAAGCUCUA 2001-2024 NO: 352 UUUC NO: 575 CUUU SEQ ID GAUUUCAUGCUACUUAACG SEQ ID UCCGUUAAGUAGCAUGA 1044-1067 NO: 353 GACU NO: 576 AAUC SEQ ID AUAGGGAAUAAUAGUCUUU SEQ ID AUAAAGACUAUUAUUCC 1643-1666 NO: 354 AUCA NO: 577 CUAU SEQ ID CUUAGUAGCAGCAAAACUU SEQ ID GAAAGUUUUGCUGCUAC 2871-2894 NO: 355 UCAU NO: 578 UAAG SEQ ID UUAACGGACUUGAGAGAGG SEQ ID CUCCUCUCUCAAGUCCG 1031-1054 NO: 356 AGAG NO: 579 UUAA SEQ ID GUAGUUAUUCUCAUCGGUC SEQ ID AGGACCGAUGAGAAUAA 361-384 NO: 357 CUCU NO: 580 CUAC SEQ ID CAAAACUUUCAUGAUGGUG SEQ ID UACACCAUCAUGAAAGU 2860-2883 NO: 358 UAUU NO: 581 UUUG SEQ ID AAUUUGUCCUCAUUUCUUC SEQ ID UUGAAGAAAUGAGGACA 2930-2953 NO: 359 AAAU NO: 582 AAUU SEQ ID GAAUAAUAGUCUUUAUCAU SEQ ID GGAUGAUAAAGACUAUU 1638-1661 NO: 360 CCAU NO: 583 AUUC SEQ ID UUAGAUUCCAGCUCAGUUU SEQ ID UAAAACUGAGCUGGAAU 519-542 NO: 361 UAAU NO: 584 CUAA SEQ ID ACAAUCUCCAUGUAGUUAU SEQ ID GAAUAACUACAUGGAGA 372-395 NO: 362 UCUC NO: 585 UUGU SEQ ID AGGAAUAGUCAGCAUCUCU SEQ ID UAAGAGAUGCUGACUAU 590-613 NO: 363 UACA NO: 586 UCCU SEQ ID AGCAGCAAAACUUUCAUGA SEQ ID CAUCAUGAAAGUUUUGC 2865-2888 NO: 364 UGGU NO: 587 UGCU SEQ ID AUCUGGUUCUGGUUUUAUG SEQ ID UACAUAAAACCAGAACC 1444-1467 NO: 365 UACU NO: 588 AGAU SEQ ID AAUUGUGCUUAGUAGCAGC SEQ ID UUGCUGCUACUAAGCAC 2878-2901 NO: 366 AAAA NO: 589 AAUU SEQ ID UUCAAAGGUGAGCUGCAGU SEQ ID CGACUGCAGCUCACCUU 2836-2859 NO: 367 CGAA NO: 590 UGAA SEQ ID UAGAUUCCAGCUCAGUUUU SEQ ID UUAAAACUGAGCUGGAA 518-541 NO: 368 AAUA NO: 591 UCUA SEQ ID GUGAUUUCCAUGACUCCAC SEQ ID UAGUGGAGUCAUGGAAA 1922-1945 NO: 369 UAAA NO: 592 UCAC SEQ ID GUGCUUAGUAGCAGCAAAA SEQ ID AGUUUUGCUGCUACUAA 2874-2897 NO: 370 CUUU NO: 593 GCAC SEQ ID UAAUUUGUCCUCAUUUCUU SEQ ID UGAAGAAAUGAGGACAA 2931-2954 NO: 371 CAAA NO: 594 AUUA SEQ ID UUUCUUUGCUGCUUCCUUG SEQ ID CUCAAGGAAGCAGCAAA 434-457 NO: 372 AGUA NO: 595 GAAA SEQ ID UCUCUUACAGAAUCCAUAU SEQ ID AUAUAUGGAUUCUGUAA 576-599 NO: 373 AUAA NO: 596 GAGA SEQ ID AUUGUUGGGACACUUAGUU SEQ ID GUAACUAAGUGUCCCAA 2974-2997 NO: 374 ACCA NO: 597 CAAU SEQ ID ACUUCGUAAAGUAGAGCUU SEQ ID UCAAGCUCUACUUUACG 2008-2031 NO: 375 GAUA NO: 598 AAGU SEQ ID UAGUUAUUCUCAUCGGUCC SEQ ID GAGGACCGAUGAGAAUA 360-383 NO: 376 UCUC NO: 599 ACUA SEQ ID UAGACAUGAGCUGCUAAAA SEQ ID GCUUUUAGCAGCUCAUG 1468-1491 NO: 377 GCUC NO: 600 UCUA SEQ ID AGCUGUUCAACAUUCUGAU SEQ ID UUAUCAGAAUGUUGAAC 654-677 NO: 378 AAAU NO: 601 AGCU SEQ ID CGUAAAGUAGAGCUUGAUA SEQ ID UGUAUCAAGCUCUACUU 2004-2027 NO: 379 CAUU NO: 602 UACG SEQ ID UUGAGUACUGUUGUUUGGA SEQ ID AUUCCAAACAACAGUAC 418-441 NO: 380 AUAG NO: 603 UCAA SEQ ID UGAUAGGGAAUAAUAGUCU SEQ ID AAAGACUAUUAUUCCCU 1645-1668 NO: 381 UUAU NO: 604 AUCA SEQ ID AAACCGAAGAUGUCAUGUU SEQ ID UGAACAUGACAUCUUCG 848-871 NO: 382 CAGA NO: 605 GUUU SEQ ID AAUUUCACCAGCUGUUCAA SEQ ID UGUUGAACAGCUGGUGA 663-686 NO: 383 CAUU NO: 606 AAUU SEQ ID GGGAAUAAUAGUCUUUAUC SEQ ID AUGAUAAAGACUAUUAU 1640-1663 NO: 384 AUCC NO: 607 UCCC SEQ ID AGCUUGAUACAUUUUCUGG SEQ ID UUCCAGAAAAUGUAUCA 1994-2017 NO: 385 AAUG NO: 608 AGCU SEQ ID UUGAUGUAAUUUGUCCUCA SEQ ID AAUGAGGACAAAUUACA 2937-2960 NO: 386 UUUC NO: 609 UCAA SEQ ID UUUUGCUAUUUCCUCCUAG SEQ ID GUCUAGGAGGAAAUAGC 1484-1507 NO: 387 ACAU NO: 610 AAAA SEQ ID UGAGUACUGUUGUUUGGAA SEQ ID UAUUCCAAACAACAGUA 417-440 NO: 388 UAGC NO: 611 CUCA SEQ ID UAGUCAGCAUCUCUUACAG SEQ ID UUCUGUAAGAGAUGCUG 585-608 NO: 389 AAUC NO: 612 ACUA SEQ ID UAUUCUUCAAAGGUGAGCU SEQ ID GCAGCUCACCUUUGAAG 2841-2864 NO: 390 GCAG NO: 613 AAUA SEQ ID AGAGUCAGACAUAAAUGAU SEQ ID AGAUCAUUUAUGUCUGA 739-762 NO: 391 CUCA NO: 614 CUCU SEQ ID AACCGAAGAUGUCAUGUUC SEQ ID CUGAACAUGACAUCUUC 847-870 NO: 392 AGAG NO: 615 GGUU SEQ ID AUGCUACUUAACGGACUUG SEQ ID CUCAAGUCCGUUAAGUA 1038-1061 NO: 393 AGAG NO: 616 GCAU SEQ ID ACAGAUAGAUCCCACAGUA SEQ ID AGUACUGUGGGAUCUAU 1237-1260 NO: 394 CUGG NO: 617 CUGU SEQ ID ACACUUCGUAAAGUAGAGC SEQ ID AAGCUCUACUUUACGAA 2010-2033 NO: 395 UUGA NO: 618 GUGU SEQ ID CUUAGAUUCCAGCUCAGUU SEQ ID AAAACUGAGCUGGAAUC 520-543 NO: 396 UUAA NO: 619 UAAG SEQ ID GAUUCUUGCUUUAUUGGUA SEQ ID AGUACCAAUAAAGCAAG 1527-1550 NO: 397 CUGA NO: 620 AAUC SEQ ID UUUUCUGGAAUGUAUUCUA SEQ ID CUUAGAAUACAUUCCAG 1983-2006 NO: 398 AGAC NO: 621 AAAA SEQ ID UUAUCAAUGAUGCAAUCAU SEQ ID AAAUGAUUGCAUCAUUG 2181-2204 NO: 399 UUCU NO: 622 AUAA SEQ ID UCCUUUGUAAAAUUUCACC SEQ ID CUGGUGAAAUUUUACAA 673-696 NO: 400 AGCU NO: 623 AGGA SEQ ID UUUGAUGUAAUUUGUCCUC SEQ ID AUGAGGACAAAUUACAU 2938-2961 NO: 401 AUUU NO: 624 CAAA SEQ ID GUUGUUUGGAAUAGCACCG SEQ ID UCCGGUGCUAUUCCAAA 409-432 NO: 402 GAAA NO: 625 CAAC SEQ ID UGGAAACAGAGCACCUUGA SEQ ID ACUCAAGGUGCUCUGUU 1169-1192 NO: 403 GUUG NO: 626 UCCA SEQ ID CAAUGAUGCAAUCAUUUCU SEQ ID GAAGAAAUGAUUGCAUC 2177-2200 NO: 404 UCCA NO: 627 AUUG SEQ ID AAUGCUUGGUUGAUUCUUG SEQ ID AGCAAGAAUCAACCAAG 1538-1561 NO: 405 CUUU NO: 628 CAUU SEQ ID AAAGUUCCUUAGAUUCCAG SEQ ID AGCUGGAAUCUAAGGAA 527-550 NO: 406 CUCA NO: 629 CUUU SEQ ID UGUACUGGACAAUAUUAAG SEQ ID AGCUUAAUAUUGUCCAG 1427-1450 NO: 407 CUGG NO: 630 UACA SEQ ID AGAAUCCAUAUAUAAACCC SEQ ID AUGGGUUUAUAUAUGGA 568-591 NO: 408 AUGG NO: 631 UUCU SEQ ID UUUUAUGUACUGGACAAUA SEQ ID AAUAUUGUCCAGUACAU 1432-1455 NO: 409 UUAA NO: 632 AAAA SEQ ID UUGAUACAUUUUCUGGAAU SEQ ID ACAUUCCAGAAAAUGUA 1991-2014 NO: 410 GUAU NO: 633 UCAA SEQ ID AACGGACUUGAGAGAGGAG SEQ ID CUCUCCUCUCUCAAGUC 1029-1052 NO: 411 AGCC NO: 634 CGUU SEQ ID UCCUUUGGAAUUGUGCUUA SEQ ID ACUAAGCACAAUUCCAA 2886-2909 NO: 412 GUAG NO: 635 AGGA SEQ ID AAGUUCCUUAGAUUCCAGC SEQ ID GAGCUGGAAUCUAAGGA 526-549 NO: 413 UCAG NO: 636 ACUU SEQ ID GAUUUUACACUGCAGUGAC SEQ ID AAGUCACUGCAGUGUAA 1083-1106 NO: 414 UUGG NO: 637 AAUC SEQ ID CUUCGUAAAGUAGAGCUUG SEQ ID AUCAAGCUCUACUUUAC 2007-2030 NO: 415 AUAC NO: 638 GAAG SEQ ID UACUGUUGUUUGGAAUAGC SEQ ID GUGCUAUUCCAAACAAC 413-436 NO: 416 ACCG NO: 639 AGUA SEQ ID GAGUACUGUUGUUUGGAAU SEQ ID CUAUUCCAAACAACAGU 416-439 NO: 417 AGCA NO: 640 ACUC SEQ ID GAUAAAUCUUAGCUGGACU SEQ ID UGAGUCCAGCUAAGAUU 638-661 NO: 418 CAUG NO: 641 UAUC SEQ ID CAUUUCUGAAGUCUGCAAG SEQ ID UGCUUGCAGACUUCAGA 2223-2246 NO: 419 CAGG NO: 642 AAUG SEQ ID UCGUAAAGUAGAGCUUGAU SEQ ID GUAUCAAGCUCUACUUU 2005-2028 NO: 420 ACAU NO: 643 ACGA SEQ ID UUCUUGUUUAAUACCCACU SEQ ID CCAGUGGGUAUUAAACA 1723-1746 NO: 421 GGGA NO: 644 AGAA SEQ ID AUUCAUUCCAGCUUGAAGA SEQ ID UGUCUUCAAGCUGGAAU 2242-2265 NO: 422 CAUU NO: 645 GAAU SEQ ID AAUUGAGGAUUUCAUGCUA SEQ ID AGUAGCAUGAAAUCCUC 1051-1074 NO: 423 CUUA NO: 646 AAUU SEQ ID UGAGCACCAAUCCUGUAGU SEQ ID CCACUACAGGAUUGGUG 1824-1847 NO: 424 GGAA NO: 647 CUCA SEQ ID GAAUUGUUGGGACACUUAG SEQ ID AACUAAGUGUCCCAACA 2976-2999 NO: 425 UUAC NO: 648 AUUC SEQ ID AUCAAUGAUGCAAUCAUUU SEQ ID AGAAAUGAUUGCAUCAU 2179-2202 NO: 426 CUUC NO: 649 UGAU SEQ ID AGUCAGACAUAAAUGAUCU SEQ ID UGAGAUCAUUUAUGUCU 737-760 NO: 427 CAAG NO: 650 GACU SEQ ID GUUUUAUGUACUGGACAAU SEQ ID AUAUUGUCCAGUACAUA 1433-1456 NO: 428 AUUA NO: 651 AAAC SEQ ID AAUCUUAGCUGGACUCAUG SEQ ID AGCAUGAGUCCAGCUAA 634-657 NO: 429 CUUC NO: 652 GAUU SEQ ID AUUUGUCCUCAUUUCUUCA SEQ ID UUUGAAGAAAUGAGGAC 2929-2952 NO: 430 AAUG NO: 653 AAAU SEQ ID UUUACACUGCAGUGACUUG SEQ ID UCCAAGUCACUGCAGUG 1080-1103 NO: 431 GAGG NO: 654 UAAA SEQ ID UCUUGCUUUAUUGGUACUG SEQ ID CUCAGUACCAAUAAAGC 1524-1547 NO: 432 AGAA NO: 655 AAGA SEQ ID CAUGUAGUUAUUCUCAUCG SEQ ID ACCGAUGAGAAUAACUA 364-387 NO: 433 GUCC NO: 656 CAUG SEQ ID AUUGUUUACAGGGCUACAG SEQ ID AUCUGUAGCCCUGUAAA 1252-1275 NO: 434 AUAG NO: 657 CAAU SEQ ID GGAAAUUGAGGAUUUCAUG SEQ ID AGCAUGAAAUCCUCAAU 1054-1077 NO: 435 CUAC NO: 658 UUCC SEQ ID GUACUGUUGUUUGGAAUAG SEQ ID UGCUAUUCCAAACAACA 414-437 NO: 436 CACC NO: 659 GUAC SEQ ID ACUGGAGAUUUUACACUGC SEQ ID CUGCAGUGUAAAAUCUC 1089-1112 NO: 437 AGUG NO: 660 CAGU SEQ ID CUGAUAGGGAAUAAUAGUC SEQ ID AAGACUAUUAUUCCCUA 1646-1669 NO: 438 UUUA NO: 661 UCAG SEQ ID GAAUUGUGCUUAGUAGCAG SEQ ID UGCUGCUACUAAGCACA 2879-2902 NO: 439 CAAA NO: 662 AUUC SEQ ID AGGAAAGGAACUCAGGUGU SEQ ID CAACACCUGAGUUCCUU 1888-1911 NO: 440 UGGA NO: 663 UCCU SEQ ID GAAUAGUCAGCAUCUCUUA SEQ ID UGUAAGAGAUGCUGACU 588-611 NO: 441 CAGA NO: 664 AUUC SEQ ID UUUACAGGGCUACAGAUAG SEQ ID AUCUAUCUGUAGCCCUG 1248-1271 NO: 442 AUCC NO: 665 UAAA SEQ ID ACAUUUCUGAAGUCUGCAA SEQ ID GCUUGCAGACUUCAGAA 2224-2247 NO: 443 GCAG NO: 666 AUGU SEQ ID AUUUCCAUGACUCCACUAA SEQ ID CUUUAGUGGAGUCAUGG 1919-1942 NO: 444 AGUA NO: 667 AAAU SEQ ID CUUUGAUGUAAUUUGUCCU SEQ ID UGAGGACAAAUUACAUC 2939-2962 NO: 445 CAUU NO: 668 AAAG SEQ ID UUGUUUGGAAUAGCACCGG SEQ ID UUCCGGUGCUAUUCCAA 408-431 NO: 446 AAAC NO: 669 ACAA Table 3 provides the modified first (antisense) sequences, together with the corresponding unmodified first (antisense) sequences for siRNA oligonucleosides according to the present invention as follows. Table 3 Antisense Modified First (Antisense) Strand SEQ ID Underlying Base SEQ ID strand ID NO (AS - Sequence NO (AS - 5’ ^ 3’ mod) unmod) 5’ ^ 3’ (Shown as an Unmodified Nucleoside Sequence) ETX- AmsUfsAmAmUmAfGmUfCfUmUmUm SEQ ID AUAAUAGUCUUUAU SEQ ID S00005908 AmUfCmAfUmCmCmAfUmsAmsAm NO: 670 CAUCCAUAA NO: 224 ETX- AmsAfsUmAmAmUfAmGfUfCmUmUm SEQ ID AAUAAUAGUCUUUA SEQ ID S00005912 UmAfUmCfAmUmCmCfAmsUmsAm NO: 671 UCAUCCAUA NO: 225 ETX- AmsUfsAmGmUmCfUmUfUfAmUmCm SEQ ID AUAGUCUUUAUCAU SEQ ID S00005916 AmUfCmCfAmUmAmAfAmsGmsGm NO: 672 CCAUAAAGG NO: 226 ETX- AmsAfsAmAmCmUfUmUfCfAmUmGm SEQ ID AAAACUUUCAUGAU SEQ ID S00005920 AmUfGmGfUmGmUmAfUmsUmsCm NO: 673 GGUGUAUUC NO: 227 ETX- AmsAfsAmCmAmCfUmUfCfGmUmAm SEQ ID AAACACUUCGUAAA SEQ ID S00005924 AmAfGmUfAmGmAmGfCmsUmsUm NO: 674 GUAGAGCUU NO: 228 ETX- GmsAfsAmAmCmAfCmUfUfCmGmUm SEQ ID GAAACACUUCGUAA SEQ ID S00005928 AmAfAmGfUmAmGmAfGmsCmsUm NO: 675 AGUAGAGCU NO: 229 ETX- UmsCfsUmUmAmCfAmGfAfAmUmCm SEQ ID UCUUACAGAAUCCA SEQ ID S00005932 CmAfUmAfUmAmUmAfAmsAmsCm NO: 676 UAUAUAAAC NO: 230 ETX- UmsAfsAmAmAmUfUmUfCfAmCmCm SEQ ID UAAAAUUUCACCAG SEQ ID S00005936 AmGfCmUfGmUmUmCfAmsAmsCm NO: 677 CUGUUCAAC NO: 231 ETX- UmsAfsCmUmUmAfAmCfGfGmAmCm SEQ ID UACUUAACGGACUU SEQ ID S00005940 UmUfGmAfGmAmGmAfGmsGmsAm NO: 678 GAGAGAGGA NO: 232 ETX- GmsUfsAmAmAmAfUmUfUfCmAmCm SEQ ID GUAAAAUUUCACCA SEQ ID S00005944 CmAfGmCfUmGmUmUfCmsAmsAm NO: 679 GCUGUUCAA NO: 233 ETX- AmsUfsCmUmCmUfUmAfCfAmGmAm SEQ ID AUCUCUUACAGAAU SEQ ID S00005948 AmUfCmCfAmUmAmUfAmsUmsAm NO: 680 CCAUAUAUA NO: 234 ETX- GmsUfsAmAmAmGfUmAfGfAmGmCm SEQ ID GUAAAGUAGAGCUU SEQ ID S00005952 UmUfGmAfUmAmCmAfUmsUmsUm NO: 681 GAUACAUUU NO: 235 ETX- UmsGfsGmAmGmAfUmUfUfUmAmCm SEQ ID UGGAGAUUUUACAC SEQ ID S00005956 AmCfUmGfCmAmGmUfGmsAmsCm NO: 682 UGCAGUGAC NO: 236 ETX- AmsUfsUmUmAmUfUmUfUfGmCmUm SEQ ID AUUUAUUUUGCUAU SEQ ID S00005960 AmUfUmUfCmCmUmCfCmsUmsAm NO: 683 UUCCUCCUA NO: 237 ETX- AmsAfsUmGmAmUfGmCfAfAmUmCm SEQ ID AAUGAUGCAAUCAU SEQ ID S00005964 AmUfUmUfCmUmUmCfCmsAmsGm NO: 684 UUCUUCCAG NO: 238 ETX- GmsAfsGmAmCmUfGmGfAfGmAmUm SEQ ID GAGACUGGAGAUUU SEQ ID S00005968 UmUfUmAfCmAmCmUfGmsCmsAm NO: 685 UACACUGCA NO: 239 ETX- AmsAfsGmAmCmAfUmUfUfCmUmGm SEQ ID AAGACAUUUCUGAA SEQ ID S00005972 AmAfGmUfCmUmGmCfAmsAmsGm NO: 686 GUCUGCAAG NO: 240 ETX- UmsGfsGmAmGmAfCmUfGfGmAmGm SEQ ID UGGAGACUGGAGAU SEQ ID S00005976 AmUfUmUfUmAmCmAfCmsUmsGm NO: 687 UUUACACUG NO: 241 ETX- UmsUfsUmUmGmAfAmGfAfAmAmAm SEQ ID UUUUGAAGAAAACU SEQ ID S00005980 CmUfUmUfGmCmAmGfCmsUmsGm NO: 688 UUGCAGCUG NO: 242 ETX- UmsUfsUmGmAmAfGmAfAfAmAmCm SEQ ID UUUGAAGAAAACUU SEQ ID S00005984 UmUfUmGfCmAmGmCfUmsGmsCm NO: 689 UGCAGCUGC NO: 243 ETX- UmsAfsGmGmGmAfAmUfAfAmUmAm SEQ ID UAGGGAAUAAUAGU SEQ ID S00005988 GmUfCmUfUmUmAmUfCmsAmsUm NO: 690 CUUUAUCAU NO: 244 ETX- UmsAfsGmAmGmCfUmUfGfAmUmAm SEQ ID UAGAGCUUGAUACA SEQ ID S00005992 CmAfUmUfUmUmCmUfGmsGmsAm NO: 691 UUUUCUGGA NO: 245 ETX- UmsUfsGmCmUmUfUmAfUfUmGmGm SEQ ID UUGCUUUAUUGGUA SEQ ID S00005996 UmAfCmUfGmAmGmAfAmsUmsGm NO: 692 CUGAGAAUG NO: 246 ETX- AmsUfsUmCmUmUfUmCfGfUmCmGm SEQ ID AUUCUUUCGUCGAA SEQ ID S00006000 AmAfUmCfUmUmAmUfCmsAmsAm NO: 693 UCUUAUCAA NO: 247 ETX- UmsAfsCmAmGmAfAmUfCfCmAmUm SEQ ID UACAGAAUCCAUAU SEQ ID S00006004 AmUfAmUfAmAmAmCfCmsCmsAm NO: 694 AUAAACCCA NO: 248 ETX- UmsUfsUmGmGmAfAmUfUfGmUmGm SEQ ID UUUGGAAUUGUGCU SEQ ID S00006008 CmUfUmAfGmUmAmGfCmsAmsGm NO: 695 UAGUAGCAG NO: 249 ETX- UmsUfsAmCmAmCfUmGfCfAmGmUm SEQ ID UUACACUGCAGUGA SEQ ID S00006012 GmAfCmUfUmGmGmAfGmsGmsGm NO: 696 CUUGGAGGG NO: 250 ETX- AmsAfsAmAmUmUfUmCfAfCmCmAm SEQ ID AAAAUUUCACCAGC SEQ ID S00006016 GmCfUmGfUmUmCmAfAmsCmsAm NO: 697 UGUUCAACA NO: 251 ETX- AmsGfsUmAmGmCfAmGfCfAmAmAm SEQ ID AGUAGCAGCAAAAC SEQ ID S00006020 AmCfUmUfUmCmAmUfGmsAmsUm NO: 698 UUUCAUGAU NO: 252 ETX- AmsGfsAmGmCmUfUmGfAfUmAmCm SEQ ID AGAGCUUGAUACAU SEQ ID S00006024 AmUfUmUfUmCmUmGfGmsAmsAm NO: 699 UUUCUGGAA NO: 253 ETX- AmsGfsAmUmUmUfUmAfCfAmCmUm SEQ ID AGAUUUUACACUGC SEQ ID S00006028 GmCfAmGfUmGmAmCfUmsUmsGm NO: 700 AGUGACUUG NO: 254 ETX- AmsUfsUmUmUmCfUmGfGfAmAmUm SEQ ID AUUUUCUGGAAUGU SEQ ID S00006032 GmUfAmUfUmCmUmAfAmsGmsAm NO: 701 AUUCUAAGA NO: 255 ETX- AmsUfsAmUmAmUfAmAfAfCmCmCm SEQ ID AUAUAUAAACCCAU SEQ ID S00006036 AmUfGmGfAmCmUmCfAmsGmsCm NO: 702 GGACUCAGC NO: 256 ETX- AmsAfsAmGmAmUfUmGfGfUmCmUm SEQ ID AAAGAUUGGUCUCU SEQ ID S00006040 CmUfAmGfCmCmGmAfUmsCmsGm NO: 703 AGCCGAUCG NO: 257 ETX- GmsUfsCmUmUmUfAmUfCfAmUmCm SEQ ID GUCUUUAUCAUCCA SEQ ID S00006044 CmAfUmAfAmAmGmGfAmsAmsAm NO: 704 UAAAGGAAA NO: 258 ETX- AmsAfsAmUmUmUfCmAfCfCmAmGm SEQ ID AAAUUUCACCAGCU SEQ ID S00006048 CmUfGmUfUmCmAmAfCmsAmsUm NO: 705 GUUCAACAU NO: 259 ETX- UmsAfsAmAmGmUfAmGfAfGmCmUm SEQ ID UAAAGUAGAGCUUG SEQ ID S00006052 UmGfAmUfAmCmAmUfUmsUmsUm NO: 706 AUACAUUUU NO: 260 ETX- AmsAfsUmAmGmUfCmUfUfUmAmUm SEQ ID AAUAGUCUUUAUCA SEQ ID S00006056 CmAfUmCfCmAmUmAfAmsAmsGm NO: 707 UCCAUAAAG NO: 261 ETX- AmsAfsUmUmUmAfUmUfUfUmGmCm SEQ ID AAUUUAUUUUGCUA SEQ ID S00006060 UmAfUmUfUmCmCmUfCmsCmsUm NO: 708 UUUCCUCCU NO: 262 ETX- AmsUfsCmUmUmAfUmCfAfAmUmGm SEQ ID AUCUUAUCAAUGAU SEQ ID S00006064 AmUfGmCfAmAmUmCfAmsUmsUm NO: 709 GCAAUCAUU NO: 263 ETX- GmsUfsAmGmCmAfGmCfAfAmAmAm SEQ ID GUAGCAGCAAAACU SEQ ID S00006068 CmUfUmUfCmAmUmGfAmsUmsGm NO: 710 UUCAUGAUG NO: 264 ETX- AmsAfsUmCmAmUfUmUfCfUmUmCm SEQ ID AAUCAUUUCUUCCA SEQ ID S00006072 CmAfGmCfAmCmAmUfAmsAmsAm NO: 711 GCACAUAAA NO: 265 ETX- AmsUfsAmGmGmAfAmUfAfGmUmCm SEQ ID AUAGGAAUAGUCAG SEQ ID S00006076 AmGfCmAfUmCmUmCfUmsUmsAm NO: 712 CAUCUCUUA NO: 266 ETX- UmsGfsUmAmGmAfAmGfCfAmGmAm SEQ ID UGUAGAAGCAGAAU SEQ ID S00006080 AmUfUmCfCmAmGmCfAmsGmsGm NO: 713 UCCAGCAGG NO: 267 ETX- GmsGfsAmAmUmAfGmUfCfAmGmCm SEQ ID GGAAUAGUCAGCAU SEQ ID S00006084 AmUfCmUfCmUmUmAfCmsAmsGm NO: 714 CUCUUACAG NO: 268 ETX- UmsUfsAmUmUmUfUmGfCfUmAmUm SEQ ID UUAUUUUGCUAUUU SEQ ID S00006088 UmUfCmCfUmCmCmUfAmsGmsAm NO: 715 CCUCCUAGA NO: 269 ETX- AmsGfsCmAmAmAfAmCfUfUmUmCm SEQ ID AGCAAAACUUUCAU SEQ ID S00006092 AmUfGmAfUmGmGmUfGmsUmsAm NO: 716 GAUGGUGUA NO: 270 ETX- 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UmsUfsCmAmAmAfGmGfUfGmAmGm SEQ ID UUCAAAGGUGAGCU SEQ ID S00006480 CmUfGmCfAmGmUmCfGmsAmsAm NO: 813 GCAGUCGAA NO: 367 ETX- UmsAfsGmAmUmUfCmCfAfGmCmUm SEQ ID UAGAUUCCAGCUCA SEQ ID S00006484 CmAfGmUfUmUmUmAfAmsUmsAm NO: 814 GUUUUAAUA NO: 368 ETX- GmsUfsGmAmUmUfUmCfCfAmUmGm SEQ ID GUGAUUUCCAUGAC SEQ ID S00006488 AmCfUmCfCmAmCmUfAmsAmsAm NO: 815 UCCACUAAA NO: 369 ETX- GmsUfsGmCmUmUfAmGfUfAmGmCm SEQ ID GUGCUUAGUAGCAG SEQ ID S00006492 AmGfCmAfAmAmAmCfUmsUmsUm NO: 816 CAAAACUUU NO: 370 ETX- UmsAfsAmUmUmUfGmUfCfCmUmCm SEQ ID UAAUUUGUCCUCAU SEQ ID S00006496 AmUfUmUfCmUmUmCfAmsAmsAm NO: 817 UUCUUCAAA NO: 371 ETX- UmsUfsUmCmUmUfUmGfCfUmGmCm SEQ ID UUUCUUUGCUGCUU SEQ ID S00006500 UmUfCmCfUmUmGmAfGmsUmsAm NO: 818 CCUUGAGUA NO: 372 ETX- UmsCfsUmCmUmUfAmCfAfGmAmAm SEQ ID UCUCUUACAGAAUC SEQ ID S00006504 UmCfCmAfUmAmUmAfUmsAmsAm NO: 819 CAUAUAUAA NO: 373 ETX- AmsUfsUmGmUmUfGmGfGfAmCmAm SEQ ID AUUGUUGGGACACU SEQ ID S00006508 CmUfUmAfGmUmUmAfCmsCmsAm NO: 820 UAGUUACCA NO: 374 ETX- AmsCfsUmUmCmGfUmAfAfAmGmUm SEQ ID ACUUCGUAAAGUAG SEQ ID S00006512 AmGfAmGfCmUmUmGfAmsUmsAm NO: 821 AGCUUGAUA NO: 375 ETX- UmsAfsGmUmUmAfUmUfCfUmCmAm SEQ ID UAGUUAUUCUCAUC SEQ ID S00006516 UmCfGmGfUmCmCmUfCmsUmsCm NO: 822 GGUCCUCUC NO: 376 ETX- UmsAfsGmAmCmAfUmGfAfGmCmUm SEQ ID UAGACAUGAGCUGC SEQ ID S00006520 GmCfUmAfAmAmAmGfCmsUmsCm NO: 823 UAAAAGCUC NO: 377 ETX- AmsGfsCmUmGmUfUmCfAfAmCmAm SEQ ID AGCUGUUCAACAUU SEQ ID S00006524 UmUfCmUfGmAmUmAfAmsAmsUm NO: 824 CUGAUAAAU NO: 378 ETX- CmsGfsUmAmAmAfGmUfAfGmAmGm SEQ ID CGUAAAGUAGAGCU SEQ ID S00006528 CmUfUmGfAmUmAmCfAmsUmsUm NO: 825 UGAUACAUU NO: 379 ETX- UmsUfsGmAmGmUfAmCfUfGmUmUm SEQ ID UUGAGUACUGUUGU SEQ ID S00006532 GmUfUmUfGmGmAmAfUmsAmsGm NO: 826 UUGGAAUAG NO: 380 ETX- UmsGfsAmUmAmGfGmGfAfAmUmAm SEQ ID UGAUAGGGAAUAAU SEQ ID S00006536 AmUfAmGfUmCmUmUfUmsAmsUm NO: 827 AGUCUUUAU NO: 381 ETX- AmsAfsAmCmCmGfAmAfGfAmUmGm SEQ ID AAACCGAAGAUGUC SEQ ID S00006540 UmCfAmUfGmUmUmCfAmsGmsAm NO: 828 AUGUUCAGA NO: 382 ETX- AmsAfsUmUmUmCfAmCfCfAmGmCm SEQ ID AAUUUCACCAGCUG SEQ ID S00006544 UmGfUmUfCmAmAmCfAmsUmsUm NO: 829 UUCAACAUU NO: 383 ETX- GmsGfsGmAmAmUfAmAfUfAmGmUm SEQ ID GGGAAUAAUAGUCU SEQ ID S00006548 CmUfUmUfAmUmCmAfUmsCmsCm NO: 830 UUAUCAUCC NO: 384 ETX- AmsGfsCmUmUmGfAmUfAfCmAmUm SEQ ID AGCUUGAUACAUUU SEQ ID S00006552 UmUfUmCfUmGmGmAfAmsUmsGm NO: 831 UCUGGAAUG NO: 385 ETX- UmsUfsGmAmUmGfUmAfAfUmUmUm SEQ ID UUGAUGUAAUUUGU SEQ ID S00006556 GmUfCmCfUmCmAmUfUmsUmsCm NO: 832 CCUCAUUUC NO: 386 ETX- UmsUfsUmUmGmCfUmAfUfUmUmCm SEQ ID UUUUGCUAUUUCCU SEQ ID S00006560 CmUfCmCfUmAmGmAfCmsAmsUm NO: 833 CCUAGACAU NO: 387 ETX- UmsGfsAmGmUmAfCmUfGfUmUmGm SEQ ID UGAGUACUGUUGUU SEQ ID S00006564 UmUfUmGfGmAmAmUfAmsGmsCm NO: 834 UGGAAUAGC NO: 388 ETX- UmsAfsGmUmCmAfGmCfAfUmCmUm SEQ ID UAGUCAGCAUCUCU SEQ ID S00006568 CmUfUmAfCmAmGmAfAmsUmsCm NO: 835 UACAGAAUC NO: 389 ETX- UmsAfsUmUmCmUfUmCfAfAmAmGm SEQ ID UAUUCUUCAAAGGU SEQ ID S00006572 GmUfGmAfGmCmUmGfCmsAmsGm NO: 836 GAGCUGCAG NO: 390 ETX- AmsGfsAmGmUmCfAmGfAfCmAmUm SEQ ID AGAGUCAGACAUAA SEQ ID S00006576 AmAfAmUfGmAmUmCfUmsCmsAm NO: 837 AUGAUCUCA NO: 391 ETX- AmsAfsCmCmGmAfAmGfAfUmGmUm SEQ ID AACCGAAGAUGUCA SEQ ID S00006580 CmAfUmGfUmUmCmAfGmsAmsGm NO: 838 UGUUCAGAG NO: 392 ETX- AmsUfsGmCmUmAfCmUfUfAmAmCm SEQ ID AUGCUACUUAACGG SEQ ID S00006584 GmGfAmCfUmUmGmAfGmsAmsGm NO: 839 ACUUGAGAG NO: 393 ETX- AmsCfsAmGmAmUfAmGfAfUmCmCm SEQ ID ACAGAUAGAUCCCA SEQ ID S00006588 CmAfCmAfGmUmAmCfUmsGmsGm NO: 840 CAGUACUGG NO: 394 ETX- AmsCfsAmCmUmUfCmGfUfAmAmAm SEQ ID ACACUUCGUAAAGU SEQ ID S00006592 GmUfAmGfAmGmCmUfUmsGmsAm NO: 841 AGAGCUUGA NO: 395 ETX- CmsUfsUmAmGmAfUmUfCfCmAmGm SEQ ID CUUAGAUUCCAGCU SEQ ID S00006596 CmUfCmAfGmUmUmUfUmsAmsAm NO: 842 CAGUUUUAA NO: 396 ETX- GmsAfsUmUmCmUfUmGfCfUmUmUm SEQ ID GAUUCUUGCUUUAU SEQ ID S00006600 AmUfUmGfGmUmAmCfUmsGmsAm NO: 843 UGGUACUGA NO: 397 ETX- UmsUfsUmUmCmUfGmGfAfAmUmGm SEQ ID UUUUCUGGAAUGUA SEQ ID S00006604 UmAfUmUfCmUmAmAfGmsAmsCm NO: 844 UUCUAAGAC NO: 398 ETX- UmsUfsAmUmCmAfAmUfGfAmUmGm SEQ ID UUAUCAAUGAUGCA SEQ ID S00006608 CmAfAmUfCmAmUmUfUmsCmsUm NO: 845 AUCAUUUCU NO: 399 ETX- UmsCfsCmUmUmUfGmUfAfAmAmAm SEQ ID UCCUUUGUAAAAUU SEQ ID S00006612 UmUfUmCfAmCmCmAfGmsCmsUm NO: 846 UCACCAGCU NO: 400 ETX- UmsUfsUmGmAmUfGmUfAfAmUmUm SEQ ID UUUGAUGUAAUUUG SEQ ID S00006616 UmGfUmCfCmUmCmAfUmsUmsUm NO: 847 UCCUCAUUU NO: 401 ETX- GmsUfsUmGmUmUfUmGfGfAmAmUm SEQ ID GUUGUUUGGAAUAG SEQ ID S00006620 AmGfCmAfCmCmGmGfAmsAmsAm NO: 848 CACCGGAAA NO: 402 ETX- UmsGfsGmAmAmAfCmAfGfAmGmCm SEQ ID UGGAAACAGAGCAC SEQ ID S00006624 AmCfCmUfUmGmAmGfUmsUmsGm NO: 849 CUUGAGUUG NO: 403 ETX- CmsAfsAmUmGmAfUmGfCfAmAmUm SEQ ID CAAUGAUGCAAUCA SEQ ID S00006628 CmAfUmUfUmCmUmUfCmsCmsAm NO: 850 UUUCUUCCA NO: 404 ETX- AmsAfsUmGmCmUfUmGfGfUmUmGm SEQ ID AAUGCUUGGUUGAU SEQ ID S00006632 AmUfUmCfUmUmGmCfUmsUmsUm NO: 851 UCUUGCUUU NO: 405 ETX- AmsAfsAmGmUmUfCmCfUfUmAmGm SEQ ID AAAGUUCCUUAGAU SEQ ID S00006636 AmUfUmCfCmAmGmCfUmsCmsAm NO: 852 UCCAGCUCA NO: 406 ETX- UmsGfsUmAmCmUfGmGfAfCmAmAm SEQ ID UGUACUGGACAAUA SEQ ID S00006640 UmAfUmUfAmAmGmCfUmsGmsGm NO: 853 UUAAGCUGG NO: 407 ETX- AmsGfsAmAmUmCfCmAfUfAmUmAm SEQ ID AGAAUCCAUAUAUA SEQ ID S00006644 UmAfAmAfCmCmCmAfUmsGmsGm NO: 854 AACCCAUGG NO: 408 ETX- UmsUfsUmUmAmUfGmUfAfCmUmGm SEQ ID UUUUAUGUACUGGA SEQ ID S00006648 GmAfCmAfAmUmAmUfUmsAmsAm NO: 855 CAAUAUUAA NO: 409 ETX- UmsUfsGmAmUmAfCmAfUfUmUmUm SEQ ID UUGAUACAUUUUCU SEQ ID S00006652 CmUfGmGfAmAmUmGfUmsAmsUm NO: 856 GGAAUGUAU NO: 410 ETX- AmsAfsCmGmGmAfCmUfUfGmAmGm SEQ ID AACGGACUUGAGAG SEQ ID S00006656 AmGfAmGfGmAmGmAfGmsCmsCm NO: 857 AGGAGAGCC NO: 411 ETX- UmsCfsCmUmUmUfGmGfAfAmUmUm SEQ ID UCCUUUGGAAUUGU SEQ ID S00006660 GmUfGmCfUmUmAmGfUmsAmsGm NO: 858 GCUUAGUAG NO: 412 ETX- AmsAfsGmUmUmCfCmUfUfAmGmAm SEQ ID AAGUUCCUUAGAUU SEQ ID S00006664 UmUfCmCfAmGmCmUfCmsAmsGm NO: 859 CCAGCUCAG NO: 413 ETX- GmsAfsUmUmUmUfAmCfAfCmUmGm SEQ ID GAUUUUACACUGCA SEQ ID S00006668 CmAfGmUfGmAmCmUfUmsGmsGm NO: 860 GUGACUUGG NO: 414 ETX- CmsUfsUmCmGmUfAmAfAfGmUmAm SEQ ID CUUCGUAAAGUAGA SEQ ID S00006672 GmAfGmCfUmUmGmAfUmsAmsCm NO: 861 GCUUGAUAC NO: 415 ETX- UmsAfsCmUmGmUfUmGfUfUmUmGm SEQ ID UACUGUUGUUUGGA SEQ ID S00006676 GmAfAmUfAmGmCmAfCmsCmsGm NO: 862 AUAGCACCG NO: 416 ETX- GmsAfsGmUmAmCfUmGfUfUmGmUm SEQ ID GAGUACUGUUGUUU SEQ ID S00006680 UmUfGmGfAmAmUmAfGmsCmsAm NO: 863 GGAAUAGCA NO: 417 ETX- GmsAfsUmAmAmAfUmCfUfUmAmGm SEQ ID GAUAAAUCUUAGCU SEQ ID S00006684 CmUfGmGfAmCmUmCfAmsUmsGm NO: 864 GGACUCAUG NO: 418 ETX- CmsAfsUmUmUmCfUmGfAfAmGmUm SEQ ID CAUUUCUGAAGUCU SEQ ID S00006688 CmUfGmCfAmAmGmCfAmsGmsGm NO: 865 GCAAGCAGG NO: 419 ETX- UmsCfsGmUmAmAfAmGfUfAmGmAm SEQ ID UCGUAAAGUAGAGC SEQ ID S00006692 GmCfUmUfGmAmUmAfCmsAmsUm NO: 866 UUGAUACAU NO: 420 ETX- UmsUfsCmUmUmGfUmUfUfAmAmUm SEQ ID UUCUUGUUUAAUAC SEQ ID S00006696 AmCfCmCfAmCmUmGfGmsGmsAm NO: 867 CCACUGGGA NO: 421 ETX- AmsUfsUmCmAmUfUmCfCfAmGmCm SEQ ID AUUCAUUCCAGCUU SEQ ID S00006700 UmUfGmAfAmGmAmCfAmsUmsUm NO: 868 GAAGACAUU NO: 422 ETX- AmsAfsUmUmGmAfGmGfAfUmUmUm SEQ ID AAUUGAGGAUUUCA SEQ ID S00006704 CmAfUmGfCmUmAmCfUmsUmsAm NO: 869 UGCUACUUA NO: 423 ETX- UmsGfsAmGmCmAfCmCfAfAmUmCm SEQ ID UGAGCACCAAUCCU SEQ ID S00006708 CmUfGmUfAmGmUmGfGmsAmsAm NO: 870 GUAGUGGAA NO: 424 ETX- GmsAfsAmUmUmGfUmUfGfGmGmAm SEQ ID GAAUUGUUGGGACA SEQ ID S00006712 CmAfCmUfUmAmGmUfUmsAmsCm NO: 871 CUUAGUUAC NO: 425 ETX- AmsUfsCmAmAmUfGmAfUfGmCmAm SEQ ID AUCAAUGAUGCAAU SEQ ID S00006716 AmUfCmAfUmUmUmCfUmsUmsCm NO: 872 CAUUUCUUC NO: 426 ETX- AmsGfsUmCmAmGfAmCfAfUmAmAm SEQ ID AGUCAGACAUAAAU SEQ ID S00006720 AmUfGmAfUmCmUmCfAmsAmsGm NO: 873 GAUCUCAAG NO: 427 ETX- GmsUfsUmUmUmAfUmGfUfAmCmUm SEQ ID GUUUUAUGUACUGG SEQ ID S00006724 GmGfAmCfAmAmUmAfUmsUmsAm NO: 874 ACAAUAUUA NO: 428 ETX- AmsAfsUmCmUmUfAmGfCfUmGmGm SEQ ID AAUCUUAGCUGGAC SEQ ID S00006728 AmCfUmCfAmUmGmCfUmsUmsCm NO: 875 UCAUGCUUC NO: 429 ETX- AmsUfsUmUmGmUfCmCfUfCmAmUm SEQ ID AUUUGUCCUCAUUU SEQ ID S00006732 UmUfCmUfUmCmAmAfAmsUmsGm NO: 876 CUUCAAAUG NO: 430 ETX- UmsUfsUmAmCmAfCmUfGfCmAmGm SEQ ID UUUACACUGCAGUG SEQ ID S00006736 UmGfAmCfUmUmGmGfAmsGmsGm NO: 877 ACUUGGAGG NO: 431 ETX- UmsCfsUmUmGmCfUmUfUfAmUmUm SEQ ID UCUUGCUUUAUUGG SEQ ID S00006740 GmGfUmAfCmUmGmAfGmsAmsAm NO: 878 UACUGAGAA NO: 432 ETX- CmsAfsUmGmUmAfGmUfUfAmUmUm SEQ ID CAUGUAGUUAUUCU SEQ ID S00006744 CmUfCmAfUmCmGmGfUmsCmsCm NO: 879 CAUCGGUCC NO: 433 ETX- AmsUfsUmGmUmUfUmAfCfAmGmGm SEQ ID AUUGUUUACAGGGC SEQ ID S00006748 GmCfUmAfCmAmGmAfUmsAmsGm NO: 880 UACAGAUAG NO: 434 ETX- GmsGfsAmAmAmUfUmGfAfGmGmAm SEQ ID GGAAAUUGAGGAUU SEQ ID S00006752 UmUfUmCfAmUmGmCfUmsAmsCm NO: 881 UCAUGCUAC NO: 435 ETX- GmsUfsAmCmUmGfUmUfGfUmUmUm SEQ ID GUACUGUUGUUUGG SEQ ID S00006756 GmGfAmAfUmAmGmCfAmsCmsCm NO: 882 AAUAGCACC NO: 436 ETX- AmsCfsUmGmGmAfGmAfUfUmUmUm SEQ ID ACUGGAGAUUUUAC SEQ ID S00006760 AmCfAmCfUmGmCmAfGmsUmsGm NO: 883 ACUGCAGUG NO: 437 ETX- CmsUfsGmAmUmAfGmGfGfAmAmUm SEQ ID CUGAUAGGGAAUAA SEQ ID S00006764 AmAfUmAfGmUmCmUfUmsUmsAm NO: 884 UAGUCUUUA NO: 438 ETX- GmsAfsAmUmUmGfUmGfCfUmUmAm SEQ ID GAAUUGUGCUUAGU SEQ ID S00006768 GmUfAmGfCmAmGmCfAmsAmsAm NO: 885 AGCAGCAAA NO: 439 ETX- AmsGfsGmAmAmAfGmGfAfAmCmUm SEQ ID AGGAAAGGAACUCA SEQ ID S00006772 CmAfGmGfUmGmUmUfGmsGmsAm NO: 886 GGUGUUGGA NO: 440 ETX- GmsAfsAmUmAmGfUmCfAfGmCmAm SEQ ID GAAUAGUCAGCAUC SEQ ID S00006776 UmCfUmCfUmUmAmCfAmsGmsAm NO: 887 UCUUACAGA NO: 441 ETX- UmsUfsUmAmCmAfGmGfGfCmUmAm SEQ ID UUUACAGGGCUACA SEQ ID S00006780 CmAfGmAfUmAmGmAfUmsCmsCm NO: 888 GAUAGAUCC NO: 442 ETX- AmsCfsAmUmUmUfCmUfGfAmAmGm SEQ ID ACAUUUCUGAAGUC SEQ ID S00006784 UmCfUmGfCmAmAmGfCmsAmsGm NO: 889 UGCAAGCAG NO: 443 ETX- AmsUfsUmUmCmCfAmUfGfAmCmUm SEQ ID AUUUCCAUGACUCC SEQ ID S00006788 CmCfAmCfUmAmAmAfGmsUmsAm NO: 890 ACUAAAGUA NO: 444 ETX- CmsUfsUmUmGmAfUmGfUfAmAmUm SEQ ID CUUUGAUGUAAUUU SEQ ID S00006792 UmUfGmUfCmCmUmCfAmsUmsUm NO: 891 GUCCUCAUU NO: 445 ETX- UmsUfsGmUmUmUfGmGfAfAmUmAm SEQ ID UUGUUUGGAAUAGC SEQ ID S00006796 GmCfAmCfCmGmGmAfAmsAmsCm NO: 892 ACCGGAAAC NO: 446 Table 4 provides the modified second (sense) sequences, together with the corresponding unmodified second (sense) sequences for siRNA oligonucleosides according to the present invention as follows. Table 4 Sense Modified Second (Sense) Strand SEQ ID Underlying Base Sequence SEQ ID strand ID NO (SS - NO (SS - 5’ ^ 3’ 5’ ^ 3’ mod) unmod) (Shown as an Unmodified Nucleoside Sequence) ETX- iaiaAmsUmsGmGmAmUmGmAmUfAf SEQ ID AUGGAUGAUAAAGACU SEQ ID S00005907 AfAmGmAmCmUmAmUmUmAmUm NO: 893 AUUAU NO: 447 ETX- iaiaUmsGmsGmAmUmGmAmUmAfAf SEQ ID UGGAUGAUAAAGACUA SEQ ID S00005911 AfGmAmCmUmAmUmUmAmUmUm NO: 894 UUAUU NO: 448 ETX- iaiaU...

Claims

CLAIMS 1. An inhibitor of expression and / or function of NR3C2, wherein said inhibitor is conjugated to one or more ligand moieties.

2. An inhibitor according to claim 1, wherein said inhibitor is an siRNA oligomer.

3. An inhibitor of expression and / or function of NR3C2, wherein said inhibitor is an siRNA oligomer.

4. An inhibitor according to claim 3, wherein said inhibitor comprises an siRNA oligomer conjugated to one or more ligand moieties.

5. An inhibitor of expression and / or function of NR3C2, such as the inhibitor of claims 1-4, for use in treatment of HFrEF, such as a ischaemic heart disease, in particular myocardial infarction and / or symptoms thereof.

6. An inhibitor according to claim 1, 2 or 4, wherein said one or more ligand moieties comprise one or more GalNAc ligands or comprise one more GalNAc ligand derivatives.

7. An inhibitor for use according to claim 1, 2 or 4 wherein said one or more ligand moieties comprise one or more GalNAc ligand derivatives.

8. An inhibitor or an inhibitor for use according to one or more preceding claims, wherein the target of the inhibitor is NR3C2.

9. An inhibitor, or inhibitor for use, according to one or more preceding claims, which is an siRNA oligomer having a first and a second strand wherein: i) the first strand of the siRNA has a length in the range of 15 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 23 or 25; even more preferably 23; and / or ii) the second strand of the siRNA has a length in the range of 15 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 21 nucleosides.

10. An inhibitor, or inhibitor for use, according to claim 9, wherein the second sense strand further comprises one or more abasic nucleosides in a terminal region of the second strand, and wherein said abasic nucleoside(s) is / are connected to an adjacent nucleoside through a reversed internucleoside linkage.

11. An inhibitor, or inhibitor for use, according to claim 10, wherein the second strand comprises: i 2, or more than 2, abasic nucleosides in a terminal region of the second strand; and / or ii 2, or more than 2, abasic nucleosides in either the 5’ or 3’ terminal region of the second strand; and / or iii 2, or more than 2, abasic nucleosides in either the 5’ or 3’ terminal region of the second strand, wherein the abasic nucleosides are present in an overhang as herein described; and / or iv 2, or more than 2, consecutive abasic nucleosides in a terminal region of the second strand, wherein preferably one such abasic nucleoside is a terminal nucleoside; and / or v 2, or more than 2, consecutive abasic nucleosides in either the 5’ or 3’ terminal region of the second strand, wherein preferably one such abasic nucleoside is a terminal nucleoside in either the 5’ or 3’ terminal region of the second strand; and / or vi a reversed internucleoside linkage connects at least one abasic nucleoside to an adjacent basic nucleoside in a terminal region of the second strand; and / or vii a reversed internucleoside linkage connects at least one abasic nucleoside to an adjacent basic nucleoside in either the 5’ or 3’ terminal region of the second strand; and / or viii an abasic nucleoside as the penultimate nucleoside which is connected via the reversed linkage to the nucleoside which is not the terminal nucleoside (called the antepenultimate nucleoside herein); and / or ix abasic nucleosides as the 2 terminal nucleosides connected via a 5’-3’ linkage when reading the strand in the direction towards that terminus; x abasic nucleosides as the 2 terminal nucleosides connected via a 3’-5’ linkage when reading the strand in the direction towards the terminus comprising the terminal nucleosides;xi abasic nucleosides as the terminal 2 positions, wherein the penultimate nucleoside is connected via the reversed linkage to the antepenultimate nucleoside, and wherein the reversed linkage is a 5-5’ reversed linkage or a 3’-3’ reversed linkage; xii abasic nucleosides as the terminal 2 positions, wherein the penultimate nucleoside is connected via the reversed linkage to the antepenultimate nucleoside, and wherein either (1) the reversed linkage is a 5-5’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides; or (2) the reversed linkage is a 3-3’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 5’3’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides.

12. An inhibitor, or inhibitor for use, according claim 10 or 11, wherein the reversed internucleoside linkage is at a terminal region which is distal to the 5’ terminal region of the second strand, or at a terminal region which is distal to the 3’ terminal region of the second strand.

13. An inhibitor, or inhibitor for use, according to any one of claims 10 to 12, wherein the reversed internucleoside linkage is a 3’3 reversed linkage.

14. An inhibitor, or inhibitor for use, according to any one of claims 10 to 12, wherein the reversed internucleoside linkage is a 5’5 reversed linkage.

15. An inhibitor, or inhibitor for use, according to any one of claims 9 to 14, wherein one or more nucleosides on the first strand and / or the second strand is / are modified, to form modified nucleosides.

16. An inhibitor, or inhibitor for use, according to claim 15, wherein the modification is a modification at the 2’-OH group of the ribose sugar, optionally selected from 2'-Me or 2’-F modifications.

17. An inhibitor, or inhibitor for use, according to claim 15 or 16, wherein the first strand comprises a 2’-F at any of position 14, position 2, position 6, or any combination thereof, counting from position 1 of said first strand.

18. An inhibitor, or inhibitor for use, according to any one of claims 15 to 17, wherein the second strand comprises a 2’-F modification at position 7 and / or 9, and / or 11 and / or 13, counting from position 1 of said second strand.

19. An inhibitor, or inhibitor for use, according to any one of claims 15 to 18, wherein the first and second strand each comprise 2'-Me and 2’-F modifications.

20. An inhibitor, or inhibitor for use, according to any one of claims 15 to 19, which is an siRNA, wherein the siRNA comprises at least one thermally destabilizing modification, suitably at one or more of positions 1 to 9 of the first strand counting from position 1 of the first strand, and / or at one or more of positions on the second strand aligned with positions 1 to 9 of the first strand, wherein the destabilizing modification is selected from a modified unlocked nucleic acid (IMUNA) and a glycol nucleic acid (GNA), preferably a glycol nucleic acid.

21. An inhibitor, or inhibitor for use, according to claim 20, wherein the siRNA comprises at least one thermally destabilizing modification at position 7 of the first strand, counting from position 1 of the first strand.

22. An inhibitor, or inhibitor for use, according to any one of claims 15 to 21, which is an siRNA, wherein the siRNA comprises 3 or more 2’-F modifications at positions 7 to 13 of the second strand, such as 4, 5, 6 or 72’-F modifications at positions 7 to 13 of the second strand, counting from position 1 of said second strand 23. An inhibitor, or inhibitor for use, according to any one of claims 15 to 22, which is an siRNA, wherein said second strand comprises at least 3, such as 4, 5 or 6, 2’-Me modifications at positions 1 to 6 of the second strand, counting from position 1 of said second strand.

24. An inhibitor, or inhibitor for use, according to any one of claims 15 to 23, which is an siRNA, wherein said first strand comprises at least 52’-Me consecutive modifications at the 3’ terminal region, preferably including the terminal nucleoside at the 3’ terminal region, or at least within 1 or 2 nucleosides from the terminal nucleoside at the 3’ terminal region.

25. An inhibitor, or inhibitor for use, according to any one of claims 15 to 24, which is an siRNA wherein said first strand comprises 72’-Me consecutive modifications at the 3’ terminal region, preferably including the terminal nucleoside at the 3’ terminal region.

26. An inhibitor, or inhibitor for use, according to any one of claims 15 to 25, wherein the siRNA oligomer further comprises one or more phosphorothioate internucleoside linkages.

27. An inhibitor, or inhibitor for use, according to claim 26, wherein said one or more phosphorothioate internucleoside linkages are respectively between at least three consecutive positions in a 5’ or 3’ near terminal region of the second strand, whereby said near terminal region is preferably adjacent said terminal region wherein said one or more abasic nucleosides of said second strand is / are located according to at least claim 10.

28. An inhibitor, or inhibitor for use, according to claim 26 or 27, wherein said one or more phosphorothioate internucleoside linkages are respectively between at least three consecutive positions in a 5’ and / or 3’ terminal region of the first strand, whereby preferably a terminal position at the 5’ and / or 3’ terminal region of said first strand is attached to its adjacent position by a phosphorothioate internucleoside linkage.

29. An inhibitor, or inhibitor for use according to any one of claims 9 to 28, wherein the oligomer is an siRNA and the second strand of the siRNA is conjugated directly or indirectly to one or more ligand moiety(s), wherein said ligand moiety is typically present at a terminal region of the second strand, preferably at the 3’ terminal region thereof.

30. An inhibitor, or inhibitor for use according to claim 29, wherein the ligand moiety comprises i) one or more GalNAc ligands; and / or ii) one or more GalNAc ligand derivatives; and / or iii) one or more GalNAc ligands and / or GalNAc ligand derivatives conjugated to said SiRNA through a linker.

31. An inhibitor, or inhibitor for use according to claim 30, wherein said one or more GalNAc ligands and / or GalNAc ligand derivatives are conjugated directly or indirectly to the 5’ or 3’ terminal region of the second strand of the siRNA oligomer, preferably at the 3’ terminal region thereof.

32. An inhibitor, or inhibitor for use according to claim 30 or 31, wherein the ligand moiety comprises33. An inhibitor, or inhibitor for use according to claim 30 or 31, having the structure:wherein: R1at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; R2 is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X1 and X2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; m is an integer of from 1 to 6; n is an integer of from 1 to 10; q, r, s, t, v are independently integers from 0 to 4, with the proviso that: (i) q and r cannot both be 0 at the same time; and (ii) s, t and v cannot all be 0 at the same time; Z is an oligomer34. An inhibitor, or inhibitor for use according to claim 30 or 31, having the structurewherein: r and s are independently an integer selected from 1 to 16; and Z is an oligomer.

35. An inhibitor, or inhibitor for use according to one or more preceding claims, formulated as a pharmaceutical composition with an excipient and / or carrier.

36. A pharmaceutical composition comprising an inhibitor according to one or more preceding claims, in combination with a pharmaceutically acceptable excipient or carrier.

37. A pharmaceutical composition comprising an inhibitor according to one or more preceding claims, in combination with a pharmaceutically acceptable excipient or carrier, for use in the treatment of HFrEF, such as an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof.

38. Use of NR3C2 as a target for identifying one or more therapeutic agents for the treatment of HFrEF, such as an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof.

39. A method of treating HFrEF, such as an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof, which comprises administering to a patient an inhibitor of NR3C2, such as an inhibitor as defined according to one or more preceding claims.

40. NR3C2 for use as a biomarker of HFrEF and associated conditions such as ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof.

41. NR3C2 for use in an in vivo method of predicting susceptibility to HFrEF, such as an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof, typically by monitoring the sequence and / or level of expression and / or function of NR3C2 in a sample obtained from a patient.

42. A method of predicting susceptibility to HFrEF, such as an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof, and optionally treating a disease related to HFrEF, such as an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof, in a patient, said method comprising: (a) obtaining a sample from the patient, (b) detecting the sequence and / or expression and / or function of NR3C2 in said sample obtained from the patient, (c) predicting susceptibility to a disease related to HFrEF, such as ischaemic heart diseases, based on the sequence and / or expression and / or function of NR3C2 in said sample obtained from the patient, (d) preferably administering to the diagnosed patient an effective amount of an inhibitor of NR3C2.

43. An inhibitor or composition according to any preceding claim, in the preparation of a medicament for use in the treatment of HFrEF, an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof.

44. The inhibitor for use or the composition for use according to any of the preceding claims, wherein the inhibitor or the composition is administered after myocardial infarction.

45. A nucleic acid for inhibiting expression of NR3C2, comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand sequences as listed in Table 2.

46. A nucleic acid for inhibiting expression of NR3C2, comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand modified sequences as listed in Table 3.

47. A nucleic acid according to claim 45 or 46, wherein the first strand comprises nucleosides 2-18 of any one of the sequences defined in claim 45 or 46, in particular wherein the first strand comprises nucleosides 2-18 of any one of the sequences defined in Tables 2 or 3.

48. A nucleic acid according to claim 45, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand sequences as listed in Table 2, and wherein the second strand has a region of at least 85% complementarity over the 17 contiguous nucleosides to the first strand.

49. A nucleic acid according to claim 46, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand modified sequences as listed in Table 4, and wherein the second strand has a region of at least 85% complementarity over the 17 contiguous nucleosides to the first strand.

50. A nucleic acid according to claim 45, wherein the first strand comprises any one of the first strand sequences as listed in Table 2.

51. A nucleic acid according to claim 46, wherein the first strand comprises any one of the first strand modified sequences as listed in Table 3.

52. A nucleic acid according to claim 48, wherein the second strand comprises any one of the second strand sequences as listed in Table 2.

53. A nucleic acid according to claim 49, wherein the second strand comprises any one of the second strand modified sequences as listed in Table 4.

54. A nucleic acid according to any one of claims 45-53, wherein the first strand has a length in the range of 17 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 19 or 23 nucleosides.

55. A nucleic acid according to any one of claims 45-54, wherein the second strand has a length in the range of 17 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 19 or 21 or 23 nucleosides.

56. A nucleic acid according to any one of claims 45-55, wherein the duplex region of the nucleic acid is between 17 and 30 nucleosides in length, more preferably is 19 or 21 or 23 nucleosides in length.

57. A nucleic acid according to any one of claims 45-56, wherein the region of complementarity between the first strand and the portion of RNA transcribed from the NR3C2 gene is between 17 and 30 nucleosides in length.

58. A nucleic acid according to any one of claims 45-57, wherein the nucleic acid further comprises one or more single-stranded nucleoside overhangs, optionally wherein the overhang is present on the first or second strand, preferably at the 3’ terminus of the first or second strand, and / or wherein the overhang comprises 1 to 4 nucleosides, more preferably 2 nucleosides.

59. A nucleic acid according to any one of claims 45-58, wherein the nucleic acid is an siRNA oligonucleoside.

60. A nucleic acid according to any of claims 49 or 53, wherein the second strand comprises 2 consecutive abasic nucleosides in the 5’ terminal region of the second strand, wherein one such abasic nucleoside is a terminal nucleoside at the 5’ terminal region of the second strand and the other abasic nucleoside is a penultimate nucleoside at the 5’ terminal region of the second strand, wherein: (a) said penultimate abasic nucleoside is connected to an adjacent first basic nucleoside in an adjacent 5’ near terminal region through a reversed internucleoside linkage; and (b) the reversed linkage is a 5-5’ reversed linkage; and (c) the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides.

61. A nucleic acid according to claim 50, wherein (i) the first strand and the second strand each has a length of 23 nucleosides; (ii) two phosphorothioate internucleoside linkages are respectively between three consecutive positions in said 5’ near terminal region of the second strand, wherein a first phosphorothioate internucleoside linkage is present between said adjacent first basic nucleoside of (a) and an adjacent second basic nucleoside in said 5’ near terminal region of the second strand, and a second phosphorothioate internucleoside linkage is present between said adjacent second basic nucleoside and an adjacent third basic nucleoside in said 5’ near terminal region of the second strand; (iii) two phosphorothioate internucleoside linkages are respectively between three consecutive positions in both 5’ and 3’ terminal regions of the first strand, whereby a terminal nucleosiderespectively at each of the 5’ and 3’ terminal regions of said first strand is each attached to a respective 5’ and 3’ adjacent penultimate nucleoside by a phosphorothioate internucleoside linkage, and each first 5’ and 3’ penultimate nucleoside is attached to a respective 5’ and 3’ adjacent antepenultimate nucleoside by a phosphorothioate internucleoside linkage; and (iv) the second strand of the nucleic acid is conjugated directly or indirectly to one or more ligand moieties at the 3’ terminal region of the second strand.

62. A nucleic acid according to claim 50 or 51, wherein the 2 consecutive inverted abasic nucleosides in the 5’ terminal region of the second strand present as the following 5’ terminal motifwherein: T represents a 2’Me ribose modification, B represents the nucleoside bases of the first two basic nucleosides in the 5' terminal region of the second strand, and Z represents the remaining 19 contiguous basic nucleosides of said second strand.

63. A nucleic acid according to any one of claims 45-62, wherein the nucleic acid is conjugated directly or indirectly to one or more ligand moieties, optionally wherein said ligand moiety is present at a terminal region of the second strand, preferably at the 3’ terminal region thereof.

64. A nucleic acid according to claim 63, wherein the ligand moiety comprises: (i) one or more N-acetyl galactosamine (GalNAc) ligands, and / or (ii) one or more N-acetyl galactosamine (GalNAc) ligand derivatives.

65. A nucleic acid according to claim 64, wherein said one or more GalNAc ligands and / or GalNAc ligand derivatives are conjugated directly or indirectly to the 5’ or 3’ terminal region of the second strand of the nucleic acid, preferably at the 3’ terminal region thereof.

66. A nucleic acid according to any one of claims 63 to 65, comprising the structure:wherein: R1 at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl; R2 is selected from the group consisting of hydrogen, hydroxy, -OC1-3alkyl, -C(=O)OC1-3alkyl, halo and nitro; X1 and X2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; m is an integer of from 1 to 6; n is an integer of from 1 to 10; q, r, s, t, v are independently integers from 0 to 4, with the proviso that: (i) q and r cannot both be 0 at the same time; and (ii) s, t and v cannot all be 0 at the same time;Z is an oligonucleoside moiety.

67. A nucleic acid according to claim 66, comprising the structure ,wherein oligonucleotide represents the contiguous nucleosides of the second strand.

68. A nucleic acid according to any one of claims 63 to 65, comprising the structure:wherein: r and s are independently an integer selected from 1 to 16; and Z is an oligonucleoside moiety.

69. A nucleic acid according to claim 68, comprising the structure, wherein oligonucleotide represents the contiguous nucleosides of the second strand.

70. A nucleic acid according to claim 67 or 69, wherein the structure is conjugated to the 3’ terminal region of the second strand.

71. A nucleic acid as defined in claims 62, 67 and 70.

72. A nucleic acid as defined in claims 62, 69 and 70.

73. A pharmaceutical composition comprising a nucleic acid according to any one of claims 45-72, in combination with a pharmaceutically acceptable excipient or carrier.

74. A nucleic acid or pharmaceutical composition according to any one of claims 45-73, for use in therapy.

75. A nucleic acid or pharmaceutical composition according to any one of claims 45-74, for use in the treatment of HFrEF, such as an ischaemic heart diseases, in particular myocardial infarction and / or symptoms thereof.

76. A nucleic acid or pharmaceutical composition according to claim 75, wherein the nucleic acid or the pharmaceutical composition is administered after myocardial infarction.

77. A nucleic acid according to claim 50, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 228, SEQ ID NO: 238, SEQ ID NO: 243, SEQ ID NO: 235, SEQ ID NO: 245 and SEQ ID NO: 250, preferably SEQ ID NO: 238 or SEQ ID NO:

245.

78. An nucleic according to claim 51, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 674, SEQ ID NO: 684, SEQ ID NO: 689, SEQ ID NO: 681, SEQ ID NO: 691 and SEQ ID NO: 696, Preferably SEQ ID NO: 684 or SEQ ID NO:

691.

79. A nucleic according to claim 52, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 451, SEQ ID NO: 461, SEQ ID NO: 466, SEQ ID NO: 458, SEQ ID NO: 468 and SEQ ID NO: 473, preferably SEQ ID NO: 461 or SEQ ID NO:

468.

80. A nucleic acid according to claim 53, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, preferably SEQ ID NO: 907 or SEQ ID NO:

914.

81. A nucleic acid according to claim 45 or claim 48, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences: Unmodified first strand Unmodified second strand SEQ ID NO: 228SEQ ID NO: 451SEQ ID NO: 238 SEQ ID NO: 461 SEQ ID NO: 243 SEQ ID NO: 466SEQ ID NO: 235 SEQ ID NO: 458 SEQ ID NO: 245 SEQ ID NO: 468 SEQ ID NO: 250 SEQ ID NO: 473 , preferably Unmodified first strand Unmodified second strand SEQ ID NO: 238 SEQ ID NO: 461 or Unmodified first strand Unmodified second strand SEQ ID NO: 245 SEQ ID NO: 468 82. A nucleic acid according to claim 46 or claim 49, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences: Unmodified first strand Unmodified second strand SEQ ID NO: 674 SEQ ID NO: 897 SEQ ID NO: 684 SEQ ID NO: 907 SEQ ID NO: 689 SEQ ID NO: 912 SEQ ID NO: 681 SEQ ID NO: 904 SEQ ID NO: 691 SEQ ID NO: 914 SEQ ID NO: 696 SEQ ID NO: 919 , preferably Modified first strand Modified second strand SEQ ID NO: 684SEQ ID NO: 907or Modified first strand Modified second strand SEQ ID NO: 691 SEQ ID NO: 914

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