Compounds and methods for reducing arhgef6 expression

Abstract

Provided are oligonucleotides, polynucleotide conjugates, and compositions and populations comprising the same, as well as methods and uses thereof for reducing the amount or activity of Rho guanine nucleotide exchange factor 6 (ARHGEF6) RNA in a cell or animal, and in certain instances reducing the amount of ARHGEF6 protein in a cell or animal Such oligonucleotides, polynucleotide conjugates, and compositions and populations, methods and uses are useful to treat kidney diseases or conditions. In particular, such oligonucleotides, polynucleotide conjugates, and compositions and populations, methods and uses are useful to treat chronic kidney disease, such as diabetic nephropathy (DN), focal segmental glomerulosclerosis (FSGS), renal hypertension (HTN), IgA nephropathy / Berger's disease (IgAN), rapidly progressive glomerulonephritis (RPGN) and systemic lupus erythematosus (SLE).

Description

[0001] COMPOUNDS AND METHODS FOR REDUCING ARHGEF6 EXPRESSION

[0002] SEQUENCE LISTING

[0003] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled P78807WO_Sequence Listing.xml, created on 04 November 2025, which is 21.4 MB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2’-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2’-OH in place of one 2’-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of an uracil of RNA). Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and / or DNA, unless otherwise stated, including, but not limited to such nucleic acids having modified nucleobases.

[0004] FIELD

[0005] Provided are oligonucleotides, polynucleotide conjugates, and compositions and populations comprising the same, as well as methods and uses thereof for reducing the amount or activity of Rho guanine nucleotide exchange factor 6 (ARHGEF6) RNA in a cell or animal, and in certain instances reducing the amount of ARHGEF6 protein in a cell or animal. Such oligonucleotides, polynucleotide conjugates, and compositions and populations, methods and uses are useful to treat kidney diseases or conditions. In particular, such oligonucleotides, polynucleotide conjugates, and compositions and populations, methods and uses are useful to treat chronic kidney disease, such as diabetic nephropathy (DN), focal segmental glomerulosclerosis (FSGS), renal hypertension (HTN), IgA nephropathy I Berger’s disease (IgAN), rapidly progressive glomerulonephritis (RPGN) and systemic lupus erythematosus (SLE).

[0006] BACKGROUND

[0007] Chronic kidney disease (CKD) is a broad term used to describe diseases of the kidney that are characterised by a gradual loss, and ultimately failure, of kidney function. As CKD progresses a kidney’s ability to filter waste and excess fluid from the blood diminishes. CKD is classified on a scale ranging from stage 1 to stage 5 based on the level of kidney damage a subject has sustained and the resultant decline in their measured glomerular filtration rate (GFR) (see KDIGO - Kidney International Supplements 2013, 3, 19-62 and Kidney International (2024), 105 (Suppl 4S), S117-S314), with stage 5 CKD, also referred to as end stage renal disease (ESRD) or kidney failure, being the most severe. The GFR can be estimated, with estimated GFR (eGFR) values being derivable from measurement of filtration markers such as serum creatinine or cystatin C. eGFR is a measure of the kidney’s ability to clean the blood relative to the expected “normal” value, albeit kidney function varies according to age, sex, and body size, and declines with age (for illustration, the “normal” eGFR of a 40 year old is around 100, while the normal value for a 70 year old is around 75). Various approaches for establishing eGFR are described in the literature and are well known to those skilled in the art (see e.g. L. A. Inker et al, N Engl J Med 2021; 385:1737-1749, DOI: 10.1056 / NEJMoa2102953; N Engl J Med 2012; 367:20-29, DOI: 10.1056 / NEJMoa1114248 and the KDIGO Guidelines referred to above).

[0008] In the early stages of CKD (stages 1 and 2) a subject may display few signs or symptoms of the condition, the latter being relatively mild (e.g. high blood pressure, swelling of the legs and urinary tract infections). Stage 1 and 2 CKD subjects have sustained kidney damage, but have apparently normal, or only mildly impaired, kidney function (stage 1 eGFR = 90% or higher / stage 2 CKD eGFR = 89 to 60). By stage 3 CKD however, subjects have mild to moderate (stage 3a, eGFR = 45 to 59) or moderate to severe (stage 3b, eGFR = 30 to 44) loss of kidney function and experience an increased number of, and severity of, symptoms (e.g. low blood count, malnutrition, bone pain, unusual pain, numbness or tingling, decreased mental sharpness or feeling unwell). Stage 3 CKD subjects also have an increased propensity to progress to stage 4 (eGFR = 29 to 15) or stage 5 CKD (also known as end stage renal disease (ESRD) or kidney failure, at which stage the eGFR is less than 15). By stage 4 CKD, subjects have experienced a severe loss in kidney function and are prone to anaemia, decreased appetite, bone disease or abnormal blood levels of phosphorus, calcium or vitamin D. Additional symptoms associated with stage 5 CKD / ESRD include uraemia, fatigue, shortness of breath, nausea, vomiting, abnormal thyroid levels, swelling in hands / legs / eyes / lower back or lower back pain. Morbidity and mortality rates for stage 4 and stage 5 CKD subjects are high.

[0009] Guidelines for the definition and classification of CKD can be found in Kidney International Supplements (2013) 3, 19-62 (KDIGO) and, more recently in the 2024 KDIGO guidelines, see Kidney International (2024), 105 (Suppl 4S), S117-S314 collectively referred to as KDIGO / KDIGO guidelines herein. According to the KDIGO guidelines, GFR is accepted as the best overall index of kidney function because a) it is generally reduced after widespread structural kidney damage and b) most other kidney functions decline in parallel with GFR in CKD. A GFR of <60 ml / min / 1.73m2for > 3 months was selected as indicative of CKD, this value is less than half of the normal value in young adult men and women (125 ml / min / 1.73m2). A GFR of 60 ml / min / 1.73m2can be detected by routine laboratory testing. Current estimating equations for GFR (eGFR) based on serum creatinine (sCr), but not sCr alone, are sensitive for detecting measured GFR. A decreased eGFR established using sCr can be confirmed by GFR estimation using an alternative filtration marker (cystatin C) or GFR measurement, as necessary.

[0010] Currently, treatment options for subjects with severe or late stage renal disease include dialysis and kidney transplantation. These treatments are intrusive, expensive and not universally available since highly developed medical systems are required for their delivery. Consequently, there is a substantial medical need to detect CKD at as early a stage as possible and provide treatments that can slow, arrest or even reverse progression of the disease. Identification of new effective strategies for therapeutic intervention in the treatment of CKD are therefore required, as are biomarkers prognostic of susceptibility to the development, initiation, presence or progression of kidney disease.

[0011] On a functional level, the kidney removes waste and excess fluid from the blood through the glomerular filtration barrier into the urinary tract for excretion. The glomerular filtration barrier is a complex structure comprising, among other elements, podocytes attached to the glomerular basement membrane (GBM). In this structure, podocytes are tightly clustered and adopt a special shape such that a slit between adjacent podocytes is formed and maintained. This slit between adjacent podocytes, sometimes referred to as the filtration slit or slit diaphragm, is spanned by various intracellular elements such as nephrin to form a matrix through which controlled diffusion of waste and excess fluid from the blood into the urinary tract can occur. The shape of the podocytes on the GBM is maintained by the podocytes’ internal actin cytoskeleton (composed of dynamic actin stress fibres). It follows that the integrity of the podocytes’ actin cytoskeleton is required for optimal kidney function. In addition to their shape, the podocytes are anchored on to the GBM through various factors such as dystroglycan, syndecan and a3 and [31 -integrins. Consequently, maintenance of the anchoring of podocytes is also a key factor in the integrity of the glomerular filtration barrier and kidney function. Efficient functioning of the glomerular filtration barrier requires both stable anchoring of podocytes to the glomerular filtration barrier and the maintenance of podocyte shape.

[0012] Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). Rho guanine nucleotide exchange factor 6 (ARHGEF6) is a GEF protein encoded in humans by the ARHGEF6 gene (NB. for the avoidance of doubt, ARHGEF6 (in italics) is used to denote the gene herein, while ARHGEF6 is used to denote protein). Amongst other names (e.g. PIXA; COOL2; MRX46; Cool-2; alphaPIX; alpha-PIX) ARHGEF6 is also referred to as Rac / Cdc42 guanine nucleotide exchange factor 6 as it characteristically binds to the GTPases Cdc42 and Rac1. Formation of a stable complex between ARHGEF6 and activated Cdc42 was observed to enhance ARHGEF6’s ability to associate with GDP bound Rac1 (see Baird et al, Current Biology 2001, 15, 1-10). The GTPases Cdc42 and Rac1 that bind to ARHGEF6 are members of the Rho subfamily of Ras-related GTP binding proteins and are implicated in a wide variety of cellular responses, including the regulation of the actin cytoskeletal architecture, cell shape and motility, intracellular trafficking, cell cycle progression, and malignant transformation. The catalytic subunit of ARHGEF6 consists of a Dbl-homology domain (DH) and a pleckstrin-homology domain (PH). Studies have suggested that the PH domain stabilises the DH domain in its binding to Rac1, with the catalytic activity of constructs comprising a DH domain and lacking a PH domain proving greatly reduced. A precise mechanistic understanding of the ARHGEF6 mediated conversion of Rac1-GDP to Rac1-GTP however remains to be established and it may be that ARHGEF6 acts upstream of the final conversion step.

[0013] It is an object of the present specification to provide new oligonucleotides targeting ARHGEF6 and polynucleotide conjugates, and compositions and populations thereof with utility in the treatment or prophylaxis for CKD / ESRD involving inhibiting ARHGEF6 activity, for example in podocytes. In particular, for the treatment of kidney conditions as described herein.

[0014] SUMMARY

[0015] The present inventors have surprisingly demonstrated that oligonucleotides targeting particular regions within an ARHGEF6 transcript are capable of significantly reducing the amount or activity of ARHGEF6 RNA in a cell in a selective manner. As such, these oligonucleotides therefore have potential utility in the treatment of diseases associated with ARHGEF6, particularly kidney conditions as described herein, including diabetic nephropathy (DN), focal segmental glomerulosclerosis (FSGS), renal hypertension (HTN), IgA nephropathy I Berger’s disease (IgAN), rapidly progressive glomerulonephritis (RPGN) and systemic lupus erythematosus (SLE).

[0016] Accordingly, the specification provides an oligonucleotide comprising or consisting of a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 1 to 37,380; 37,397 to 73,959; 73,977 to 75,731; 75,752 to 115,303; 115,320 to 116,399; or 116,416 to 117,742 of SEQ ID NO: 3291.

[0017] An oligonucleotide of the specification may comprise or consist of a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 45,000 to 70,000; 75,000 to 75,500; 80,000 to 95,000; or 100,000 to 115,200 of SEQ ID NO: 3291, particularly nucleobases 48,000 to 67,000; 75,000 to 75,500; 85,000 to 94,000; or 100,000 to 115,200 of SEQ ID NO: 3291. The oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94%, or 100% complementary to said equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 45,000 to 70,000; 75,000 to 75,500; 80,000 to 95,000; or 100,000 to 115,200 of SEQ ID NO: 3291, particularly nucleobases 48,000 to 67,000; 75,000 to 75,500; 85,000 to 94,000; or 100,000 to 115,200 of SEQ ID NO: 3291. The oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 50,000 to 60,000; 90,000 to 95,000; 100,000 to 105,000; or 110,000 to 115,200 of SEQ ID NO: 3291, particularly nucleobases 54,000 to 57,000; 92,000 to 95,000; 100,500 to 104,000; or 113,000 to 115,200 of SEQ ID NO: 3291. The oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94%, or 100% complementary to said equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 50,000 to 60,000; 90,000 to 95,000; 100,000 to 105,000; or 110,000 to 115,200 of SEQ ID NO: 3291, particularly nucleobases 54,000 to 57,000; 92,000 to 95,000; 100,500 to 104,000; or 113,000 to 115,200 of SEQ ID NO: 3291. The equal length portion may be of between about 12 to about 50 contiguous nucleobases, preferably between about 14 to about 25 contiguous nucleobases.

[0018] An oligonucleotide of the specification may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94%, or 100% identical to any of SEQ ID NOs: 1-3290, preferably any one of SEQ ID Nos: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241; more preferably any one of SEQ ID Nos: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0019] An oligonucleotide of the specification may have a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or at least 21 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of the nucleobase sequences of any of SEQ ID NOs: 1-3290, preferably any one of SEQ ID Nos: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241; more preferably any one of SEQ ID Nos: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0020] An oligonucleotide of the specification may comprise the nucleobase sequences of any of SEQ ID NOs: 1-3290, preferably any one of SEQ ID Nos: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241; more preferably any one of SEQ ID Nos: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0021] An oligonucleotide of the specification may consist of the nucleobase sequences of any of SEQ ID NOs: 1-3290, preferably any one of SEQ ID Nos: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241; more preferably any one of SEQ ID Nos: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0022] The nucleobases sequence of an oligonucleotide of the specification may consist of between 12 to 50, 12 to 40, 12 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 12 to 20, 13 to 20, 14 to 20, or 15 to 20 linked nucleosides, preferably of between 14 to 25 linked nucleosides.

[0023] An oligonucleotide of the specification may comprise at least one modification, optionally at least one modified sugar moiety. The modified sugar moiety may comprise a bicyclic sugar moiety. The bicyclic modified sugar moiety may comprise: (a) a 2’-4’ bridge selected from -O-CH2-and -O-CH(CH3)-; and / or (b) a LNA, a cEt modified sugar moiety, a BNA and / or an ENA. The modified sugar moiety may comprise a non-bicyclic sugar moiety. The non-bicyclic modified sugar moiety may be a 2’-OMe modified sugar moiety, a 2’-MOE modified sugar moiety, a 2’-F modified sugar moiety, a glycol nucleic acid (GNA), a threose nucleic acid (TNA), a morpholino nucleic acid (PMO), a 2’-MOEOE modified sugar moiety and / or a 2’- NMA modified sugar moiety. The non-bicyclic modified sugar moiety may be a 2’-OMe modified sugar moiety and / or a 2’-MOE modified sugar moiety.

[0024] An oligonucleotide of the specification may comprise: (a) at least one LNA; (b) at least one LNA and at least one 2’-OMe modified sugar moiety; (c) at least one LNA and at least one 2’-MOE modified sugar moiety; (d) at least one LNA, at least one 2’-OMe modified sugar moiety and at least one 2’-MOE modified sugar moiety; (e) at least one 2’-MOE modified sugar moiety; (f) at least one cEt modified sugar moiety; (g) at least one cEt modified sugar moiety and at least one 2’-MOE modified sugar moiety; (h) at least one cEt modified sugar moiety and at least one 2’-OMe modified sugar moiety; or (i) at least one cEt modified sugar moiety, at least one 2’-OMe modified sugar moiety and at least one 2’-MOE modified sugar moiety.

[0025] An oligonucleotide of the specification may comprise:

[0026] (a) a 5 '-region consisting of 1-5 linked 5 '-region nucleosides; (b) a central region consisting of 9-12 linked central region nucleosides; and

[0027] (c) a 3 '-region consisting of 2-5 linked 3 '-region nucleosides;

[0028] wherein:

[0029] (i) each of the 5 '-region nucleosides and each of the 3 '-region nucleosides comprises a modified sugar moiety; and

[0030] (ii) at most two of the central region nucleosides comprises a modified sugar moiety and the remainder of the central region nucleosides comprises an unmodified 2' - deoxyribosyl sugar moiety.

[0031] An oligonucleotide of the specification may or consist of: (a) 5’ [cEt]a[dR]10[cEt]a3’; (b) 5’ [cEt]b[mR][dR]9[cEt]c3’; (c) 5’ [cEt]2[dR]9[MOE][cEt]43’; (d) 5’ [cEt]3[dR]d[mR][dR]e[cEt]33’; (e) 5’ [cEt]2[MOE][cEt][dR]9[cEt]33’; (f) 5’ [cEt]2[MOE][cEt][mR][dR]8[cEt]33’; (g) 5’ [LR]a[dR]f[LR]a3’; (h) 5’ [LR]a[dR]9[LR]a[MOE]d3’; (i) 5’ [LR]a[dR]9[LR]d[MOE][LR]g3’; 0) 5’ [LR]2[dR]9[LR][MOE][LR][MOE][LR] 3’; (k) 5’ [LR]a[dR]9[MOE][LR]a3’; (I) 5’ [LR]a[dR]h[mR][dR]i[LR]a3’; (m) 5’ [LR]3[dR]2[mR][dR]6[LR]3[MOE] 3’; (n) 5’ [LR]3[dR]d[mR][dR]j[LR]d[MOE][LR]d3’; (o) 5’ [LR]3[dR][mR][dR]7[MOE][LR]33’; (p) 5’ [LR]a[MOE][dR]9[LR]a3’; (q) 5’ [LR]3[MOE][dR][mR][dR]7[LR]33’; (r) 5’ [LR]g[MOE][LR]d[dR]9[LR]a3’; (s) 5’ [LR]d[MOE][LR]d[dR]d[mR][dR]j[LR]33’; (t) 5’ [LR]d[MOE][LR]d[mR][dR]8[LR]33’; (u) 5’ [LR]3[MOE][mR][dR]8[LR]33’; (v) 5’ [LR]a[mR][dR]9[LR]a3’; (w) 5’ [LR]3[mR][dR]8[LR]3[MOE] 3’; (x) 5’ [LR]3[mR][dR]8[LR]2[MOE][LR] 3’; (y) 5’ [LR]3[mR][dR]8[MOE][LR]33’; (z) 5’ [MOE]5[dR]f[MOE]53’; (aa) 5’ [MOE][LR]a[dR]9[LR]a3’; or (bb) 5’ [MOE][LR]3[dR][mR][dR]7[LR]33’;

[0032] wherein [cEt] stands for a constrained ethyl modified nucleotide, [LR] stands for a LNA, [dR] stands for an deoxyribonucleotide, [mR] stands for a 2’-OMe modified nucleotide and [MOE] stands for a 2’-MOE modified nucleotide; and

[0033] wherein: a is 2, 3 or 4; b is 2 or 3; c is 3 or 4; d is 1 or 2; e is 7 or 8; f is 8, 9, 10, 11 or 12; g is 1, 2 or 3; h is 1, 2, 3 or 4; i is 5, 6, 7 or 8; and j is 6 or 7.

[0034] An oligonucleotide of the specification may comprise or consist of: (a) a 5 '-region consisting of 2 linked 5 '-region nucleosides; (b) a central region consisting of 10 linked central region nucleosides; and (c) a 3 '-region consisting of 4 linked 3 '-region nucleosides; wherein optionally one of the central region nucleosides comprises a non-bicyclic modified sugar moiety, preferably a 2’-OMe modified sugar moiety or a 2’-MOE modified sugar moiety.

[0035] An oligonucleotide of the specification may comprise at least one modified internucleoside linkage. The at least one modified internucleoside linkage may be a phosphorothioate (PS) internucleoside linkage, a N3' —> P5' phosphoramidite (PN) internucleoside linkage or a mesylphosphoramidate (MsPA) linkage. Each internucleoside linkage of an oligonucleotide of the specification may be independently selected from a phosphodiester or a phosphorothioate internucleoside linkage. Each internucleoside linkage of an oligonucleotide may be a modified internucleoside linkage, optionally a phosphorothioate internucleoside linkage. An oligonucleotide may comprise at least one phosphodiester internucleoside linkage. In an oligonucleotide of the specification: (a) at least 10, at least 11, at least 12, at least 13, at least 14 or more of the internucleoside linkages of the oligonucleotide may be phosphorothioate internucleoside linkages; and / or (b) all of the internucleoside of the oligonucleotide may be phosphorothioate internucleoside linkages. An oligonucleotide of the specification may comprise: (a) at least 1 modified internucleoside linkage at the 5’ end; and / or (b) at least 1 modified internucleoside linkage at the 3’ end.

[0036] The internucleoside linkages of an oligonucleotide may be arranged: (a) 5’ [PS]d[P]k[PS]i[P]g[PS]d 3’; or (b) 5’ [PS]m[P]h[PS]n3’; wherein [PS] stands for a phosphorothioate internucleoside linkage, and [P] stands for a phosphodiester internucleoside linkage; and wherein: d is 1 or 2; g is 1, 2 or 3; h is 1, 2, 3 or 4; k is 1, 2 or 4; I is 9, 10 or 11; m is 1, 2, 3 or 12; and n is 1, 12, 13, 14 or 15.

[0037] An oligonucleotide of the specification may comprise at least one modified nucleobase, optionally selected from 5-methylcytosine or methyl-uracil, G-clamp, 8-methylguanine, 2-aminopurine (2-AP) and inosine.

[0038] An oligonucleotide of the specification may be a single-stranded oligonucleotide.

[0039] The specification also provides a polynucleotide conjugate comprising an oligonucleotide of the specification and a conjugate group. The conjugate group may comprise or consist of a conjugate linker and a conjugate moiety. The conjugate linker may consist of a single bond. The conjugate linker may be cleavable. The conjugate linker may comprise or consist of 1 to 3 linker-nucleosides. The conjugate linker may be a phosphate. The conjugate group may be attached to the oligonucleotide at the 5’-end of the oligonucleotide. The conjugate group may be attached to the oligonucleotide at the 3’-end of the oligonucleotide. The conjugate group may comprise or consist of a cell-targeting moiety.

[0040] The polynucleotide conjugate may comprise a non-nucleoside terminal group. The terminal group may be an abasic sugar moiety.

[0041] The specification also provides a chirally enriched population of oligonucleotide of the specification, or the polynucleotide conjugates of the specification, wherein the population is enriched for oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration, or polynucleotide conjugates comprising said oligonucleotides. The population may be enriched for oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) or (Rp) configuration, or polynucleotide conjugates comprising said oligonucleotides. The population may be enriched for oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage, or polynucleotide conjugates comprising said oligonucleotides. The population may be enriched for oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages, or polynucleotide conjugates comprising said oligonucleotides. The chirally enriched population may be enriched for oligonucleotides having at least 2 or at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5’ to 3’ direction, or polynucleotide conjugates comprising said oligonucleotides. All of the phosphorothioate internucleoside linkages of an oligonucleotide (in an oligonucleotide of the specification, a population thereof, or a polynucleotide conjugate of the specification) may be stereorandom.

[0042] The specification also provides a pharmaceutical composition comprising an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification and a pharmaceutically acceptable diluent or carrier. The pharmaceutically acceptable diluent may be water or phosphate-buffered saline. The pharmaceutical composition may consist essentially of an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, and water or phosphate-buffered saline.

[0043] The specification further provides a method comprising administering to a subject an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, or a pharmaceutical composition of the specification.

[0044] The specification also provides a method of treating or preventing a disease associated with ARHGEF6 comprising administering to a subject having a disease associated with ARHGEF6 a therapeutically effective amount of an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, or a pharmaceutical composition of the specification; thereby treating or preventing the disease associated with ARHGEF6. The disease associated with ARHGEF6 may be a kidney condition.

[0045] The specification further provides a method of reducing ARHGEF6 RNA or ARHGEF6 protein in a kidney of a subject having or at risk of developing a kidney disease or condition comprising administering a therapeutically effective amount of an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, or a pharmaceutical composition of the specification to the subject, thereby reducing ARHGEF6 RNA or ARHGEF6 protein in the kidney.

[0046] The kidney condition may be chronic kidney disease (CKD), optionally end-stage kidney disease (ESKD).

[0047] The subject may be diagnosed as having: (a) Hypertensive Nephrosclerosis, Glomerular Diseases to include but not limited to diabetic kidney disease (DKD), Focal Segmental Glomerulosclerosis (FSGS), Alport Syndrome, Membranous Nephropathy (MN), Minimal Change Disease (MCD), Lupus Nephritis, IgA Nephropathy (IgAN), Membranoproliferative Glomerulonephritis (MPGN), Renal Vasculitis, Anti-glomerular basement membrane disease (Anti-GBM Disease), Paraprotein-Related Kidney Disease, C3 Glomerulopathy (C3G); and / or (b) DN (diabetic nephropathy), FSGS (focal segmental glomerulosclerosis), HTN (renal hypertension), IgAN (IgA nephropathy / Berger’s disease), RPGN (rapidly progressive glomerulonephritis) and / or SLE (systemic lupus erythematosus).

[0048] A method may be for the treatment and / or prevention of a kidney condition that is chronic kidney disease (CKD) or diabetic kidney disease (DKD) by administering to a subject an oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition of the specification.

[0049] Administering may comprise oral administration, intravenous administration or intramuscular administration.

[0050] The method may ameliorate at least one symptom or hallmark of the kidney condition. The symptom or hallmark may be selected from high blood pressure, urinary tract infection, loss of kidney function, low blood count, malnutrition, bone pain, unusual pain, numbness or tingling, decreased mental sharpness, anaemia, decreased appetite, bone disease, abnormal blood levels of phosphorus, calcium or vitamin D, uraemia, fatigue, shortness of breath, nausea, vomiting, abnormal thyroid levels, swelling in hands / legs / eyes / lower back and lower back pain; optionally wherein the symptom or hallmark is selected from: (a) high blood pressure, swelling in hands / legs / eyes / lower back and loss of kidney function; and / or (b) anaemia, abnormal blood levels of phosphorus, calcium or vitamin D, fatigue, shortness of breath, nausea and vomiting.

[0051] The method may prevent or slow disease progression.

[0052] The method of treatment may be indicated on the basis of measured GFR, eGFR or UACR obtained from a sample from a subject that indicates the subject has chronic kidney disease. The subject may have a measured eGFR or GFR of < 70mL / min / 1.73 m2or may have a measured UACR of > 30mg / g.

[0053] The specification further provides an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, or a pharmaceutical composition of the specification for use in a method of treating or preventing a disease associated with ARHGEF6 in a subject. The disease associated with ARHGEF6 may be a kidney condition.

[0054] The specification further provides an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, or a pharmaceutical composition of the specification for use in a method of reducing ARHGEF6 RNA or ARHGEF6 protein in a kidney of a subject having or at risk of developing a kidney disease or condition.

[0055] The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use may be for the treatment and / or prevention of a kidney condition that is chronic kidney disease (CKD), optionally end stage kidney disease (ESKD). The subject may be diagnosed as having: (a) Hypertensive Nephrosclerosis, Glomerular Diseases to include but not limited to diabetic kidney disease (DKD), Focal Segmental Glomerulosclerosis (FSGS), Alport Syndrome, Membranous Nephropathy (MN), Minimal Change Disease (MCD), Lupus Nephritis, IgA Nephropathy (IgAN), Membranoproliferative Glomerulonephritis (MPGN), Renal Vasculitis, Anti-glomerular basement membrane disease (Anti-GBM Disease), Paraprotein-Related Kidney Disease, C3 Glomerulopathy (C3G); and / or (b) DN (diabetic nephropathy), FSGS (focal segmental glomerulosclerosis), HTN (renal hypertension), IgAN (IgA nephropathy I Berger’s disease), RPGN (rapidly progressive glomerulonephritis) and / or SLE (systemic lupus erythematosus).

[0056] The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use may be for the treatment and / or prevention of a kidney condition that is chronic kidney disease (CKD) or diabetic kidney disease (DKD).

[0057] The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use may be administered by oral administration, intravenous administration or intramuscular administration.

[0058] The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use may ameliorate at least one symptom or hallmark of the kidney condition. The symptom or hallmark may be selected from high blood pressure, urinary tract infection, loss of kidney function, low blood count, malnutrition, bone pain, unusual pain, numbness or tingling, decreased mental sharpness, anaemia, decreased appetite, bone disease, abnormal blood levels of phosphorus, calcium or vitamin D, uraemia, fatigue, shortness of breath, nausea, vomiting, abnormal thyroid levels, swelling in hands / legs / eyes / lower back and lower back pain; optionally wherein the symptom or hallmark is selected from: (a) high blood pressure, swelling in hands / legs / eyes / lower back and loss of kidney function; and / or (b) anaemia, abnormal blood levels of phosphorus, calcium or vitamin D, fatigue, shortness of breath, nausea and vomiting.

[0059] The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use may prevent or slow disease progression.

[0060] The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use may be indicated on the basis of measured GFR, eGFR or UACR obtained from a sample from a subject that indicates the subject has chronic kidney disease. The subject may have a measured eGFR or GFR of < 70mL / min / 1.73 m2or may have a measured UACR of > 30mg / g.

[0061] The specification also provides the use of an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification in the manufacture of a medicament for treating or preventing a disease associated with ARHGEF6 in a subject. The disease associated with ARHGEF6 may be a kidney condition.

[0062] The specification further provides the use of an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification in the manufacture of a medicament for use in a method of reducing ARHGEF6 RNA or ARHGEF6 protein in a kidney of a subject having or at risk of developing a kidney disease or condition.

[0063] The kidney condition may be chronic kidney disease (CKD), optionally end stage kidney disease (ESKD). The subject may be diagnosed as having: (a) Hypertensive Nephrosclerosis, Glomerular Diseases to include but not limited to diabetic kidney disease (DKD), Focal Segmental Glomerulosclerosis (FSGS), Alport Syndrome, Membranous Nephropathy (MN), Minimal Change Disease (MCD), Lupus Nephritis, IgA Nephropathy (IgAN), Membranoproliferative Glomerulonephritis (MPGN), Renal Vasculitis, Anti-glomerular basement membrane disease (Anti-GBM Disease), Paraprotein-Related Kidney Disease, C3 Glomerulopathy (C3G); and / or (b) DN (diabetic nephropathy), FSGS (focal segmental glomerulosclerosis), HTN (renal hypertension), IgAN (IgA nephropathy I Berger’s disease), RPGN (rapidly progressive glomerulonephritis) and / or SLE (systemic lupus erythematosus).

[0064] The medicament may be for the treatment and / or prevention of a kidney condition that is diabetic kidney disease (DKD) or diabetic kidney disease (DKD).

[0065] The medicament may be administered by oral administration, intravenous administration or intramuscular administration.

[0066] The use may ameliorate at least one symptom or hallmark of the kidney condition. The symptom or hallmark may be selected from high blood pressure, urinary tract infection, loss of kidney function, low blood count, malnutrition, bone pain, unusual pain, numbness or tingling, decreased mental sharpness, anaemia, decreased appetite, bone disease, abnormal blood levels of phosphorus, calcium or vitamin D, uraemia, fatigue, shortness of breath, nausea, vomiting, abnormal thyroid levels, swelling in hands / legs / eyes / lower back and lower back pain; optionally wherein the symptom or hallmark is selected from: (a) high blood pressure, swelling in hands / legs / eyes / lower back and loss of kidney function; and / or (b) anaemia, abnormal blood levels of phosphorus, calcium or vitamin D, fatigue, shortness of breath, nausea and vomiting. The method may prevent or slow disease progression.

[0067] In a use of the specification, the method of treatment may be indicated on the basis of measured GFR, eGFR or UACR obtained from a sample from a subject that indicates the subject has chronic kidney disease. The subject may have a measured eGFR or GFR of < 70mL / min / 1.73 m2or may have a measured UACR of > 30mg / g.

[0068] The specification also provides an article of manufacture comprising an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, or a pharmaceutical composition of the specification.

[0069] The specification further provides a kit comprising an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, or a pharmaceutical composition of the specification, optionally further comprising instructions for use.

[0070] The specification also provides a method of reducing expression of ARHGEF6 in a cell comprising contacting the cell with an oligonucleotide of the specification, a polynucleotide conjugate of the specification, or a population of the specification, or a pharmaceutical composition of the specification.

[0071] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 provides a schematic of exemplary sugar and linkage modification patterns. X can be any nucleobase.

[0072] Figure 2 - Knock-Down of ARHGEF6 results in maintained podocytes and increased collagen IV deposition. (A) Relative presence of staining of the GlomSpheres for podocytes stable GFP-expressing podocytes (top) and collagen IV staining (bottom) in the treated GlomSpheres; (B) Quantitative values for the levels of podocytes and collagen IV levels in compound #1715 and control ASO (SEQ ID NO: 3307) treated GlomSpheres relative to untreated; (C) qPCR results showing dose dependent reduction in ARHGEF6 gene expression levels with compound #1715 at 1 μM, 2.5 μM and 5 μM. * denotes P< 0.05 ** denotes P< 0.01; *** denotes P< 0.001; and **** denotes P< 0.0001, calculated using one-way ANOVA with a Tukey post-hoc test.

[0073] Figure 3 - In vivo dose-response study in humanized ARHGEF6 mice. (A) Dose-scheme of compound #1715; (B) ARHGEF6 expression relative PBS control as a function of compound #1715 dose. Points represent observed data; the solid line shows the 4-parameter inhibition model fit, and the shaded band indicates the 95% confidence interval from simulation.

[0074] DETAILED DESCRIPTION

[0075] Definitions

[0076] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

[0077] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated-by-reference for the portions of the document discussed herein, as well as in their entirety.

[0078] Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts described herein to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0079] As used herein, the term "capable of when used with a verb, encompasses or means the action of the corresponding verb. For example, "capable of interacting" also means interacting, "capable of inhibiting" also means inhibits, "capable of binding" also means binds and "capable of specifically targeting..." also means specifically targets.

[0080] Numeric ranges are inclusive of the numbers defining the range. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure.

[0081] “About” may generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. Preferably, the term “about” shall be understood herein as plus or minus (±) 5%, preferably ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, of the numerical value of the number with which it is being used.

[0082] The term "consisting of' refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the specification. As used herein the term "consisting essentially of' refers to those elements required for a given specification. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that specification (i.e., inactive or non-immunogenic ingredients).

[0083] Embodiments described herein as “comprising” one or more features may also be considered as disclosure of the corresponding embodiments “consisting of’ and / or “consisting essentially of’ such features.

[0084] Concentrations, amounts, volumes, percentages and other numerical values may be presented herein in a range format. It is also to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

[0085] The oligonucleotides of the present specification may be prepared by any means known in the art. For example, large amounts of the oligonucleotides may be produced by replication in a suitable host cell. The polynucleotides of the present specification may preferably be produced by chemical synthesis, e.g., by the phosphoramidite method or the tri-ester method and may be performed on commercial automated oligonucleotide synthesizers.

[0086] A “variant” nucleic acid sequence has substantial homology or substantial similarity to a reference nucleic acid sequence (or a fragment thereof). A nucleic acid sequence or fragment thereof is “substantially homologous” (or “substantially identical”) to a reference sequence if, when optimally aligned (with appropriate nucleotide insertions or deletions) with the other nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 70%, 75%, 80%, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9 or more% of the nucleotide bases. Methods for homology determination of nucleic acid sequences are known in the art.

[0087] Alternatively, a “variant” nucleic acid sequence is substantially homologous with (or substantially identical to) a reference sequence (or a fragment thereof) if the “variant” and the reference sequence are capable of hybridizing under stringent (e.g., highly stringent) hybridization conditions. Nucleic acid sequence hybridization is affected by conditions such as salt concentration (e.g. NaCI), temperature, or organic solvents, in addition to the base composition, length of the complementary strands, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. Stringent temperature conditions are preferably employed, and generally include temperatures in excess of 30°C, typically in excess of 37°C and preferably in excess of 45°C. Stringent salt conditions will ordinarily be less than 1000 mM, typically less than 500 mM, and preferably less than 200 mM. The pH is typically between 7.0 and 8.3. The combination of parameters is much more important than any single parameter. Methods of determining nucleic acid percentage sequence identity are known in the art. By way of example, when assessing nucleic acid sequence identity, a sequence having a defined number of contiguous nucleotides may be aligned with a nucleic acid sequence (having the same number of contiguous nucleotides) from the corresponding portion of a nucleic acid sequence of the present specification. Tools known in the art for determining nucleic acid percentage sequence identity include Nucleotide BLAST (as described below).

[0088] The terms “decrease” "reduced", "reduction", or "inhibit" are all used herein to mean a decrease by a statistically significant amount. The terms "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reduction" or "inhibition" encompasses a complete inhibition or reduction as compared to a reference level. "Complete inhibition" is a 100% inhibition (i.e., abrogation) as compared to a reference level.

[0089] The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. The terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 25%, at least 50% as compared to a reference level, for example an increase of at least about 50%, or at least about 75%, or at least about 80%, or at least about 90%, at least about 95%, or at least about 98%, or at least about 99%, or at least about 100%, or at least about 250% or more compared with a reference level, or at least about a 1.5-fold, or at least about a 2-fold, or at least about a 2.5-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 1.5-fold and 10-fold or greater as compared to a reference level.

[0090] Unless otherwise indicated, the following terms have the following meanings:

[0091] As used herein, “2’-deoxynucleoside” means a nucleoside comprising a 2’-H(H) deoxyfuranosyl sugar moiety. In certain embodiments, a 2’-deoxynucleoside is a 2’-|3-D-deoxynucleoside and comprises a 2’-|3-D-deoxyribosyl sugar moiety, which has the [3-D ribosyl configuration as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2’-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

[0092] As used herein, “2’-MOE” means a 2’-OCH2CH2OCH3group in place of the 2’-OH group of a furanosyl sugar moiety. A “2’-MOE sugar moiety” means a sugar moiety with a 2’-OCH2CH2OCH3 group in place of the 2’-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2’-MOE sugar moiety is in the p-D-ribosyl configuration. “MOE” means O-methoxyethyl. As used herein, “2’-M0E nucleoside” means a nucleoside comprising a 2’-MOE sugar moiety.

[0093] As used herein, “2’-MOEOE” means a 2’-(2-methoxyethoxy)ethyl) group in place of the 2’-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2’-MOEOE sugar moiety is in the p-D-ribosyl configuration.

[0094] As used herein, “2’-MOEOE nucleoside” means a nucleoside comprising a 2’-MOEOE sugar moiety.

[0095] As used herein, “2’-OMe” means a 2’-OCH3group in place of the 2’-OH group of a furanosyl sugar moiety. A “2’-O-methyl sugar moiety” or “2’-OMe sugar moiety” means a sugar moiety with a 2’-OCH3group in place of the 2’-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2’-MOE sugar moiety is in the p-D-ribosyl configuration.

[0096] As used herein, “2’-OMe nucleoside” means a nucleoside comprising a 2’-OMe sugar moiety.

[0097] As used herein, a bridged nucleic acid or “BNA” is a means a nucleoside in which the furanosyl sugar moiety comprises a two-ring structure, such that the furanosyl sugar moiety is locked in an RNA-like (C3’-endo) conformation. Non-limiting examples of 2’-4’ linkages present in a BNA include -O-CH2- and -O-CH(CH3).

[0098] As used herein, a 2'-O,4'-C-ethylene-bridged nucleic acid or “ENA” means a nucleoside in which the furanosyl sugar moiety comprises an ethylene bridge between the 2'-oxygen and 4'-carbon of ribose. ENAs are a specific class of BNAs.

[0099] As used herein, a locked nucleic acid or “LNA” means a nucleoside in which the furanosyl sugar moiety comprises a 2'-O, 4'-C methylene linkage, such that the furanosyl sugar moiety is locked in an RNA-like (C3’-endo) conformation. LNAs are a specific class of BNAs.

[0100] As used herein, a “cEt” modified sugar moiety means a p-D ribosyl bicyclic sugar moiety wherein the second ring of the bicyclic sugar is formed via a bridge connecting the 4’-carbon and the 2’-carbon of the p-D ribosyl sugar moiety, wherein the bridge has the formula 4'-CH(CH3)-O-2', and wherein the methyl group of the bridge is in the S configuration.

[0101] As used herein, “cEt nucleoside” means a nucleoside comprising a cEt modified sugar moiety.

[0102] As used herein, “2’-F” or “2’-fluoro” means a F group in place of the 2’-OH group of a furanosyl sugar moiety. A “2’-F sugar moiety” or “2’-fluoro sugar moiety” means a sugar moiety with a 2’-F group in place of the 2’-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2’-F sugar moiety is in the p-D-ribosyl configuration.

[0103] As used herein, “2’-F nucleoside” means a nucleoside comprising a 2’-F sugar moiety. As used herein, “2’-NMA” means that a 2’-OCH2CONHCH3group is present in place of the 2’-OH group of a furanosyl sugar moiety. A “2’-NMA sugar moiety” means a sugar moiety with a 2’-OCH2CONHCH3group in place of the 2’-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2’-NMA sugar moiety is in the p-D-ribosyl configuration. “NMA” means “O-[2-(methylamino)-2-oxoethyl]”.

[0104] As used herein, “2’-NMA nucleoside” means a nucleoside comprising a 2’-NMA sugar moiety.

[0105] As used herein, “2’-substituted nucleoside” means a nucleoside comprising a 2’-substituted sugar moiety. As used herein, “2’-substituted” in reference to a sugar moiety means a sugar moiety comprising at least one 2'-substituent group other than H or OH.

[0106] As used herein, “3’ target site” refers to the 3’-most nucleotide of a target nucleic acid which is complementary to an oligonucleotide, when the oligonucleotide is hybridized to the target nucleic acid.

[0107] As used herein, “5’ target site” refers to the 5’-most nucleotide of a target nucleic acid which is complementary to an oligonucleotide, when the oligonucleotide is hybridized to the target nucleic acid.

[0108] Hydbridization is the process wherein a contiguous sequence of nucleobases in a strand of a first nucleic acid form base pairs with a contiguous complementary sequence of nucleobases in a strand of a second nucleic acid to form a double stranded unit.

[0109] As used herein, “5-methylcytosine” means a cytosine modified with a methyl group attached to the C-5 position of cytosine. A 5-methyl cytosine is a modified nucleobase.

[0110] As used herein, “abasic sugar moiety” means a sugar moiety of a nucleoside that is not attached to a nucleobase. Such abasic sugar moieties are sometimes referred to in the art as “abasic nucleosides.”

[0111] As used herein, “bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. For the avoidance of doubt, the term “bicyclic sugar” as used herein typically does not refer to a disaccharide (or greater) wherein individual monosaccharides are joined by a glycosidic linkage. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

[0112] As used herein, “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring. Such “non-bicyclic modified sugar moieties” are referred to interchangeably herein as “non-bicyclic sugar moieties”.

[0113] As used herein, “cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, ora human.

[0114] As used herein, “complementary” in reference to an oligonucleotide means that at least 70% of the nucleobases of the oligonucleotide and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions. “Complementary region” in reference to a region of an oligonucleotide means that at least 70% of the nucleobases of that region and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions, i.e. the nucleobase sequences are reverse complementary. For the avoidance of doubt, all references herein to an oligonucleotide (e.g. an antisense oligonucleotide of the specification) as complementary to a target sequence means that the nucleobase sequence of said oligonucleotide (e.g. the antisense oligonucleotide of the specification) is reverse complementary to said target sequence.

[0115] Complementary nucleobases mean nucleobases that are capable of forming hydrogen bonds with one another. Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methyl cytosine (mC) and guanine (G). Certain modified nucleobases that pair with natural nucleobases or with other modified nucleobases are known in the art and are not considered complementary nucleobases as defined herein unless indicated otherwise. For example, inosine can pair, but is not considered complementary, with adenosine, cytosine, or uracil. Complementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. As used herein, “fully complementary” or “100% complementary” in reference to oligonucleotides means that oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide.

[0116] As used herein, “conjugate group” means a group of atoms that is directly attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linkerthat attaches the conjugate moiety to the oligonucleotide.

[0117] As used herein, “conjugate linker” means a single bond or a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

[0118] As used herein, “conjugate moiety” means a group of atoms that modifies one or more properties of a molecule compared to the identical molecule lacking the conjugate moiety, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance.

[0119] As used herein, “hotspot region” is a range of nucleobases on a target nucleic acid that is amenable to oligomeric agent or oligomeric compound-mediated reduction of the amount or activity of the target nucleic acid.

[0120] As used herein, “internucleoside linkage” is the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein “modified internucleoside linkage” means any internucleoside linkage other than a phosphodiester internucleoside linkage.

[0121] As used herein, “linked nucleosides” are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are presented between those that are linked). As used herein, “linker-nucleoside” means a nucleoside that links, either directly or indirectly, an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of an oligomeric compound. Linker-nucleosides are not considered part of the oligonucleotide portion of an oligomeric compound even if they are contiguous with the oligonucleotide.

[0122] As used herein, “mismatch” or“non-complementary” means a nucleobase of a first nucleic acid sequence that is not complementary with the corresponding nucleobase of a second nucleic acid sequence or target nucleic acid when the first and second nucleic acid sequences are aligned.

[0123] As used herein, “motif’ means the pattern of unmodified and / or modified sugar moieties, nucleobases, and / or internucleoside linkages, in an oligonucleotide.

[0124] As used herein, “modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety.

[0125] As used herein, "nucleobase" means an unmodified nucleobase or a modified nucleobase. A nucleobase is a heterocyclic moiety. As used herein an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a “modified nucleobase” is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one other nucleobase. A “5-methyl cytosine” is a modified nucleobase. A universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases.

[0126] As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification. By way of example and without limitation, an oligomeric compound having the nucleobase sequence “ATCGATCG” encompasses any compounds having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and compounds having other modified nucleobases, such as “ATmCGAUCG,” whereinmC indicates a cytosine base comprising a methyl group at the 5-position. Finally, for clarity, unless otherwise indicated, the phrase “nucleobase sequence of SEQ ID NO: X”, refers only to the sequence of nucleobases in that SEQ ID NO.: X, independent of any sugar or internucleoside linkage modifications also described in such SEQ ID.

[0127] As used herein, “nucleoside” means a compound or fragment of a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified.

[0128] As used herein, " polynucleotide conjugate" means an oligonucleotide and one or more additional features, such as a conjugate group or terminal group.

[0129] As used herein, “antisense activity” means any detectable and / or measurable change attributable to the hybridization of an oligonucleotide to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the oligonucleotide. In certain embodiments, antisense activity is the modulation of splicing of a target pre-mRNA.

[0130] As used herein, “antisense oligonucleotide” or “ASO” means an oligonucleotide, that is capable of hybridizing to a target nucleic acid and is capable of at least one antisense activity. Antisense oligonucleotides include but are not limited to single-stranded antisense RNAi oligonucleotides (ssRNA) and gapmers.

[0131] As used herein, a “gapmer” means a single-stranded antisense oligonucleotide consisting of a DNA core flanked by RNA-based structures. Typically the flanking RNA structures are modified and resistant to RNase H.

[0132] As used herein, an “ssRNAi” means a single-stranded antisense RNA oligonucleotides which engage the cellular RNAi machinery and are capable of at least one antisense activity (particularly degradation of the target mRNA).

[0133] As used herein, "oligonucleotide" means a strand of nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications.

[0134] As used herein, “stabilized phosphate group” means a 5’-phosphate analog that is metabolically more stable than a 5’-phosphate as naturally occurs in DNA or RNA.

[0135] As used herein, “standard cell assay” means the assays described in the Examples and reasonable variations thereof.

[0136] As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a 2’-OH(H) ribosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2’-H(H) deoxyribosyl sugar moiety, as found in DNA (an “unmodified DNA sugar moiety”). Unmodified sugar moieties have one hydrogen at each of the 1’, 3’, and 4’ positions, an oxygen at the 3’ position, and two hydrogens at the 5’ position. As used herein, “modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate.

[0137] As used herein, "sugar surrogate" means a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or target nucleic acids. As used herein, “target nucleic acid” and “target RNA” mean a nucleic acid that an oligomeric compound is designed to affect. Target RNA means an RNA transcript and includes pre-mRNA and mRNA unless otherwise specified.

[0138] As used herein, “target region” means a portion of a target nucleic acid to which an oligomeric compound is designed to hybridize.

[0139] As used herein, "terminal group" means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide. Typically, a “terminal group” of the specification is a non-nucleoside terminal group.

[0140] As used herein, “cell-targeting moiety” means a conjugate group or portion of a conjugate group that is capable of binding to a particular cell type or particular cell types.

[0141] As used herein, “hybridization” means the annealing of oligonucleotides and / or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense compound and a nucleic acid target. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an oligonucleotide and a nucleic acid target.

[0142] As used herein, “RNAi agent” means an antisense agent that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. RNAi agents include, but are not limited to, single-stranded RNAi (ssRNAi), and microRNA, including microRNA mimics. RNAi agents may comprise conjugate groups and / or terminal groups. In certain embodiments, an RNAi agent modulates the amount and / or activity, of a target nucleic acid. The term RNAi agent excludes antisense agents that act through RNase H.

[0143] As used herein, “RNase H agent” means an antisense agent that acts through RNase H to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. In certain embodiments, RNase H agents are single-stranded. RNase H compounds may comprise conjugate groups and / or terminal groups. In certain embodiments, an RNase H agent modulates the amount and / or activity of a target nucleic acid. The term RNase H agent excludes antisense agents that act principally through RISC / Ago2.

[0144] As used herein, “reducing” or “inhibiting” ARHGEF6 means reducing expression of ARHGEF6 RNA and / or protein levels in the presence of an oligonucleotide described herein compared to expression of ARHGEF6 RNA and / or protein levels that would otherwise be present in the absence of an oligonucleotide described herein.

[0145] As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an animal. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution or sterile artificial cerebrospinal fluid.

[0146] For example, the term “pharmaceutically acceptable” may refer to salts, excipients, carriers, diluents, etc. approved by a regulatory agency of the Federal or a state government, or listed in the U. S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia.

[0147] As used herein “pharmaceutical composition” means a mixture of substances suitable for administering to a subject. For example, a pharmaceutical composition may comprise an oligonucleotide and a sterile aqueous solution. In certain embodiments, a pharmaceutical composition shows activity in free uptake assay in certain cell lines.

[0148] As used herein, “treating” means improving a subject’s disease or condition by administering an oligonucleotide described herein. In certain embodiments, treating a subject improves a symptom relative to the same symptom in the absence of the treatment. In certain embodiments, treatment reduces in the severity or frequency of a symptom, or delays the onset of a symptom, slows the progression of a symptom, or slows the severity or frequency of a symptom.

[0149] As used herein, “therapeutically effective amount” means an amount of a pharmaceutical agent or composition that has been observed to provide a therapeutic benefit to an animal. For example, a therapeutically effective amount may be observed to improve a symptom of a disease.

[0150] The terms "individual”, "subject”, and "patient”, are used interchangeably herein to refer to a mammalian subject for whom diagnosis, prognosis, disease monitoring, treatment, therapy, and / or therapy optimisation is desired. The mammal can be (without limitation) a human, nonhuman primate, mouse, rat, dog, cat, horse, or cow. In a preferred embodiment, the individual, subject, or patient is a human. An “individual” may be an adult, juvenile or infant. An “individual” may be male or female.

[0151] A "subject in need" of treatment for a particular condition can be an individual having that condition, diagnosed as having that condition, or at risk of developing that condition.

[0152] A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications or symptoms related to such a condition, and optionally, have already undergone treatment for a condition as defined herein or the one or more complications or symptoms related to said condition. Alternatively, a subject can also be one who has not been previously diagnosed as having a condition as defined herein or one or more or symptoms or complications related to said condition. For example, a subject can be one who exhibits one or more risk factors for a condition, or one or more or symptoms or complications related to said condition or a subject who does not exhibit risk factors.

[0153] As used herein, the term “healthy individual” refers to an individual or group of individuals who are in a healthy state, e.g., individuals who have not shown any symptoms of the disease, have not been diagnosed with the disease and / or are not likely to develop the disease e.g., a thrombotic event. Preferably said healthy individual(s) is not on medication affecting haemostasis and has not been diagnosed with any other disease. The one or more healthy individuals may have a similar sex, age, and / or body mass index (BMI) as compared with the test individual. Application of standard statistical methods used in medicine permits determination of normal levels of expression in healthy individuals, and significant deviations from such normal levels.

[0154] Herein the terms “control” and “reference population” are used interchangeably.

[0155] ARHGEF6

[0156] The present inventors have surprisingly demonstrated that oligonucleotides targeting particular regions of the transcript for Rho guanine nucleotide exchange factor 6 (ARHGEF6) are capable of significantly reducing the amount or activity of ARHGEF6 RNA in a cell. Accordingly, the present specification relates to oligonucleotides which target said ARHGEF6 transcript regions. In other words, the target nucleic acid of the present specification is said ARHGEF6 transcript, or a region or fragment thereof. The oligonucleotides of the specification are antisense oligonucleotides.

[0157] Contacting a cell with an oligonucleotide which targets said ARHGEF6 transcript typically reduces the amount of ARHGEF6 RNA. Contacting a cell with an oligonucleotide which targets said ARHGEF6 transcript may reduce the amount of ARHGEF6 protein. Said oligonucleotide may be as described herein, and may be in the form of an isolated oligonucleotide, or a polynucleotide conjugate, or a composition comprising such an oligonucleotide, as described herein.

[0158] The oligonucleotides of the specification comprises a nucleobase sequence that is at least 80% complementary to an equal portion of said ARHGEF6 transcript.

[0159] Said ARHGEF6 transcript is typically a human ARHGEF6 transcript which has the nucleic acid sequence set forth in SEQ ID NO: 3291 (the pre-mRNA of ENSEMBL Accession No. ENST00000250617.7 (accessed 05 October 2024). Other human ARHGEF6 transcripts include ENSEMBL Accession Nos. ENST00000370622.5 and ENST00000370620.5 (accessed 05 October 2024). An exemplary human ARHGEF6 protein sequence is set forth in UniProt Accession No. Q15052 (version 2, accessed 04 October 2024).

[0160] The ARHGEF6 transcript may have a nucleic acid sequence that is at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, a least 98%, at least 99%, at least 99.5%, at least 99.9% or more identical to SEQ ID NO: 3291.

[0161] The ARHGEF6 transcript may have a nucleic acid sequence that differs from SEQ ID NO: 3291 by no more than 1,000, no more than 500, no more than 400, no more than 300, no more than 200, no more than 150, no more than 100, no more than 50, no more than 40, no more than 30, no more than 25, no more than 20, no more than 15, no more than 10, no more than 9, no more than 8, no more than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 nucleobase from SEQ ID NO: 3291. The ARHGEF6 transcript of SEQ ID NO: 3291 is 115.38 kb in length. An oligonucleotide of the specification may target any equal length portion of said transcript. By way of non-limiting example, an oligonucleotide of the specification may target a region of the ARHGEF6 transcript corresponding to nucleobases 1 to 37,380; nucleobases 37,397 to 73,959; nucleobases 73,977 to 75,731; nucleobases 75,752 to 115,303; nucleobases 115,320 to 116,399; or nucleobases 116,416 to 117,742 of SEQ ID NO: 3291.

[0162] The present inventors have identified hotspots within the ARHGEF6 transcript of SEQ ID NO: 3291. As exemplified herein, oligonucleotides targeting regions comprising or consisting of these hotspots, or fragments thereof may have increased antisense activity compared with oligonucleotides targeting other regions of said ARHGEF6 transcript. In other words, oligonucleotides targeting regions comprising or consisting of these hotspots, or fragments thereof may reduce the amount of ARHGEF6 RNA and / or ARHGEF6 protein by a greater amount than oligonucleotides targeting regions outside these hotspots.

[0163] An ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 45,000 to about nucleobase 70,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 80,000 to about nucleobase 95,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0164] An ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 45,000 to about nucleobase 70,000 of SEQ ID NO: 3291. In particular, an ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 45,000 to about nucleobase 69,000; from about nucleobase 45,000 to about nucleobase 68,000; from about nucleobase 45,000 to about nucleobase 67,000; from about nucleobase 46,000 to about nucleobase 70,000; from about nucleobase 46,000 to about nucleobase 69,000; from about nucleobase 46,000 to about nucleobase 68,000; from about nucleobase 46,000 to about nucleobase 67,000; from about nucleobase 47,000 to about nucleobase 70,000; from about nucleobase 47,000 to about nucleobase 47,000; from about nucleobase 47,000 to about nucleobase 68,000; from about nucleobase 47,000 to about nucleobase 67,000; from about nucleobase 48,000 to about nucleobase 70,000; from about nucleobase 48,000 to about nucleobase 69,000; from about nucleobase 48,000 to about nucleobase 68,000; from about nucleobase 48,000 to about nucleobase 67,000; from about nucleobase 48,500 to about nucleobase 70,000; from about nucleobase 48,500 to about nucleobase 69,000; from about nucleobase 48,500 to about nucleobase 68,000; or from about nucleobase 48,500 to about nucleobase 67,000, of SEQ ID NO: 3291. In some preferred embodiments, anARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 48,000 to about nucleobase 67,000 of SEQ ID NO: 3291. An ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 75,000 to about nucleobase 75,500 of SEQ ID NO: 3291. In particular, an ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 75,000 to about nucleobase 75,400; from about nucleobase 75,000 to about nucleobase 75,300; from about nucleobase 75,000 to about nucleobase 75,200; from about nucleobase 75,100 to about nucleobase 75,500; from about nucleobase 75, 100 to about nucleobase 75,400; from about nucleobase 75,100 to about nucleobase 75,300; or from about nucleobase 75,100 to about nucleobase 75,200, of SEQ ID NO: 3291. In some preferred embodiments, an ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 75,000 to about nucleobase 75,500 of SEQ ID NO: 3291.

[0165] An ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 80,000 to about nucleobase 95,000 of SEQ ID NO: 3291. In particular, an ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 80,000 to about nucleobase 94,000; from about nucleobase 81,000 to about nucleobase 95,000; from about nucleobase 81,000 to about nucleobase 94,000; 82,000 to about nucleobase 95,000; from about nucleobase 82,000 to about nucleobase 94,000; 83,000 to about nucleobase 95,000; from about nucleobase 83,000 to about nucleobase 94,000; 84,000 to about nucleobase 95,000; from about nucleobase 84,000 to about nucleobase 94,000; 85,000 to about nucleobase 95,000; or from about nucleobase 85,000 to about nucleobase 94,000, of SEQ ID NO: 3291. In some preferred embodiments, an ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 85,000 to about nucleobase 94,000 of SEQ ID NO: 3291.

[0166] An ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In particular, an ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to or from about nucleobase 100,500 to about nucleobase 115,200 of SEQ ID NO: 3291. In some preferred embodiments, an ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0167] In some preferred embodiments, an ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 48,000 to about nucleobase 67,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 85,000 to about nucleobase 94,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291. An ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 50,000 to about nucleobase 60,000; from about nucleobase 90,000 to about nucleobase 95,000; from about nucleobase 100,000 to about nucleobase 105,000; or from about nucleobase 110,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0168] An ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 50,000 to about nucleobase 60,000 of SEQ ID NO: 3291. In particular, an ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 50,000 to about nucleobase 59,000; from about nucleobase 50,000 to about nucleobase 58,000; from about nucleobase 50,000 to about nucleobase 57,000; from about nucleobase 51,000 to about nucleobase 60,000; from about nucleobase 51,000 to about nucleobase 59,000; from about nucleobase 51,000 to about nucleobase 58,000; from about nucleobase 51,000 to about nucleobase 57,000; from about nucleobase 52,000 to about nucleobase 60,000; from about nucleobase 52,000 to about nucleobase 59,000; from about nucleobase 52,000 to about nucleobase 58,000; from about nucleobase 52,000 to about nucleobase 57,000; from about nucleobase 53,000 to about nucleobase 60,000; from about nucleobase 53,000 to about nucleobase 59,000; from about nucleobase 53,000 to about nucleobase 58,000; from about nucleobase 53,000 to about nucleobase 57,000; from about nucleobase 54,000 to about nucleobase 60,000; from about nucleobase 54,000 to about nucleobase 59,000; from about nucleobase 54,000 to about nucleobase 58,000; from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 55,000 to about nucleobase 60,000; from about nucleobase 55,000 to about nucleobase 59,000; from about nucleobase 55,000 to about nucleobase 58,000; from about nucleobase 55,000 to about nucleobase 57,000; from about nucleobase 56,000 to about nucleobase 60,000; from about nucleobase 56,000 to about nucleobase 59,000; from about nucleobase 56,000 to about nucleobase 58,000; or from about nucleobase 56,000 to about nucleobase 57,000 of SEQ ID NO: 3291. In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000 of SEQ ID NO: 3291. In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 56,000 to about nucleobase 57,000 of SEQ ID NO: 3291.

[0169] An ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 90,000 to about nucleobase 95,000 of SEQ ID NO: 3291. In particular, an ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 90,000 to about nucleobase 94,000; from about nucleobase 90,000 to about nucleobase 93,000; from about nucleobase 91,000 to about nucleobase 95,000; from about nucleobase 91,000 to about nucleobase 94,000; from about nucleobase 91,000 to about nucleobase 93,000; from about nucleobase 92,000 to about nucleobase 95,000; from about nucleobase 92,000 to about nucleobase 94,000; or from about nucleobase 92,000 to about nucleobase 93,000 of SEQ ID NO: 3291. In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 92,000 to about nucleobase 95,000 of SEQ ID NO: 3291. In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 92,000 to about nucleobase 94,000 of SEQ ID NO: 3291. In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 92,000 to about nucleobase 93,000 of SEQ ID NO: 3291.

[0170] An ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 100,000 to about nucleobase 105,000 of SEQ ID NO: 3291. In particular, an ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 100,000 to about nucleobase 104,000; from about nucleobase 100,500 to about nucleobase 105,000; from about nucleobase 100,500 to about nucleobase 104,000; from about nucleobase 101,000 to about nucleobase 105,000; or from about nucleobase 101,000 to about nucleobase 104,000 of SEQ ID NO: 3291. In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 100,500 to about nucleobase 104,000 of SEQ ID NO: 3291. In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 101,000 to about nucleobase 104,000 of SEQ ID NO: 3291.

[0171] An ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 110,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In particular, an ARHGEF6 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 111,000 to about nucleobase 115,200; from about nucleobase 112,000 to about nucleobase 115,200; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0172] In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 92,000 to about nucleobase 95,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0173] In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0174] In some particularly preferred embodiments, a ARHGEF6 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 56,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 102,000; or from about nucleobase 113,500 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0175] Oligonucleotides

[0176] The present specification particularly relates to oligonucleotides which target an ARHGEF6 transcript or region thereof, particularly an ARHGEF6 hotspot as defined herein.

[0177] The oligonucleotides of the specification may consist essentially of RNA or DNA, or a combination of DNA and RNA. In particular, an oligonucleotide of the specification is a singlestranded oligonucleotide, such as a gapmer.

[0178] The oligonucleotides of the specification comprise or consist of linked nucleosides. Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or may be modified oligonucleotides. Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DNA. That is, modified oligonucleotides comprise at least one modified nucleoside (comprising a modified sugar moiety and / or a modified nucleobase) and / or at least one modified internucleoside linkage. Certain modified nucleosides and modified internucleoside linkages suitable for use in modified oligonucleotides are described below.

[0179] In particular, the specification provides a oligonucleotide which comprises a nucleobase sequence which comprises or consists of a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within an ARHGEF6 nucleic acid having the nucleobase sequence of SEQ ID NO: 3291.

[0180] Typically, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within an ARHGEF6 hotspot as defined herein. Thus, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 37,380; from about nucleobase 37,397 to about nucleobase 73,959; from about nucleobase 73,977 to about nucleobase 75,731; from about nucleobase 75,752 to about nucleobase 115,303; from about nucleobase 115,320 to about nucleobase 116,399; or from about nucleobase 116,416 to about nucleobase 117,742 of SEQ ID NO: 3291.

[0181] In particular, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 45,000 to about nucleobase 70,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 80,000 to about nucleobase 95,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 48,000 to about nucleobase 67,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 85,000 to about nucleobase 94,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0182] In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 50,000 to about nucleobase 60,000; from about nucleobase 90,000 to about nucleobase 95,000; from about nucleobase 100,000 to about nucleobase 105,000; or from about nucleobase 110,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94 or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 92,000 to about nucleobase 95,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 56,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 102,000; or from about nucleobase 113,500 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0183] An oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a region defined by a pair of t-start and t-end nucleobases identified in Table 1. Alternatively, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80%, at least 86%, at least 87%, at least 93%, at least 94%, or more, up to 100% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within to a region defined by: (i) a t-start nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-start nucleobases identified in Table 1; and / or (ii) a t-end nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-end nucleobases identified in Table 1.

[0184] An oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 45,000 to about nucleobase 70,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 80,000 to about nucleobase 95,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 48,000 to about nucleobase 67,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 85,000 to about nucleobase 94,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0185] In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 50,000 to about nucleobase 60,000; from about nucleobase 90,000 to about nucleobase 95,000; from about nucleobase 100,000 to about nucleobase 105,000; or from about nucleobase 110,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 92,000 to about nucleobase 95,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0186] In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 56,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 102,000; or from about nucleobase 113,500 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0187] An oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a region defined by a pair of t-start and t-end nucleobases identified in Table 1. Alternatively, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within to a region defined by: (i) a t-start nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-start nucleobases identified in Table 1; and / or (ii) a t-end nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-end nucleobases identified in Table 1.

[0188] An oligonucleotide of the specification may comprise a nucleobase sequence that is at least 87% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 45,000 to about nucleobase 70,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 80,000 to about nucleobase 95,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 87% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 48,000 to about nucleobase 67,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 85,000 to about nucleobase 94,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0189] In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 87% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 50,000 to about nucleobase 60,000; from about nucleobase 90,000 to about nucleobase 95,000; from about nucleobase 100,000 to about nucleobase 105,000; or from about nucleobase 110,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 87% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 92,000 to about nucleobase 95,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0190] In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 87% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 87% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 56,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 102,000; or from about nucleobase 113,500 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0191] An oligonucleotide of the specification may comprise a nucleobase sequence that is at least 87% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a region defined by a pair of t-start and t-end nucleobases identified in Table 1. Alternatively, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 87% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within to a region defined by: (i) a t-start nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-start nucleobases identified in Table 1; and / or (ii) a t-end nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-end nucleobases identified in Table 1.

[0192] An oligonucleotide of the specification may comprise a nucleobase sequence that is at least 94% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 45,000 to about nucleobase 70,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 80,000 to about nucleobase 95,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 94% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 48,000 to about nucleobase 67,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 85,000 to about nucleobase 94,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0193] In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 94% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 50,000 to about nucleobase 60,000; from about nucleobase 90,000 to about nucleobase 95,000; from about nucleobase 100,000 to about nucleobase 105,000; or from about nucleobase 110,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 94% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 92,000 to about nucleobase 95,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0194] In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 94% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 94% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 56,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 102,000; or from about nucleobase 113,500 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0195] An oligonucleotide of the specification may comprise a nucleobase sequence that is at least 94% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a region defined by a pair of t-start and t-end nucleobases identified in Table 1. Alternatively, an oligonucleotide of the specification may comprise a nucleobase sequence that is at least 94% complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within to a region defined by: (i) a t-start nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-start nucleobases identified in Table 1; and / or (ii) a t-end nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-end nucleobases identified in Table 1.

[0196] An oligonucleotide of the specification may comprise a nucleobase sequence that is complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 45,000 to about nucleobase 70,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 80,000 to about nucleobase 95,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 48,000 to about nucleobase 67,000; from about nucleobase 75,000 to about nucleobase 75,500; from about nucleobase 85,000 to about nucleobase 94,000; or from about nucleobase 100,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0197] In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 50,000 to about nucleobase 60,000; from about nucleobase 90,000 to about nucleobase 95,000; from about nucleobase 100,000 to about nucleobase 105,000; or from about nucleobase 110,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 92,000 to about nucleobase 95,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0198] In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 54,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 104,000; or from about nucleobase 113,000 to about nucleobase 115,200 of SEQ ID NO: 3291. In some particularly preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence that is complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a nucleobase sequence corresponding to from about nucleobase 56,000 to about nucleobase 57,000; from about nucleobase 100,500 to about nucleobase 102,000; or from about nucleobase 113,500 to about nucleobase 115,200 of SEQ ID NO: 3291.

[0199] An oligonucleotide of the specification may comprise a nucleobase sequence that is complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within a region defined by a pair of t-start and t-end nucleobases identified in Table 1. Alternatively, an oligonucleotide of the specification may comprise a nucleobase sequence that is complementary to an equal length portion of at least 10 contiguous nucleobases, preferably at least 12 contiguous nucleobases, more preferably at least 14 contiguous nucleobases within to a region defined by: (i) a t-start nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-start nucleobases identified in Table 1; and / or (ii) a t-end nucleobase that is no more than ± 10 nucleobases, preferably no more than ± 5 nucleobases, no more than ± 4 nucleobases, no more than ± 3 nucleobases, no more than ± 2 nucleobases, or no more than ± 1 nucleobase, from the any of the t-end nucleobases identified in Table 1.

[0200] As defined herein, said equal length portion may be at least about 10, such as at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 15, at least about 20, at least about 25, at least about 30, at least about 40, or at least about 50 contiguous nucleobases. Said equal length portion may be of between about 10 to about 50 (i.e.

[0201] 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, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50) contiguous nucleobases, typically between about 12 to about 50 (i.e. 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50) contiguous nucleobases, such as between about 13 to about 50 contiguous nucleobases, between about 14 to about 50 contiguous nucleobases, between about 15 to about 50 contiguous nucleobases, between about 16 to about 50 contiguous nucleobases, between about 12 to about 40 contiguous nucleobases, such as between about 13 to about 40 contiguous nucleobases, between about 14 to about 40 contiguous nucleobases, between about 15 to about 40 contiguous nucleobases, between about 16 to about 40 contiguous nucleobases, between about 12 to about 30 contiguous nucleobases, such as between about 13 to about 30 contiguous nucleobases, between about 14 to about 30 contiguous nucleobases, between about 15 to about 30 contiguous nucleobases, between about 16 to about 30 contiguous nucleobases, between about 12 to about 25 contiguous nucleobases, such as between about 13 to about 25 contiguous nucleobases, between about 14 to about 25 contiguous nucleobases, between about 15 to about 25 contiguous nucleobases, between about 16 to about 25 contiguous nucleobases. Preferably said equal portion is between about 14 to about 25 (i.e. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25) contiguous nucleobases.

[0202] Exemplary unmodified nucleobase sequences for oligonucleotides of the specification are given in column 2 of Table 1, with the corresponding sequence identifier in column 1. The position of the left-most (5'-most) residue of the corresponding nucleobase sequence in the ARHGEF6 transcript of SEQ ID NO: 3291 which is complementary to a given antisense nucleobase sequence is given in column 3. The position of the right-most (3'-most) residue of the corresponding nucleobase sequence in the ARHGEF6 transcript of SEQ ID NO: 3291 which is complementary to a given antisense nucleobase sequence is given in column 4.

[0203] Exemplary modified nucleobase sequences for oligonucleotides of the specification are given in column 4 of Table 2, with the corresponding sequence identifier in column 3. The compound number is shown in column 1. The sequence identifier for the corresponding unmodified nucleobase sequence is given in column 2. For each modified nucleobase sequence, the sugar composition is given in column 5, the sugar pattern is given in column 6, the linkage composition is given in column 7 and the linkage pattern is given in column 8 in Table 2.

[0204] Preferred exemplary unmodified nucleobase sequences selected for further modification and experimentation are given in Table 3. In Table 3, the unmodified nucleobase sequences are given in column 2 of Table 1, with the corresponding sequence identifier in column 1. The position of the left-most (5'-most) residue of the corresponding nucleobase sequence in the ARHGEF6 transcript of SEQ ID NO: 3291 which is complementary to a given antisense nucleobase sequence is given in column 3. The position of the right-most (3'-most) residue of the corresponding nucleobase sequence in the ARHGEF6 transcript of SEQ ID NO: 3291 which is complementary to a given antisense nucleobase sequence is given in column 4.

[0205] Preferred modified nucleobase sequences with further sugar modifications are given in Table 4. In Table 4, the sequence identifier is given in column 3. The compound number is shown in column 1. The sequence identifier of the corresponding unmodified nucleobase sequence is given in column 2. The sugar composition, sugar pattern, linkage composition and linkage pattern can be found in the corresponding row in Table 2.

[0206] Particularly preferred modified nucleobase sequences with further sugar modifications are given in Table 5. In Table 5, the sequence identifier is given in column 3. The compound number is shown in column 1. The sequence identifier of the corresponding unmodified nucleobase sequence is given in column 2. The sugar composition, sugar pattern, linkage composition and linkage pattern can be found in the corresponding row in Table 2. Preferred exemplary modified nucleobase sequences with further sugar modifications are given in Table 6. In Table 6, the sequence identifier is given in column 3. The compound number is shown in column 1. The sequence identifier of the corresponding unmodified nucleobase sequence is given in column 2. The sugar composition, sugar pattern, linkage composition and linkage pattern can be found in the corresponding row in Table 2.

[0207] Particularly preferred exemplary modified nucleobase sequences with further sugar modifications are given in Table 7. In Table 7, the sequence identifier is given in column 3. The compound number is shown in column 1. The sequence identifier of the corresponding unmodified nucleobase sequence is given in column 2. The sugar composition, sugar pattern, linkage composition and linkage pattern can be found in the corresponding row in Table 2.

[0208] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 1 to 3290.

[0209] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 1 to 1212.

[0210] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 1213 to 3290.

[0211] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; or 1203.

[0212] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0213] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0214] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241. The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0215] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; or 1197.

[0216] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0217] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0218] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236. The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0219] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 718; 912; 975; 1029; 1078; 1090; 1715; 1771; 1864; 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0220] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80%, at least 87%, at least 94% or 100% identical to any of SEQ ID NOs: 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0221] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 1 to 3290.

[0222] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 1 to 1212.

[0223] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 1213 to 3290.

[0224] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; or 1203.

[0225] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0226] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0227] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241. The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0228] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; or 1197.

[0229] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0230] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0231] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0232] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236. The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 718; 912; 975; 1029; 1078; 1090; 1715; 1771; 1864; 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0233] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 80% identical to any of SEQ ID NOs: 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0234] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 1 to 3290.

[0235] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 1 to 1212.

[0236] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 1213 to 3290.

[0237] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; or 1203.

[0238] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290. The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0239] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0240] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0241] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; or 1197.

[0242] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0243] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0244] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0245] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0246] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 718; 912; 975; 1029; 1078; 1090; 1715; 1771; 1864; 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0247] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 87% identical to any of SEQ ID NOs: 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076. The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 1 to 3290.

[0248] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 1 to 1212.

[0249] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 1213 to 3290.

[0250] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; or 1203.

[0251] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0252] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0253] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0254] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241. The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; or 1197.

[0255] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0256] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0257] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0258] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0259] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 718; 912; 975; 1029; 1078; 1090; 1715; 1771; 1864; 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0260] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is at least 94% identical to any of SEQ ID NOs: 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0261] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 or at least 22 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 1 to 3290. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0262] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 or at least 22 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 1 to 1212. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0263] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 or at least 22 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 1213 to 3290. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0264] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; or 1203. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0265] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0266] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17 or at least 18contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0267] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0268] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases ofanyofSEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0269] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; or 1197. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0270] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0271] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0272] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below.

[0273] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below.

[0274] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 718; 912; 975; 1029; 1078; 1090; 1715; 1771; 1864; 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below.

[0275] The nucleobase sequence of the oligonucleotide may have a nucleobase sequence comprising at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076. Where a particular SEQ ID NO has more than specified number of contiguous nucleobases, the additional nucleobases can be disregarded, as discussed in more detail below.

[0276] Where a particular SEQ ID NO has more than specified number of contiguous nucleobases indicated above, the additional nucleobases can be disregarded. By way of nonlimiting example, SEQ ID NO: 3007 is 22 nucleobases in length. As such an oligonucleotide comprising at least 16 contiguous nucleobase sequences from SEQ ID NO: 3007, the remaining 6 nucleobases may be disregarded, such that an oligonucleotide may comprise nucleobases 1 to 16 of SEQ ID NO: 3007 and nucleobases 17 to 22 may be disregarded, an oligonucleotide may comprise nucleobases 2 to 17 of SEQ ID NO: 3007 and nucleobases 1 and 18 to 22 may be disregarded, an oligonucleotide may comprise nucleobases 3 to 18 of SEQ ID NO: 3007 and nucleobases 1, 2 and 19 to 22 may be disregarded, an oligonucleotide may comprise nucleobases 4 to 19 of SEQ ID NO: 3007 and nucleobases 1 to 3 and 20 to 22 may be disregarded, an oligonucleotide may comprise nucleobases 5 to 20 of SEQ ID NO: 3007 and nucleobases 1 to 4, 21 and 22 may be disregarded, an oligonucleotide may comprise nucleobases 6 to 21 of SEQ ID NO: 3007 and nucleobases 1 to 5 and 22 may be disregarded, or an oligonucleotide may comprise nucleobases 7 to 22 of SEQ ID NO: 3007 and nucleobases 1 to 6 may be disregarded.

[0277] Where a particular SEQ ID NO has more than specified number of contiguous nucleobases indicated above, an oligonucleotide may comprise the specified number of nucleobases, up to the total number of nucleobases in a particular SEQ ID NO, as discussed in more detail below. By way of non-limiting example, SEQ ID NO: 2997 is 18 nucleobases in length. As such an oligonucleotide may comprise at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobase sequences from SEQ ID NO: 2997.

[0278] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1 to 3290.

[0279] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1 to 1212.

[0280] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1213 to 3290.

[0281] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; or 1203.

[0282] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0283] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0284] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0285] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0286] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; or 1197.

[0287] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636: 700: 783: 947: 1055:

[0288]

[0289] 1155; 1168; 1197; 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0290] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0291] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0292] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0293] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 718; 912; 975; 1029; 1078; 1090; 1715; 1771; 1864; 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0294] The nucleobase sequence of the oligonucleotide may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0295] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 1 to 3290.

[0296] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 1 to 1212.

[0297] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 1213 to 3290.

[0298] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; or 1203.

[0299] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0300] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0301] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0302] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0303] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; or 1197.

[0304] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0305] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0306] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0307] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0308] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 718; 912; 975; 1029; 1078; 1090; 1715; 1771; 1864; 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0309] The nucleobase sequence of the oligonucleotide may comprise a nucleobase sequence that is identical to any of SEQ ID NOs: 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0310] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1 to 3290. The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1 to 1212.

[0311] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1213 to 3290.

[0312] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; or 1203.

[0313] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0314] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1590; 1592; 1593; 1594; 1595; 1596; 1597; 1598; 1599; 1600; 1601; 1607; 1608; 1609; 1610; 1611; 1612; 1613; 1614; 1615; 1616; 1623; 1626; 1627; 1628; 1631; 1632; 1635; 1636; 1637; 1639; 1640; 1641; 1643; 1644; 1645; 1646; 1647; 1648; 1649; 1650; 1651; 1652; 1653; 1654; 1655; 1656; 1657; 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666; 1667; 1668; 1669; 1670; 1671; 1672; 1673; 1674; 1675; 1676; 1677; 1678; 1679; 1682; 1686; 1687; 1690; 1691; 1858; 1866; 1870; 1886; 1888; 1928; 1929; 1930; 1931; 1988; 1995; 1997; 1998; 2029; 2070; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2089; 2090; 2091; 2092; 2093; 2094; 2095; 2096; 2097; 2098; 2099; 2100; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2113; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2216; 2217; 2218; 2219; 2220; 2221; 2222; 2223; 2224; 2225; 2226; 2227; 2228; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2236; 2238; 2239; 2241; 2242; 2243; 2244; 2245; 2246; 2247; 2248; 2249; 2250; 2251; 2252; 2256; 2257; 2258; 2259; 2260; 2261; 2262; 2263; 2264; 2265; 2267; 2269; 2270; 2271; 2272; 2273; 2274; 2275; 2276; 2277; 2278; 2279; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2317; 2318; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2685; 2686; 2695; 2696; 2703; 2704; 2708; 2715; 2716; 2717; 2718; 2719; 2720; 2721; 2722; 2723; 2724; 2725; 2726; 2727; 2728; 2729; 2730; 2731; 2732; 2733; 2734; 2735; 2736; 2737; 2741; 2742; 2743; 2744; 2745; 2746; 2748; 2749; 2751; 2752; 2753; 2754; 2755; 2756; 2757; 2759; 2760; 2761; 2763; 2764; 2765; 2766; 2772; 2774; 2776; 2777; 2778; 2779; 2780; 2781; 2782; 2783; 2784; 2785; 2786; 2787; 2788; 2789; 2790; 2791; 2792; 2793; 2794; 2795; 2796; 2797; 2798; 2799; 2800; 2801; 2802; 2803; 2804; 2805; 2806; 2807; 2808; 2809; 2810; 2811; 2812; 2813; 2814; 2815; 2816; 2817; 2818; 2819; 2820; 2821; 2822; 2823; 2824; 2825; 2826; 2827; 2828; 2829; 2830; 2831; 2832; 2833; 2834; 2835; 2836; 2837; 2838; 2839; 2840; 2841; 2842; 2843; 2844; 2845; 2846; 2847; 2848; 2850; 2851; 2852; 2853; 2854; 2855; 2856; 2858; 2860; 2862; 2863; 2864; 2866; 2867; 2870; 2872; 2873; 2874; 2875; 2877; 2878; 2879; 2881; 2883; 2884; 2885; 2886; 2888; 2889; 2891; 2893; 2894; 2895; 2896; 2901; 2903; 2905; 2906; 2907; 2908; 2909; 2911; 2913; 2914; 2915; 2916; 2918; 2919; 2920; 2921; 2922; 2923; 2924; 2925; 2927; 2929; 2933; 2934; 2935; 2936; 2937; 2938; 2939; 2940; 2941; 2942; 2943; 2944; 2945; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2956; 2957; 2958; 2959; 2960; 2961; 2962; 2963; 2964; 2965; 2966; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 2995; 2996; 2997; 3000; 3001; 3002; 3011; 3012; 3013; 3014; 3015; 3017; 3020; 3023; 3024; 3025; 3026; 3027; 3028; 3029; 3032; 3033; 3034; 3037; 3038; 3039; 3040; 3041; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3054; 3055; 3056; 3057; 3058; 3059; 3060; 3061; 3062; 3065; 3066; 3067; 3070; 3071; 3072; 3073; 3074; 3075; 3076; 3077; 3080; 3081; 3082; 3083; 3085; 3087; 3088; 3089; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3104; 3105; 3106; 3107; 3108; 3109; 3110; 3111; 3112; 3115; 3116; 3117; 3120; 3121; 3122; 3123; 3124; 3125; 3126; 3127; 3130; 3131; 3132; 3133; 3134; 3136; 3138; 3140; 3142; 3143; 3144; 3145; 3148; 3149; 3150; 3153; 3154; 3155; 3156; 3157; 3158; 3159; 3160; 3163; 3164; 3165; 3179; 3181; 3183; 3185; 3186; 3188; 3189; 3190; 3191; 3194; 3195; 3196; 3199; 3200; 3201; 3202; 3203; 3204; 3205; 3206; 3209; 3210; 3211; 3212; 3213; 3214; 3215; 3216; 3217; 3218; 3219; 3220; 3221; 3222; 3223; 3224; 3225; 3226; 3230; 3231; 3232; 3234; 3235; 3236; 3237; 3238; 3239; 3240; 3241; 3244; 3245; 3246; 3247; 3248; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0315] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0316] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241.

[0317] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; or 1197.

[0318] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0319] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1400; 1531; 1532; 1866; 1886; 1888; 1928; 1929; 1930; 1931; 1995; 2072; 2077; 2078; 2079; 2080; 2081; 2082; 2083; 2084; 2085; 2086; 2087; 2088; 2102; 2103; 2104; 2105; 2106; 2107; 2108; 2109; 2111; 2112; 2114; 2115; 2116; 2117; 2118; 2119; 2120; 2121; 2122; 2123; 2124; 2125; 2140; 2141; 2152; 2153; 2154; 2155; 2156; 2157; 2158; 2159; 2160; 2161; 2162; 2164; 2165; 2166; 2167; 2168; 2169; 2170; 2171; 2172; 2173; 2174; 2176; 2177; 2178; 2179; 2180; 2181; 2182; 2183; 2184; 2185; 2186; 2187; 2188; 2189; 2229; 2230; 2231; 2232; 2233; 2234; 2235; 2238; 2239; 2241; 2242; 2281; 2282; 2283; 2284; 2285; 2286; 2287; 2288; 2289; 2290; 2291; 2293; 2294; 2295; 2296; 2297; 2298; 2299; 2300; 2301; 2302; 2304; 2306; 2307; 2308; 2309; 2310; 2311; 2312; 2313; 2314; 2315; 2316; 2318; 2485; 2593; 2632; 2686; 2695; 2708; 2717; 2720; 2721; 2722; 2725; 2728; 2732; 2733; 2736; 2742; 2743; 2744; 2745; 2749; 2753; 2756; 2763; 2772; 2774; 2777; 2780; 2784; 2785; 2786; 2789; 2792; 2796; 2797; 2798; 2801; 2804; 2808; 2809; 2810; 2813; 2816; 2820; 2821; 2822; 2825; 2831; 2832; 2835; 2838; 2842; 2843; 2846; 2853; 2854; 2855; 2866; 2874; 2881; 2891; 2901; 2903; 2906; 2908; 2911; 2913; 2916; 2927; 2933; 2934; 2935; 2936; 2937; 2939; 2942; 2944; 2946; 2947; 2948; 2949; 2950; 2951; 2952; 2953; 2954; 2955; 2964; 2965; 2967; 2968; 2974; 2976; 2977; 2978; 2979; 2980; 2981; 2982; 2983; 2984; 2986; 2987; 2988; 2990; 2991; 2992; 3026; 3028; 3029; 3032; 3033; 3034; 3038; 3042; 3043; 3044; 3047; 3048; 3049; 3050; 3051; 3052; 3053; 3059; 3061; 3062; 3065; 3066; 3067; 3071; 3075; 3076; 3077; 3090; 3091; 3092; 3093; 3094; 3095; 3096; 3097; 3098; 3099; 3100; 3101; 3102; 3103; 3109; 3111; 3112; 3115; 3116; 3117; 3122; 3125; 3126; 3127; 3130; 3131; 3132; 3142; 3144; 3145; 3148; 3149; 3150; 3154; 3158; 3159; 3160; 3188; 3190; 3191; 3194; 3195; 3196; 3200; 3204; 3205; 3206; 3212; 3213; 3214; 3215; 3216; 3217; 3223; 3225; 3226; 3230; 3231; 3232; 3235; 3236; 3240; 3241; 3244; 3250; 3251; 3252; 3255; 3256; 3257; 3258; 3268; 3269; 3270; 3271; 3272; 3273; 3274; 3275; 3276; 3277; 3278; 3279; 3280; 3281; 3282; 3283; 3284; 3285; 3286; 3287; 3288; 3289; or 3290.

[0320] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0321] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

[0322] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 718; 912; 975; 1029; 1078; 1090; 1715; 1771; 1864; 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0323] The nucleobase sequence of the oligonucleotide may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 1930; 2124; 2187; 2241; 2290; 2302; 2927; 2983; or 3076.

[0324] An oligonucleotide of the specification may have a nucleobase sequence of any compound as shown in any one of Tables 1 to 7. Preferably, an oligonucleotide of the specification may have a nucleobase sequence of any compound as shown in any one of Tables 7.

[0325] An oligonucleotide of the specification may have a nucleobase sequence of any compound as shown in any one of Tables 2 or 4 to 7. Preferably, an oligonucleotide of the specification may have a nucleobase sequence of any compound as shown in any one of Tables 4 to 7, more preferably Table 5 or 7, yet more preferably Table 7.

[0326] It is possible to increase or decrease the length of an oligonucleotide without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNAin an oocyte injection model. Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target RNA, albeit to a lesser extent than the oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.

[0327] Accordingly, oligonucleotides of the specification can have any of a variety of ranges of lengths. In certain embodiments, oligonucleotides consist of Xto Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range. In certain such embodiments, X and Y are each independently selected from 8, 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, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; provided that X≤Y. For example, in certain embodiments, oligonucleotides consist of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 16 to 22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 17 to 18, 17 to 19, 17 to 20, 17 to 21, 17 to 22, 17 to 23, 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to 28, 17 to 29, 17 to 30, 18 to 19, 18 to 20, 18 to 21, 18 to 22, 18 to 23, 18 to 24, 18 to 25, 18 to 26, 18 to 27, 18 to 28, 18 to 29, 18 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24, 19 to 25, 19 to 26, 19 to 29, 19 to 28, 19 to 29, 19 to 30, 20 to 21, 20 to 22, 20 to 23, 20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28, 20 to 29, 20 to 30, 21 to 22, 21 to 23, 21 to 24, 21 to 25, 21 to 26, 21 to 27, 21 to 28, 21 to 29, 21 to 30, 22 to 23, 22 to 24, 22 to 25, 22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25, 23 to 26, 23 to 27, 23 to 28, 23 to 29, 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides.

[0328] In particular, an oligonucleotide of the specification may comprise a nucleobase sequence that consists of between 10 to 50, 10 to 40, 10 to 30, 10 to 25, 10 to 25, 12 to 50, 12 to 40, 12 to 30, 11 to 25, 12 to 25, 14 to 25, 15 to 25, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, or 15 to 20 linked nucleosides, preferably of between 14 to 25 linked nucleosides. In some preferred embodiments, an oligonucleotide of the specification may comprise a nucleobase sequence of between 14 to 25 linked nucleosides. In other words, an oligonucleotide of the specification may comprise a nucleobase sequence of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleosides.

[0329] An oligonucleotide of the specification may be selective for ARHGEF6 mRNA, i.e. it may have perfect complementary only to ARHGEF6 mRNA, for example human ARHGEF6.

[0330] An oligonucleotide of the specification does not comprise or consist of GTATTAGCAGCACTAA (SEQ ID NO: 3292); TGTACCATGTAGCTAT (SEQ ID NO: 3293); AATGTGCATACTTCCT (SEQ ID NO: 3294); GATGGTTTGCACAGTA (SEQ ID NO. 3295); GGTTTGCACAGTAAGC (SEQ ID NO. 3296); GGATGGTTTGCACAGT (SEQ ID NO. 3297); or TACAGTTTTCTTGGTC (SEQ ID NO. 3298) or the modified 3-10-3 LNA-DNA-LNA versions thereof, corresponding to SEQ ID Nos: 3299 to 3305 respectively.

[0331] Modifications

[0332] One or more nucleoside within an oligonucleotide of the specification may be a modified nucleoside as described herein.

[0333] Modified nucleosides may comprise a modified sugar moiety or a modified nucleobase or both a modified sugar moiety and a modified nucleobase. Modified nucleosides comprising the following modified sugar moieties and / or the following modified nucleobases may be incorporated into an oligonucleotide of the specification. An oligonucleotide comprising one or more modified nucleoside may be referred to as a modified oligonucleotide. Thus, an oligonucleotide of the specification comprising one or more modified nucleotide may be referred to as a modified oligonucleotide. Accordingly, and for the avoidance of doubt, any reference herein to an oligonucleotide of the specification encompasses a modified oligonucleotide of the specification unless expressly stated to the contrary.

[0334] Modified Sugars

[0335] In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.

[0336] In any of the oligonucleotides described herein, at least one nucleoside may comprise a modified sugar moiety.

[0337] Examples of suitable modified sugar moieties include, but are not limited to, a non-bicyclic sugar moiety, such as a 2’-MOE sugar moiety, a 2’-F sugar moiety, a 2’-OMe sugar moiety, a 2’-NMA sugar moiety, a glycol nucleic acid (GNA), a threose nucleic acid (TNA), a morpholino nucleic acid (PMO), a or 2’-MOEOE modified sugar moiety; and / or a bicyclic sugar moiety, such as a LNA, a cEt modified sugar moiety, a BNA, an ENA or 2’-4’ bridge selected from -O-CH2-; and -O-CH(CH3)-.

[0338] Modification of at least one nucleoside with a non-bicyclic sugar moiety may be preferred. A non-bicyclic modified sugar moiety may be selected from 2’-MOE sugar moiety, a 2’-F sugar moiety, a 2’-OMe sugar moiety, a 2’-NMA sugar moiety, a glycol nucleic acid (GNA), a threose nucleic acid (TNA), a morpholino nucleic acid (PMO), or a 2’-MOEOE modified sugar moiety. Preferably, a non-bicyclic modified sugar moiety may be selected from a 2’-OMe modified sugar moiety, a 2’-MOE modified sugar moiety, a 2’-F modified sugar moiety, and / or a 2’- NMA modified sugar moiety. More preferably, a non-bicyclic modified sugar moiety may be selected from a 2’-OMe modified sugar moiety and / or a 2’-MOE modified sugar moiety.

[0339] Alternatively or in addition, modification of at least one nucleoside with a bicyclic sugar moiety may be preferred. A bicyclic modified sugar moiety may be selected from a LNA, a cEt modified sugar moiety, a BNA, an ENAor2’-4’ bridge selected from -O-CH2-; and -O-CH(CH3)-. Preferably, a bicyclic modified sugar moiety may be selected from a BNA, an LNA and / or a cEt modified sugar moiety. More preferably, a bicyclic modified sugar moiety may be selected from an LNA and / or a cEt modified sugar moiety.

[0340] Modification of at least one nucleoside with a non-bicyclic sugar moiety and at least one nucleoside with a bicyclic sugar moiety may be particularly preferred.

[0341] In any of the oligonucleotides described herein, at least one nucleoside may comprise a locked nucleic acid (LNA). In other words, one or more nucleobase within an oligonucleotide of the specification may have a backbone in which the furanosyl sugar moiety comprises a 2'-O, 4'-C methylene linkage, such that the furanosyl sugar moiety is locked in an RNA-like (C3’-endo) conformation:

[0342]

[0343] where B represents any nucleobase.

[0344] In any of the oligonucleotides described herein, at least one nucleoside may comprise a sugar surrogate. Examples of suitable sugar surrogates include, but are not limited to, morpholino (PMO), peptide nucleic acid (PNA), glycol nucleic acid (GNA), and unlocked nucleic acid (UNA).

[0345] In any of the oligonucleotides described herein, at least one nucleoside may comprise a xeno nucleic acid (XNA). In other words, one or more nucleobase within an oligonucleotide of the specification may have with a backbone constructed from sugars that are distinct from the natural ribose sugars found in RNA. Inclusion of one or more XNA may improve the off-target profile of the oligonucleotide, i.e. may decrease off-target binding. Examples of suitable XNA include, but are not limited to, unlocked nucleic acids (UNA), glycol nucleic acids (GNA), DNA, 2'-deoxy-2'-fluoro-arabinonucleic acids (2’F-ANA), threose nucleic acids (TNA), serinol nucleic acids (SNA), flexible nucleic acids (FNA), 2’NH2-RNA, 1’,2’-seco-DNA, 3(S),5-dihydroxypentyl nucleic acids, or a nucleoside analogue comprising a six-membered tetrahydropyran (THP, e.g. a hexitol nucleic acid (HNA), arabinonucleic nucleic acid (ANA), altritol nucleic acid, or mannitol nucleic acid (MNA). In some preferred embodiments, the XNA is a GNA, UNA or DNA.

[0346] In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties comprising a furanosyl ring with one or mor...

Claims

1. CLAIMS1. An oligonucleotide comprising a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 1 to 37,380; 37,397 to 73,959; 73,977 to 75,731; 75,752 to 115,303; 115,320 to 116,399; or 116,416 to 117,742 of SEQ ID NO: 3291.

2. The oligonucleotide of claim 1, comprising a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 45,000 to 70,000; 75,000 to 75,500; 80,000 to 95,000; or 100,000 to 115,200 of SEQ ID NO: 3291, particularly nucleobases 48,000 to 67,000; 75,000 to 75,500; 85,000 to 94,000; or 100,000 to 115,200 of SEQ ID NO: 3291.

3. The oligonucleotide of claim 2, wherein the oligonucleotide comprises a nucleobase sequence that is at least 80%, at least 87%, at least 94%, or 100% complementary to said equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 45,000 to 70,000; 75,000 to 75,500; 80,000 to 95,000; or 100,000 to 115,200 of SEQ ID NO: 3291, particularly nucleobases 48,000 to 67,000; 75,000 to 75,500; 85,000 to 94,000; or 100,000 to 115,200 of SEQ ID NO: 3291.

4. The oligonucleotide of any one of the preceding claims, comprising a nucleobase sequence that is at least 80% complementary to an equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 50,000 to 60,000; 90,000 to 95,000; 100,000 to 105,000; or 110,000 to 115,200 of SEQ ID NO: 3291, particularly nucleobases 54,000 to 57,000; 92,000 to 95,000; 100,500 to 104,000; or 113,000 to 115,200 of SEQ ID NO: 3291.

5. The oligonucleotide of claim 4, wherein the oligonucleotide comprises a nucleobase sequence that is at least 80%, at least 87%, at least 94%, or 100% complementary to said equal length portion of at least 12 contiguous nucleobases within a nucleobase sequence corresponding to nucleobases 50,000 to 60,000; 90,000 to 95,000; 100,000 to 105,000; or 110,000 to 115,200 of SEQ ID NO: 3291, particularly nucleobases 54,000 to 57,000; 92,000 to 95,000; 100,500 to 104,000; or 113,000 to 115,200 of SEQ ID NO: 3291.

6. The oligonucleotide of any one of the preceding claims, wherein the equal length portion is of between about 12 to about 50 contiguous nucleobases, preferably between about 14 to about 25 contiguous nucleobases.

7. The oligonucleotide of any one of the preceding claims, wherein the oligonucleotide comprises or consists of a nucleobase sequence that is at least 80%, at least 87%, at least 94%, or 100% identical to any of SEQ ID NOs: 1-3290, preferably any one of SEQ ID Nos: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241; more preferably any one of SEQ ID Nos: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

8. The oligonucleotide of any one of the preceding claims, wherein the oligonucleotide has a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or at least 21 contiguous nucleobases, particularly 14, 15, or 16 contiguous nucleobases of any of the nucleobase sequences of any of SEQ ID NOs: 1-3290, preferably any one of SEQ ID Nos: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155;1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241; more preferably any one of SEQ ID Nos: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

9. The oligonucleotide of any one of the preceding claims, wherein the oligonucleotide comprises the nucleobase sequences of any of SEQ ID NOs: 1-3290, preferably any one of SEQ ID Nos: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241; more preferably any one of SEQ ID Nos: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

10. The oligonucleotide of claim of any one of the preceding claims, wherein the oligonucleotide consists of the nucleobase sequences of any of SEQ ID NOs: 1-3290, preferably any one of SEQ ID Nos: 37; 148; 188; 212; 213; 242; 290; 310; 318; 319; 320; 334; 346; 563; 571; 575; 591; 593; 633; 634; 635; 636; 693; 700; 702; 703; 734; 775; 782; 783; 803; 879; 886; 890; 901; 905; 934; 935; 943; 947; 956; 976; 981; 982; 983; 1000; 1001; 1002; 1051; 1055; 1056; 1079; 1083; 1086; 1087; 1094; 1095; 1097; 1103; 1104; 1106; 1131; 1155; 1156; 1163; 1164; 1168; 1175; 1181; 1184; 1194; 1197; 1198; 1201; 1202; 1203; 1249; 1360; 1400; 1424; 1425; 1454; 1502; 1522; 1530; 1531; 1532; 1546; 1558; 1627; 1639; 1641; 1672; 1674; 1687; 1858; 1870; 1928; 1929; 1930; 1931; 2029; 2072; 2078; 2094; 2096; 2097; 2098; 2099; 2109; 2112; 2114; 2124; 2166; 2187; 2241; 2258; 2276; 2286; 2290; 2299; 2302; 2308; 2310; 2417; 2424; 2428; 2439; 2443; 2472; 2473; 2481; 2485; 2494; 2514; 2519; 2520; 2521; 2538; 2539; 2540; 2589; 2593; 2594; 2617; 2621; 2624; 2625; 2632; 2633; 2635; 2641; 2642; 2644; 2669; 2695; 2696; 2703; 2704; 2708; 2717; 2722; 2725; 2732; 2737; 2742; 2745; 2746; 2752; 2759; 2760; 2763; 2777; 2785; 2789; 2804; 2832; 2858; 2873; 2874; 2885; 2918; 2921; 2927; 2938; 2943; 2944; 2946; 2956; 2957; 2966; 2967; 2977; 2983; 2995; 2997; 3012; 3024; 3026; 3049; 3052; 3061; 3070; 3076; 3083; 3090; 3095; 3183; 3205; 3213; 3214; 3236; or 3241; more preferably any one of SEQ ID Nos: 188; 319; 320; 571; 591; 593; 633; 634; 635; 636; 700; 783; 947; 1055; 1094; 1155; 1168; 1197; 1400; 1531; 1929; 1930; 1931; 2072; 2114; 2124; 2187; 2241; 2290; 2302; 2308; 2593; 2632; 2708; 2717; 2722; 2725; 2745; 2763; 2874; 2927; 2977; 2983; 3026; 3049; 3061; 3076; 3090; 3205; or 3236.

11. The oligonucleotide of any one of the preceding claims, wherein the nucleobases sequence consists of between 12 to 50, 12 to 40, 12 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 12 to 20, 13 to 20, 14 to 20, or 15 to 20 linked nucleosides, preferably of between 14 to 25 linked nucleosides.

12. The oligonucleotide of any one of the preceding claims, which comprises at least one modification, optionally at least one modified sugar moiety.

13. The oligonucleotide of claim 12, wherein the modified sugar moiety comprises a bicyclic sugar moiety.

14. The oligonucleotide of claim 13, wherein the bicyclic modified sugar moiety comprises:(a) a 2’-4’ bridge selected from -O-CH2- and -O-CH(CH3)-; and / or (b) a LNA, a cEt modified sugar moiety, a BNA and / or an ENA.

15. The oligonucleotide of claim 12, wherein the modified sugar moiety comprises a non- bicyclic sugar moiety.

16. The oligonucleotide of claim 15, wherein the non-bicyclic modified sugar moiety is a 2’-OMe modified sugar moiety, a 2’-MOE modified sugar moiety, a 2’-F modified sugar moiety, a glycol nucleic acid (GNA), a threose nucleic acid (TNA), a morpholino nucleic acid (PMO), a 2’-MOEOE modified sugar moiety and / or a 2’- NMA modified sugar moiety.

17. The oligonucleotide of claim 15 or 16, wherein the non-bicyclic modified sugar moiety is a 2’-OMe modified sugar moiety and / or a 2’-MOE modified sugar moiety.

18. The oligonucleotide of any one of claims 15 to 17, which comprises:18.(a) at least one LNA;19.(b) at least one LNA and at least one 2’-OMe modified sugar moiety;20.(c) at least one LNA and at least one 2’-MOE modified sugar moiety;21.(d) at least one LNA, at least one 2’-OMe modified sugar moiety and at least one 2’- MOE modified sugar moiety;22.(e) at least one 2’-MOE modified sugar moiety;23.(f) at least one cEt modified sugar moiety;24.(g) at least one cEt modified sugar moiety and at least one 2’-MOE modified sugar moiety;25.(h) at least one cEt modified sugar moiety and at least one 2’- OMe modified sugar moiety; or26.(i) at least one cEt modified sugar moiety, at least one 2’-OMe modified sugar moiety and at least one 2’-MOE modified sugar moiety.

19. The oligonucleotide of any one of the preceding claims, which comprises:28.(d) a 5 '-region consisting of 1-5 linked 5 '-region nucleosides;29.(e) a central region consisting of 9-12 linked central region nucleosides; and30.(f) a 3 '-region consisting of 2-5 linked 3 '-region nucleosides; wherein:31.(iii) each of the 5 '-region nucleosides and each of the 3 '-region nucleosides comprises a modified sugar moiety; and32.(iv) at most two of the central region nucleosides comprises a modified sugar moiety and the remainder of the central region nucleosides comprises an unmodified 2' -deoxyribosyl sugar moiety.

20. The oligonucleotide of any one of the preceding claims, which comprises or consists of:34.(a) 5’ [cEt]a[dR]10[cEt]a3’;35.(b) 5’ [cEt]b[mR][dR]9[cEt]c3’;36.(c) 5’ [cEt]2[dR]9[MOE][cEt]43’;37.(d) 5’ [cEt]3[dR]d[mR][dR]e[cEt]33’;38.(e) 5’ [cEt]2[MOE][cEt][dR]9[cEt]33’;39.(f) 5’ [cEt]2[MOE][cEt][mR][dR]8[cEt]33’;40.(g) 5’ [LR]a[dR]f[LR]a3’;41.(h) 5’ [LR]a[dR]9[LR]a[MOE]d3’;42.(i) 5’ [LR]a[dR]9[LR]d[MOE][LR]g3’;43.(j) 5’ [LR]2[dR]9[LR][MOE][LR][MOE][LR] 3’;44.(k) 5’ [LR]a[dR]9[MOE][LR]a3’;45.(l) 5’ [LR]a[dR]h[mR][dR]i[LR]a3’;46.(m) 5’ [LR]3[dR]2[mR][dR]6[LR]3[MOE] 3’;47.(n) 5’ [LR]3[dR]d[mR][dR]j[LR]d[MOE][LR]d 3’;48.(o) 5’ [LR]3[dR][mR][dR]7[MOE][LR]33’;49.(p) 5’ [LR]a[MOE][dR]9[LR]a3’;50.(q) 5’ [LR]3[MOE][dR][mR][dR]7[LR]33’;51.(r) 5’ [LR]g[MOE][LR]d[dR]9[LR]a3’;52.(s) 5’ [LR]d[MOE][LR]d[dR]d[mR][dR]j[LR]33’;53.(t) 5’ [LR]d[MOE][LR]d[mR][dR]8[LR]33’;54.(u) 5’ [LR]3[MOE][mR][dR]8[LR]33’;55.(v) 5’ [LR]a[mR][dR]9[LR]a3’;56.(w) 5’ [LR]3[mR][dR]8[LR]3[MOE] 3’;57.(x) 5’ [LR]3[mR][dR]8[LR]2[MOE][LR] 3’;58.(y) 5’ [LR]3[mR][dR]8[MOE][LR]33’;59.(z) 5’ [MOE]5[dR]f[MOE]53’; (aa) 5’ [MOE][LR]a[dR]9[LR]a3’; or60.(bb) 5’ [MOE][LR]3[dR][mR][dR]7[LR]33’;61.wherein [cEt] stands for a constrained ethyl modified nucleotide, [LR] stands for a LNA, [dR] stands for a deoxyribonucleotide, [mR] stands for a 2’-0Me modified nucleotide and [MOE] stands for a 2’-M0E modified nucleotide; and62.wherein:63.a is 2, 3 or 464.b is 2 or 365.c is 3 or 466.d is 1 or 267.e is 7 or 868.f is 8, 9, 10, 11 or 1269.g is 1, 2 or 370.h is 1, 2, 3 or 471.i is 5, 6, 7 or 872.j is 6 or 7.

21. The oligonucleotide of claim 19 or 20, which comprises or consists of:74.(a) a 5 '-region consisting of 2 linked 5 '-region nucleosides;75.(b) a central region consisting of 10 linked central region nucleosides; and76.(c) a 3 '-region consisting of 4 linked 3 '-region nucleosides;77.wherein optionally one of the central region nucleosides comprises a non-bicyclic modified sugar moiety, preferably a 2’-OMe modified sugar moiety or a 2’-MOE modified sugar moiety.

22. The oligonucleotide of any one of the preceding claims, which comprises at least one modified internucleoside linkage.

23. The oligonucleotide of claim 22, wherein the at least one modified internucleoside linkage is a phosphorothioate (PS) internucleoside linkage, a N3' —> P5' phosphoramidite (PN) internucleoside linkage or a mesylphosphoramidate (MsPA) linkage.

24. The oligonucleotide of claim 22 or 23, wherein each internucleoside linkage is independently selected from a phosphodiester or a phosphorothioate internucleoside linkage.

25. The oligonucleotide of any one of claims 22 to 24, wherein:81.(a) each internucleoside linkage of the oligonucleotide is a modified internucleoside linkage, optionally a phosphorothioate internucleoside linkage; or82.(b) the oligonucleotide comprises at least one phosphodiester internucleoside linkage.

26. The oligonucleotide of any one of claims 19 to 22, wherein:84.(a) at least 10, at least 11, at least 12, at least 13, at least 14 or more of the internucleoside linkages of the oligonucleotide are phosphorothioate internucleoside linkages; and / or85.(b) all of the internucleoside of the oligonucleotide are phosphorothioate internucleoside linkages.

27. The oligonucleotide of any one of claims 19 to 23, wherein:87.(a) the oligonucleotide comprises at least 1 modified internucleoside linkage at the 5’ end; and / or88.(b) the oligonucleotide comprises at least 1 modified internucleoside linkage at the 3’ end.

28. The oligonucleotide of any one of claims 19 to 24, wherein the internucleoside linkages are arranged:90.(c) 5’ [PS]d[P]k[PS]i[P]g[PS]d3’; or91.(d) 5’ [PS]m[P]h[PS]n 3’;92.wherein [PS] stands for a phosphorothioate internucleoside linkage, and [P] stands for a phosphodiester internucleoside linkage; and93.wherein:94.d is 1 or 295.g is 1, 2 or 396.h is 1, 2, 3 or 4 k is 1, 2 or 497.I is 9, 10 or 1198.m is 1, 2, 3 or 1299.n is 1, 12, 13, 14 or 15.

29. The oligonucleotide of any one of the preceding claims, which comprises at least one modified nucleobase, optionally selected from 5-methylcytosine or methyl-uracil, G- clamp, 8-methylguanine, 2-aminopurine (2-AP) and inosine.

30. The oligonucleotide of any one of the preceding claims, which is a single-stranded oligonucleotide.

31. A polynucleotide conjugate comprising an oligonucleotide of any one of the preceding claims and a conjugate group.

32. The polynucleotide conjugate of claim 31, wherein the conjugate group comprises a conjugate linker and a conjugate moiety.

33. The polynucleotide conjugate of claim 32, wherein the conjugate linker consists of a single bond.

34. The polynucleotide conjugate of claim 32 or 33, wherein the conjugate linker is cleavable.

35. The polynucleotide conjugate of any one of claims 31 to 34, wherein the conjugate linker comprises 1 to 3 linker-nucleosides.

36. The polynucleotide conjugate of any one of claims 31 to 35, wherein the conjugate linker is a phosphate.

37. The polynucleotide conjugate of any one of claims 31 to 36, wherein the conjugate group is attached to the oligonucleotide at the 5’-end of the oligonucleotide.

38. The polynucleotide conjugate of any one of claims 31 to 36, wherein the conjugate group is attached to the oligonucleotide at the 3’-end of the oligonucleotide.

39. The polynucleotide conjugate of any one of claims 31 to 38, wherein the conjugate group comprises a cell-targeting moiety.

40. The polynucleotide conjugate of any one of claims 31 to 39, which comprises a nonnucleoside terminal group.

41. The polynucleotide conjugate of claim 40, wherein the terminal group is an abasic sugar moiety.

42. A chirally enriched population of oligonucleotide as defined in any one of claims 1-30, or the polynucleotide conjugates as defined in any of claims 31 to 41, wherein the population is enriched for oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration, or polynucleotide conjugates comprising said oligonucleotides.

43. The chirally enriched population of claim 42, wherein the population is enriched for oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) or (Rp) configuration, or polynucleotide conjugates comprising said oligonucleotides.

44. The chirally enriched population of claim 42, wherein the population is enriched for oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage, or polynucleotide conjugates comprising said oligonucleotides.

45. The chirally enriched population of claim 42, wherein the population is enriched for oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages, or polynucleotide conjugates comprising said oligonucleotides.

46. The chirally enriched population of claim 42, wherein the population is enriched for oligonucleotides having at least 2 or at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5’ to 3’ direction, or polynucleotide conjugates comprising said oligonucleotides.

47. A population of oligonucleotides comprising oligonucleotides as defined in any one of claims 1-30, or the polynucleotide conjugates as defined in any of claims 31 to 41, wherein all of the phosphorothioate internucleoside linkages of the oligonucleotides are stereorandom.

48. A pharmaceutical composition comprising an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, or a population as defined in any one of claims 42 to 47 and a pharmaceutically acceptable diluent or carrier.

49. The pharmaceutical composition of claim 48, wherein the pharmaceutically acceptable diluent is water or phosphate-buffered saline.

50. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition consists essentially of an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, or a population as defined in any one of claims 42 to 47, and water or phosphate-buffered saline.

51. A method comprising administering to a subject an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, a population as defined in any one of claims 42 to 47, or a pharmaceutical composition as defined in any one of claims 48 to 50.

52. A method of treating or preventing a disease associated with ARHGEF6 comprising administering to a subject having a disease associated with ARHGEF6 a therapeutically effective amount of an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, a population as defined in any one of claims 42 to 47 or a pharmaceutical composition as defined in any one of claims 48 to 50; thereby treating or preventing the disease associated with ARHGEF6.

53. A method of reducing ARHGEF6 RNA or ARHGEF6 protein in a kidney of a subject having or at risk of developing a kidney disease or condition comprising administering a therapeutically effective amount of an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, a population as defined in any one of claims 42 to 47, or a pharmaceutical compositionas defined in any one of claims 48 to 50 to the subject, thereby reducing ARHGEF6 RNA or ARHGEF6 protein in the kidney.

54. The method of claim 52, wherein the disease associated with ARHGEF6 is a kidney condition.

55. The method of claim 53 or 54, wherein the kidney condition is chronic kidney disease (CKD), optionally end-stage kidney disease (ESKD).

56. The method of claim 55, wherein the subject is diagnosed as having:126.(a) Hypertensive Nephrosclerosis, Glomerular Diseases to include but not limited to diabetic kidney disease (DKD), Focal Segmental Glomerulosclerosis (FSGS), Alport Syndrome, Membranous Nephropathy (MN), Minimal Change Disease (MCD), Lupus Nephritis, IgA Nephropathy (IgAN), Membranoproliferative Glomerulonephritis (MPGN), Renal Vasculitis, Anti-glomerular basement membrane disease (Anti-GBM Disease), Paraprotein-Related Kidney Disease, C3 Glomerulopathy (C3G); and / or127.(b) DN (diabetic nephropathy), FSGS (focal segmental glomerulosclerosis), HTN (renal hypertension), IgAN (IgA nephropathy I Berger’s disease), RPGN (rapidly progressive glomerulonephritis) and / or SLE (systemic lupus erythematosus).

57. The method of any one of claims 51 to 56, wherein the administering comprises oral administration, intravenous administration or intramuscular administration.

58. The method of any one of claims 51 to 57, wherein at least one symptom or hallmark of the kidney condition is ameliorated.

59. The method of claim 58, wherein the symptom or hallmark is selected from high blood pressure, urinary tract infection, loss of kidney function, low blood count, malnutrition, bone pain, unusual pain, numbness or tingling, decreased mental sharpness, anaemia, decreased appetite, bone disease, abnormal blood levels of phosphorus, calcium or vitamin D, uraemia, fatigue, shortness of breath, nausea, vomiting, abnormal thyroid levels, swelling in hands / legs / eyes / lower back and lower back pain;131.optionally wherein the symptom or hallmark is selected from: (a) high blood pressure, swelling in hands / legs / eyes / lower back and loss of kidney function; and / or132.(b) anaemia, abnormal blood levels of phosphorus, calcium or vitamin D, fatigue, shortness of breath, nausea and vomiting.

60. The method of any one of claims 51 to 59, wherein the method prevents or slows disease progression.

61. The method of any one of claims 51 to 60, wherein the method of treatment is indicated on the basis of measured GFR, eGFR or UACR obtained from a sample from a subject that indicates the subject has chronic kidney disease.

62. The method of claim 61, wherein the subject has a measured eGFR or GFR of < 70mL / min / 1.73 m2or has a measured UACR of > 30mg / g.

63. An oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, a population as defined in any one of claims 42 to 47 or a pharmaceutical composition as defined in any one of claims 48 to 50 for use in a method of treating or preventing a disease associated with ARHGEF6 in a subject.

64. An oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, a population as defined in any one of claims 42 to 47 or a pharmaceutical composition as defined in any one of claims 48 to 50 for use in a method of reducing ARHGEF6 RNA or ARHGEF6 protein in a kidney of a subject having or at risk of developing a kidney disease or condition.

65. The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use of claim 63, wherein the disease associated with ARHGEF6 is a kidney condition.

66. The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use of claim 64 or 65, wherein the kidney condition is chronic kidney disease (CKD), optionally end stage kidney disease (ESKD).

67. The method of claim 55, wherein the subject is diagnosed as having:(a) Hypertensive Nephrosclerosis, Glomerular Diseases to include but not limited to diabetic kidney disease (DKD), Focal Segmental Glomerulosclerosis (FSGS), Alport Syndrome, Membranous Nephropathy (MN), Minimal Change Disease (MCD), Lupus Nephritis, IgA Nephropathy (IgAN), Membranoproliferative Glomerulonephritis (MPGN), Renal Vasculitis, Anti-glomerular basement membrane disease (Anti-GBM Disease), Paraprotein-Related Kidney Disease, C3 Glomerulopathy (C3G); and / or141.(b) DN (diabetic nephropathy), FSGS (focal segmental glomerulosclerosis), HTN (renal hypertension), IgAN (IgA nephropathy I Berger’s disease), RPGN (rapidly progressive glomerulonephritis) and / or SLE (systemic lupus erythematosus).

68. The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use of any one of claims 63 to 67, wherein the oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition is administered by oral administration, intravenous administration or intramuscular administration.

69. The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use of any one of claims 63 to 68, wherein at least one symptom or hallmark of the kidney condition is ameliorated.

70. The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use of claim 69, wherein the symptom or hallmark is selected from high blood pressure, urinary tract infection, loss of kidney function, low blood count, malnutrition, bone pain, unusual pain, numbness or tingling, decreased mental sharpness, anaemia, decreased appetite, bone disease, abnormal blood levels of phosphorus, calcium or vitamin D, uraemia, fatigue, shortness of breath, nausea, vomiting, abnormal thyroid levels, swelling in hands / legs / eyes / lower back and lower back pain;145.optionally wherein the symptom or hallmark is selected from:146.(a) high blood pressure, swelling in hands / legs / eyes / lower back and loss of kidney function; and / or147.(b) anaemia, abnormal blood levels of phosphorus, calcium or vitamin D, fatigue, shortness of breath, nausea and vomiting.

71. The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use of any one of claims 63 to 70, wherein the method prevents or slows disease progression.

72. The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use of any one of claims 63 to 71, wherein the method of treatment is indicated on the basis of measured GFR, eGFR or UACR obtained from a sample from a subject that indicates the subject has chronic kidney disease.

73. The oligonucleotide, polynucleotide conjugate, population or pharmaceutical composition for use of claim 72, wherein the subject has a measured eGFR or GFR of < 70mL / min / 1.73 m2or has a measured UACR of > 30mg / g.

74. Use of an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41 or a population as defined in any one of claims 42 to 47 for use in the manufacture of a medicament for treating or preventing a disease associated with ARHGEF6 in a subject.

75. Use of an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41 or a population as defined in any one of claims 42 to 47 for use in the manufacture of a medicament for use in a method of reducing ARHGEF6 RNA or ARHGEF6 protein in a kidney of a subject having or at risk of developing a kidney disease or condition.

76. The use of claim 74, wherein the disease associated with ARHGEF6 is a kidney condition.

77. The use of claim 73 or 74, wherein the kidney condition is chronic kidney disease (CKD), optionally end stage kidney disease (ESKD).

78. The method of claim 77, wherein the subject is diagnosed as having:155.(a) Hypertensive Nephrosclerosis, Glomerular Diseases to include but not limited to diabetic kidney disease (DKD), Focal Segmental Glomerulosclerosis (FSGS), Alport Syndrome, Membranous Nephropathy (MN), Minimal Change Disease (MCD), Lupus Nephritis, IgA Nephropathy (IgAN), Membranoproliferative Glomerulonephritis (MPGN), Renal Vasculitis, Anti-glomerular basement membrane disease (Anti-GBM Disease), Paraprotein-Related Kidney Disease, C3 Glomerulopathy (C3G); and / or156.(b) DN (diabetic nephropathy), FSGS (focal segmental glomerulosclerosis), HTN (renal hypertension), IgAN (IgA nephropathy I Berger’s disease), RPGN (rapidly progressive glomerulonephritis) and / or SLE (systemic lupus erythematosus).

79. The use of any one of claims 74 to 78, wherein the medicament is administered by oral administration, intravenous administration or intramuscular administration.

80. The use of any one of claims 74 to 79, wherein at least one symptom or hallmark of the kidney condition is ameliorated.

81. The use of claim 80, wherein the symptom or hallmark is selected from high blood pressure, urinary tract infection, loss of kidney function, low blood count, malnutrition, bone pain, unusual pain, numbness or tingling, decreased mental sharpness, anaemia, decreased appetite, bone disease, abnormal blood levels of phosphorus, calcium or vitamin D, uraemia, fatigue, shortness of breath, nausea, vomiting, abnormal thyroid levels, swelling in hands / legs / eyes / lower back and lower back pain;160.optionally wherein the symptom or hallmark is selected from:161.(a) high blood pressure, swelling in hands / legs / eyes / lower back and loss of kidney function; and / or162.(b) anaemia, abnormal blood levels of phosphorus, calcium or vitamin D, fatigue, shortness of breath, nausea and vomiting.

82. The use of any one of claims 74 to 81, wherein the method prevents or slows disease progression.

83. The use of any one of claims 74 to 81, wherein the method of treatment is indicated on the basis of measured GFR, eGFR or UACR obtained from a sample from a subject that indicates the subject has chronic kidney disease.

84. The use of claim 83, wherein the subject has a measured eGFR or GFR of < 70mL / min / 1.73 m2or has a measured UACR of > 30mg / g.

85. An article of manufacture comprising an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, apopulation as defined in any one of claims 42 to 47 or a pharmaceutical composition as defined in any one of claims 48 to 50.

86. A kit comprising an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, a population as defined in any one of claims 42 to 47 or a pharmaceutical composition as defined in any one of claims 48 to 50, optionally further comprising instructions for use.

87. A method of reducing expression of ARHGEF6 in a cell comprising contacting the cell with an oligonucleotide as defined in any one of claims 1 to 30, a polynucleotide conjugate as defined in any one of claims 31 to 41, a population as defined in any one of claims 42 to 47, or a pharmaceutical composition as defined in any one of claims 48 to 50.

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