Treatment of dkk2 related diseases and disorders

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets DKK2. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of decreasing DKK2 expression by providing an oligonucleotide that targets DKK2 to a subject in need thereof. Some embodiments include methods of treating hair loss by providing the oligonucleotide.

Description

TREATMENT OF DKK2 RELATED DISEASES AND DISORDERSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 433,948 filed on December 20, 2022, which is incorporated by reference herein in its entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 54462-748_601_SL.xml, created November 17, 2023, which is 15,354,114 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0003] Alopecia (hair loss) is ever abundant, and affects many people. Improved therapeutics are needed for treating hair loss.SUMMARY OF THE INVENTION

[0004] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount increases a hair count in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821. In some embodiments, the hair count is increased by about 10% or more, as compared to prior to administration. In some embodiments, the hair count includes a vellus hair count, a non-vellus hair count, or a total hair count.

[0005] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount increases a hair thickness measurement in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821. In some embodiments, the hair thickness measurement is increased by about 10% or more, as compared to prior to administration.

[0006] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount increases a hair density measurement in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821. In some embodiments, the hair density measurement is increased by about 10% or more, as compared to prior to administration.

[0007] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount increases a number of hair follicles in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821. In some embodiments, the number of hair follicles is increased by about 10% or more, as compared to prior to administration. In some embodiments, the number of hair follicles includes a number of terminal hair follicles, a number of anagen hair follicles, a number of telogen hair follicles, anumber of catagen hair follicles, a number of vellus-like miniaturized hair follicles, a number of indeterminate hair follicles, or a total number of hair follicles.

[0008] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount changes a hair loss assessment score in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821. In some embodiments, the hair loss assessment score is changed by about 10% or more, as compared to prior to administration.

[0009] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount changes a protein or mRNA level of [3-catenin, a-SMA, collagen I, or collagen III, in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821. In some embodiments, the protein or mRNA level of [3-catenin, a-SMA, collagen I, or collagen III is changed by about 10% or more, as compared to prior to administration.

[0010] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to the skin of a subject in an effective amount decreases a level of DKK2 mRNA or DKK2 protein wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821. In some embodiments, the skin comprises scalp skin. In some embodiments, the level of DKK2 mRNA or DKK2 protein decreased by about 10% or more, as compared to prior to administration. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified intemucleoside linkage comprises one or more phosphorothioate or phosphate linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified intemucleoside linkages, 3 or more modified intemucleoside linkages, 4 or more modified intemucleoside linkages, 5 or more modified intemucleoside linkages, 6 or more modified intemucleoside linkages, 7 or more modified intemucleoside linkages, 8 or more modified intemucleoside linkages, 9 or more modified intemucleoside linkages, 10 or more modified intemucleoside linkages, 11 or more modified intemucleoside linkages, 12 or more modified intemucleoside linkages, 13 or more modified intemucleoside linkages, 14 or more modified intemucleoside linkages, 15 or more modified intemucleoside linkages, 16 or more modified intemucleoside linkages, 17 or more modified intemucleoside linkages, 18 or more modified intemucleoside linkages, 19 or more modified intemucleoside linkages, or 20 or more modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA.In some embodiments, the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-0-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-0-DMAE0E) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 14-30 nucleosides in length. In some embodiments, the antisense strand is 14-30 nucleosides in length.

[0011] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that inhibits the expression of dickkopf WNT signaling pathway inhibitor 2 (DKK2) wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of SEQ ID NO: 1 wherein the sense strand is selected from SEQ ID NO: 7770-7821, and wherein the antisense strand is selected from SEQ ID NO: 7822-7873.

[0012] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that inhibits the expression of dickkopf WNT signaling pathway inhibitor 2 (DKK2), wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of a full-length human DKK2 pre- mRNA sequence wherein the sense strand is selected from SEQ ID NO: 7770-7821 and wherein the antisense strand is selected from SEQ ID NO: 7822-7873. In some embodiments, the sense strand is selected from the group consisting of SEQ ID NO: 7787, SEQ ID NO: 7799, and SEQ ID NO: 7804; wherein the antisense strand is selected from the group consisting of SEQ ID NO: 7839, SEQ ID NO: 7821, and SEQ ID NO: 7856. In some embodiments, the sense strand is selected from the groupconsisting of: SEQ ID NO: 7684, SEQ ID NO: 7874, and SEQ ID NO: 7875; wherein the antisense strand is selected from the group consisting of: SEQ ID NO: 7328, SEQ ID NO: 7747, and SEQ ID NO: 7752. In some embodiments, the oligonucleotide further comprises a modification pattern. In some embodiments, the modification pattern is selected from the group consisting of: 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, and 17AS, wherein "N" is any nucleotide, “dN” is a 2’ deoxy-modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside and “s” is a phosphorothioate or phosphate linkage.

[0013] In certain aspects, disclosed herein is a composition comprising a small interfering RNA (siRNA) that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a cell decreases expression of DKK2, wherein the siRNA comprises a sense strand and an antisense strand; and wherein the antisense strand comprises modification pattern 6AS, 7AS, 8AS, 9AS, 10AS, 1 IAS, 12AS, HAS. 14AS, 15AS, 16AS, and 17AS ; or wherein the sense strand comprises a modification pattern selected from the group consisting of: 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, and 68S, wherein “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside and “s” is a phosphorothioate or phosphate linkage. In some embodiments, disclosed herein is a method of treating hair loss in a subject in need thereof comprising administering to the subject a composition described herein. In some embodiments, the hair loss comprises any one or more of male pattern baldness, female pattern baldness, alopecia areata, or non-scarring hair loss. In some embodiments, the administration is topical.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 depicts a plot of DKK2 mRNA expression in Lymphoblastoid Cell Lines from donors with known rs35290077 (G96R) genotypes following treatment with Vitamin D (dark, left) or vehicle (light, right). The plot shows each copy of the rs35290077 alternative (G) allele results in approximately 50% reduction of DKK2 mRNA induction in the presence of Vitamin D. The x-axis is labeled rs35290077 Donor genotype for (left to right) C / C / , C / G, and G / G / ; the y-axis is labeled relative DKK2 expression from 0 to 4 at 1 unit intervals.

[0015] FIG. 2A depicts images of 2 mice 14 days following hair removal, and after topical treatment with a negative control siRNA (ETD01043). The images show whitening and graying of the fur on the backs of the mice in the hair that grew back.

[0016] FIG. 2B depicts images of 2 mice 14 days following hair removal, and after topical treatment with a DKK2 siRNA (ETD01551). The images indicate that coat color of the mice was retained in the hair that grew back on these mice.

[0017] FIG. 3 depicts the percent of hair follicles in anagen (bottom portion of each bar) versus early catagen (top portion of each bar) stages. From left to right, the conditions are follicles administered vehicle at 4 days after application, follicles administered 1 pM DKK2 siRNA (1) at 4 days afterapplication, follicles administered 1 pM DKK2 siRNA (2) at 4 days after application, follicles administered 1 pM DKK2 siRNA (3) at 4 days after application, follicles administered vehicle at 5 days after application, and follicles administered 1 pM DKK2 siRNA (2) at 5 days after application. n=4 for each experimental condition. The y-axis is labeled % of HF’s in each hair cycle stage from 0 to 100 at 50 unit intervals.DETAILED DESCRIPTION OF THE INVENTION

[0018] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) detects associations between genetic variants and traits in a population sample and this improves understanding of the biology of disease and provides evidence of applicable treatments. A GWAS generally utilizes genotyping and / or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is considered associated with disease. Association statistics used in a GWAS include p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

[0019] Functional annotation of variants and / or wet lab experimentation is used to identify a causal genetic variant identified via GWAS, and in many cases leads to the identification of disease -causing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) allows that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.

[0020] Identification of such gene-disease associations has provided insights into disease biology and is used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate the therapeutic insights derived from human genetics, disease biology in patients is exogenously ‘programmed’ into replicating the observation from human genetics. There are several options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality depends on several factors such as the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, skin) and a relevant indication.

[0021] Hair loss is a common problem, particularly among men, but is also common among women. It may be affected by any of several factors, including heredity, hormones, thyroid disorders, nutritionalstatus, environmental factors, physical stress, or emotional stress. Hair loss may include, among other things, androgenetic alopecia (male pattern baldness), alopecia areata, or non-scarring hair loss. The DKK2 gene is located on chromosome 4 and encodes dickkopf WNT signaling pathway inhibitor 2 (DKK2), a member of the dickkopf family. A non-limiting example of a DKK2 gene is included on GenBank under NCBI reference sequence NM_014421.3 (May 9, 2020). DKK2 proteins may be secreted, include two cysteine rich regions, and be involved in embryonic development through interactions with the Wnt signaling pathway. DKK2 can act as either an agonist or antagonist of Wnt / beta-catenin signaling, depending on the cellular context and the presence of the co-factor kremen 2. Activity of DKK2 may also be modulated by binding to the Wnt co-receptor LDL-receptor related protein 6 (LRP6). In some cases, DKK2 protein is intracellular. In some cases, DKK2 protein is secreted. The secreted DKK2 protein may be locally secreted. Here, it is shown that genetic variants that cause inactivation of the DKK2 gene in humans are associated with decreased risk of male pattern baldness. Therefore, inhibition of DKK2 serve as a therapeutic strategy for treatment of hair loss such as male pattern baldness, alopecia areata, or non-scarring hair loss.

[0022] Disclosed herein are compositions comprising an oligonucleotide that targets DKK2. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating hair loss by providing an oligonucleotide that targets DKK2 to a subject in need thereof.I. COMPOSITIONS

[0023] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2). In some embodiments, the composition consists of an oligonucleotide that targets DKK2. In some embodiments, the oligonucleotide reduces DKK2 mRNA expression in the subject. In some embodiments, the oligonucleotide reduces DKK2 protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) described herein. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder as described herein.

[0024] Some embodiments include a composition comprising an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount decreases DKK2 mRNA or protein levels in a cell, fluid or tissue. Some embodiments include a composition comprising an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount decreases DKK2 mRNA levels in a cell or tissue. In some embodiments, the cell is a skin cell. In some embodiments, the tissue is skin (e.g. scalp dermis). In some embodiments, the DKK2 mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the DKK2 mRNA levels are decreased by about 10% or more, as compared to prior to administration. In someembodiments, the DKK2 mRNA levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the DKK2 mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the DKK2 mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the DKK2 mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the DKK2 mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0025] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount decreases DKK2 protein levels in a cell, fluid or tissue. In some embodiments, the cell is a skin cell. In some embodiments, the fluid is a blood, serum, or plasma. In some cases, the administration of the oligonucleotide decreases circulatingDKK2 protein levels. In some embodiments, the tissue is skin (e.g. scalp dermis). In some embodiments, the DKK2 protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the DKK2 protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the DKK2 protein levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the DKK2 protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the DKK2 protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the DKK2 protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the DKK2 protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0026] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount decreases hair loss (e.g. male pattern baldness, alopecia areata, or non-scarring hair loss) or a symptom of hair loss. In some embodiments, the hair loss or symptom of hair loss is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the hair loss or symptom of hair loss is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the hairloss or symptom of hair loss is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the hair loss or symptom of hair loss is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hair loss or symptom of hair loss is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the hair loss or symptom of hair loss is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the hair loss or symptom of hair loss is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. In some embodiments, the hair loss or symptom of hair loss is assessed by phototrichogram. In some embodiments, the hair loss or symptom of hair loss is assessed by a macrophotography analysis.

[0027] In some embodiments, the hair loss or symptom of hair loss is assessed by a questionnaire such as a Men's Hair Growth Questionnaire (MHGQ) or a Kingsley Alopecia Profile (KAP) questionnaire. In some embodiments, the hair loss or symptom of hair loss is assessed by a scalp biopsy. In some embodiments, the decrease in hair loss or symptom of hair loss is determined as a change in a hair loss hair loss assessment score. For example, the change in the hair loss assessment score may be an increase in the hair loss assessment score. In some embodiments, the change in the hair loss assessment score is a decrease in the hair loss assessment score. In some embodiments, the hair loss assessment score is obtained as part of an assessment that includes the questionnaire. In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount results in a change in an hair loss assessment score. In some embodiments, the hair loss assessment score is changed by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the hair loss assessment score is changed by about 10% or more, as compared to prior to administration. In some embodiments, the hair loss assessment score is changed by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the hair loss assessment score is changed by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the hair loss assessment score is changed by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hair loss assessment score is changed by no more than about 10%, as compared to prior to administration. In some embodiments, the hair loss assessment score is changed by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more thanabout 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the hair loss assessment score is changed by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the hair loss assessment score is changed by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0028] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases a total hair count (e.g. a vellus and non-vellus hair count). In some embodiments, the total hair count is determined in an area of skin. In some embodiments, the total hair count is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the total hair count is increased by about 10% or more, as compared to prior to administration. In some embodiments, the total hair count is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the total hair count is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the total hair count is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the total hair count is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the total hair count is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the total hair count is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the total hair count is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages. In some embodiments, the total hair count is assessed by phototrichogram. In some embodiments, the total hair count is assessed by a macrophotography analysis.

[0029] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases a vellus hair count. In some embodiments, the vellus hair count is determined in an area of skin. In some embodiments, the vellus hair count is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.In some embodiments, the vellus hair count is increased by about 10% or more, as compared to prior to administration. In some embodiments, the vellus hair count is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the vellus hair count is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the vellus hair count is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the vellus hair count is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the vellus hair count is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the vellus hair count is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the vellus hair count is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages. In some embodiments, the vellus hair count is assessed by phototrichogram. In some embodiments, the vellus hair count is assessed by a macrophotography analysis.

[0030] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases a non-vellus hair count. In some embodiments, the non-vellus hair count is determined in an area of skin. In some embodiments, the non-vellus hair count is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the non-vellus hair count is increased by about 10% or more, as compared to prior to administration. In some embodiments, the non-vellus hair count is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the non-vellus hair count is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the non-vellus hair count is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the non-vellus hair count is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the non-vellus hair count is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, nomore than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the non-vellus hair count is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the non-vellus hair count is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages. In some embodiments, the non-vellus hair count is assessed by phototrichogram. In some embodiments, the non-vellus hair count is assessed by a macrophotography analysis.

[0031] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases hair thickness. In some embodiments, the thicknesses (e.g. widths) of individual hairs are increased. In some embodiments, the hair thickness is determined in an area of skin. The increased hair thickness may include an increased vellus hair thickness. The increased hair thickness may include an increased non-vellus hair thickness. In some embodiments, the hair thickness is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the hair thickness is increased by about 10% or more, as compared to prior to administration. In some embodiments, the hair thickness is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the hair thickness is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the hair thickness is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hair thickness is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the hair thickness is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the hair thickness is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the hair thickness is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages. In some embodiments, the hair thickness is assessed by phototrichogram. In some embodiments, the hair thickness is assessed by a macrophotography analysis.

[0032] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases hair density. In some embodiments, the hair density is determined in an area of skin. In some embodiments, the hair density comprises a number of hairs per an area of skin. The increased hair density may include an increased vellus hair density. The increased hair density may include an increased non-vellus hair density. In some embodiments, the hair density is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the hair density is increased by about 10% or more, as compared to prior to administration. In some embodiments, the hair density is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the hair density is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the hair density is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hair density is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the hair density is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the hair density is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the hair density is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages. In some embodiments, the hair density is assessed by phototrichogram. In some embodiments, the hair density is assessed by a macrophotography analysis.

[0033] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases a number of hair follicles. In some embodiments, the number of hair follicles is determined in an area of skin. The hair follicles may include terminal hair follicles, anagen hair follicles, telogen hair follicles, catagen hair follicles, vellus or vellus- like miniaturized hair follicles, or indeterminate hair follicles. In some embodiments, the hair follicles include terminal hair follicles. In some embodiments, the hair follicles include anagen hair follicles. In some embodiments, the hair follicles include telogen hair follicles. In some embodiments, the hair follicles include catagen hair follicles. In some embodiments, the hair follicles include vellus or vellus- like miniaturized hair follicles. In some embodiments, the hair follicles include indeterminate hair follicles. In some embodiments, the number of hair follicles is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, thenumber of hair follicles is increased by about 10% or more, as compared to prior to administration. In some embodiments, the number of hair follicles is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the number of hair follicles is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the number of hair follicles is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the number of hair follicles is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the number of hair follicles is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the number of hair follicles is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the number of hair follicles is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages. In some embodiments, the number of hair follicles is assessed in a scalp biopsy.

[0034] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases a hair color measurement. In some embodiments, the hair color measurement is determined on an area of skin. In some embodiments, the hair color measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the hair color measurement is increased by about 10% or more, as compared to prior to administration. In some embodiments, the hair color measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the hair color measurement is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the hair color measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the hair color measurement is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the hair color measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more thanabout 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the hair color measurement is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the hair color measurement is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0035] In some embodiments, the composition comprises an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount results in a change in expression of a gene or protein. The gene or protein may include a [3-catenin gene. The gene or protein may include a [3-catenin protein. The gene or protein may include an a-SMA gene. The gene or protein may include an a-SMA protein. The gene or protein may include a collagen I gene. The gene or protein may include a collagen I protein. The gene or protein may include a collagen III gene. The gene or protein may include a collagen III protein. In some embodiments, the change in expression is determined in a tissue (e.g. skin), cell, or fluid sample. In some embodiments, the expression is changed by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the expression is changed by about 10% or more, as compared to prior to administration. In some embodiments, the expression is changed by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the expression is changed by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the expression is changed by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the expression is changed by no more than about 10%, as compared to prior to administration. In some embodiments, the expression is changed by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the expression is changed by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the expression is changed by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.A. siRNAs

[0036] In some embodiments, the composition comprises an oligonucleotide that targets DKK2, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets DKK2, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length. In some embodiments, the sense strand is 14-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the antisense strand is 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is at least about 10, 11, 12, 13, 14, 15, 1516 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers.

[0038] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of a full-length human DKK2 pre-mRNA sequence. In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 15, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of the pre-mRNA sequence.

[0039] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of a full-length human DKK2 mRNA sequence such as SEQ ID NO: 7599. In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 15, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 7599. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any one of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of 7599. Any of the aforementioned siRNAs may include an antisense strand that lacks a 5’ U of an antisense sequence of one of SEQ ID NO: 7599.

[0040] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double -stranded RNA duplex. In some embodiments, the first base pair of the double -stranded RNA duplex is an AU base pair.

[0041] In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0042] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0043] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human DKK2 mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human DKK2 mRNA.

[0044] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in a non -human primate DKK2 mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non-human primate DKK2 mRNA.

[0045] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human DKK2 mRNA, or a combination thereof. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, and 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human DKK2 mRNA.

[0046] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human DKK2 mRNA and less than or equal to 20 human off- targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. Insome embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 40 human off- targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 10 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 20 human off- targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human DKK2 mRNA and less than or equal to 50 human off- targets, with no more than 3 mismatches in the antisense strand.

[0047] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human DKK2 mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos. 2-18). In some embodiments, the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0048] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 2B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 2B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 2B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 2B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 2B. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’A of a sense strand of one of the sequences of Table 2B. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of Table 2B.

[0049] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with a base sequence of an siRNA in any of Table 4-6. In some embodiments, the sense strand or antisense strand sequence comprises or consists of sequence at least 75% identical, at least 80%identical, at least 85% identical, at least 90% identical, or at least 95% identical to a base sequence of an siRNA in any of Table 4-6. In some embodiments, the sense strand or antisense strand sequence comprises or consists of the sequence of a base sequence of an siRNA in any of Table 4-6, or a sense strand or antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand sequence comprises or consists of the sequence of a base sequence of an siRNA in any of Table 4-6, or a sense strand or antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand sequence comprises or consists of a sequence 100% identical to a base sequence of an siRNA in any of Table 4-6. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5 ’ to 3 ’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise a modification pattern described herein. The sense strand or antisense strand may comprise, or may lack an overhang. The sense strand or antisense strand may comprise a lipid moiety. The sense strand or antisense strand may comprise a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’A of a sense strand of one of the sequences of Tables4-6. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5 ’ U of an antisense strand sequence of any one of the sequences of T ables 4- 6.

[0050] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 13B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 13B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 13B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 13B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 13B. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’A of a sense strand of one of the sequences of Table 13B. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of Table 13B.

[0051] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 13C. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 13C. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 13C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 13C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 13C. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’A of a sense strand of one of the sequences of Table 13C. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5 ’ U of an antisense strand sequence of any one of the sequences of Table 13C.

[0052] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 18. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 18. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 18, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 18, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 18. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’A of a sense strand of one of the sequences of Table 18. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of Table 18.

[0053] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 1-3636. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 1-3636, at least 80% identical to any one of SEQ ID NOs: 1-3636, at least 85% identical to of any one of SEQ ID NOs: 1-3636, at least 90% identical to any one of SEQ ID NOs: 1-3636, or at least 95% identical to any one of SEQ ID NOs: 1-3636. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-3636, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-3636, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions,additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 1-3636. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5 ’ to 3 ’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’A of a sense strand of one of SEQ ID NO: 1-3636.

[0054] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 7770-7821. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 7770-7821, at least 80% identical to any one of SEQ ID NOs: 7770-7821, at least 85% identical to of any one of SEQ ID NOs: 7770-7821, at least 90% identical to any one of SEQ ID NOs: 7770-7821, or at least 95% identical to any one of SEQ ID NOs: 7770-7821. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 7770-7821, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-3636, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 7770-7821. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’A of a sense strand of one of SEQ ID NO: 7770-7821.

[0055] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 3637-7272. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3637-7272, at least 80% identical to any one of SEQ ID NOs: 3637-7272, at least 85% identical to of any one of SEQ ID NOs: 3637-7272, at least 90% identical to any one of SEQ ID NOs: 3637-7272, or at least 95% identical to any one of SEQ ID NOs: 3637-7272. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3637-7272, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3637-7272, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 3637-7272. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of SEQ ID NO 3637-7272.

[0056] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 7822-7873. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 7822-7873, at least 80% identical to any one of SEQ ID NOs: 7822-7873, at least 85% identical to of any one of SEQ ID NOs: 7822-7873, at least 90% identical to any one of SEQ ID NOs: 7822-7873, or at least 95% identical to any one of SEQ ID NOs: 7822-7873. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 7822-7873, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 7822-7873, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 7822- 7873. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of SEQ ID NO 7822-7873.

[0057] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset A. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’A of a sense strand of one of thesequences of subset A. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of subset A.

[0058] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’A of a sense strand of one of the sequences of subset B. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of subset B.

[0059] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset C. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’A of a sense strand of one of the sequences of subset C. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of subset C.

[0060] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 3 or 4nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset D. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’A of a sense strand of one of the sequences of subset D. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of subset D.

[0061] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset E. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’A of a sense strand of one of the sequences of subset E. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of subset E.

[0062] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset F. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’A of a sense strand of one of thesequences of subset F. Any one of the aforementioned siRNA may include an antisense strand that lacks a 5’ U of an antisense strand sequence of any one of the sequences of subset F.

[0063] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 7787. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 7787, at least 80% identical to SEQ ID NO: 7787, at least 85% identical to SEQ ID NO: 7787, at least 90% identical to SEQ ID NO: 7787, or at least 95% identical to SEQ ID NO: 7787. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO 7787, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 7787, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 7787. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 7839. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 7839, at least 80% identical to SEQ ID NO: 7839, at least 85% identical to SEQ ID NO: 7839, at least 90% identical to SEQ ID NO: 7839, or at least 95% identical to SEQ ID NO: 7839. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO 7839, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 7839, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 7839. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of SEQ ID NO: 7787. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5 ’ U of an antisense strand sequence of one of SEQ ID NO: 7839.

[0064] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 7799. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 7799, at least 80% identical to SEQ ID NO: 7799, at least 85% identical to SEQ ID NO: 7799, at least 90% identical to SEQ ID NO: 7799, or at least 95% identical to SEQ ID NO: 7799. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO 7799, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 7799, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 7799. The sense strand may comprise anymodifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 7851. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 7851, at least 80% identical to SEQ ID NO: 7851, at least 85% identical to SEQ ID NO: 7851, at least 90% identical to SEQ ID NO: 7851, or at least 95% identical to SEQ ID NO: 7851. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO 7851, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 7851, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 7851. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 7799. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5 ’ U of an antisense strand sequence of one of SEQ ID NO: 7851.

[0065] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 7804. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 7804, at least 80% identical to SEQ ID NO: 7804, at least 85% identical to SEQ ID NO: 7804, at least 90% identical to SEQ ID NO: 7804, or at least 95% identical to SEQ ID NO: 7804. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO 7804, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 7804, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 7804. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 7856. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 7856, at least 80% identical to SEQ ID NO: 7856, at least 85% identical to SEQ ID NO: 7856, at least 90% identical to SEQ ID NO: 7856, or at least 95% identical to SEQ ID NO: 7856. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO 7856, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 7856, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 7856. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strandmay comprise a moiety such as a GalNAc moiety or a lipid moiety. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 7804. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5 ’ U of an antisense strand sequence of one of SEQ ID NO: 7856.B. ASOs

[0066] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0067] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human DKK2 pre-mRNA sequence; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0068] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human DKK2 mRNA sequence such as SEQ ID NO: 7599; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more contiguous nucleosides of SEQ ID NO: 7599.C. Oligonucleotide modifications

[0069] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified intemucleoside linkage comprises one or more phosphorothioate linkages A phosphorothioate may include a nonbridgingoxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified intemucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified intemucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0070] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0071] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a modified intemucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages, or a range of modified intemucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified intemucleoside linkages, 3 or more modified intemucleoside linkages, 4 or more modified intemucleoside linkages, 5 or more modified intemucleoside linkages, 6 or more modified intemucleoside linkages, 7 or more modified intemucleoside linkages, 8 or more modified intemucleoside linkages, 9 or more modified intemucleoside linkages, 10 or more modified intemucleoside linkages, 11 or more modified intemucleoside linkages, 12 or more modified intemucleoside linkages, 13 or more modified intemucleoside linkages, 14 or more modified intemucleoside linkages, 15 or more modified intemucleoside linkages, 16 or more modified intemucleoside linkages, 17 or more modified intemucleoside linkages, 18 or more modified intemucleoside linkages, 19 or more modified intemucleoside linkages, or 20 or more modified intemucleoside linkages.

[0072] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HLA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'-O-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl group. In some embodiments, the modified nucleoside comprises 2’-O-methoxyethyl. In some embodiments, the modified nucleoside comprises a methoxyethyl. For example, position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2’-O-methoxyethyl thymine. In some embodiments, the modified nucleoside comprises 2'-O-methyl. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'- deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'- deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-0-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-0-DMAE0E) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-0-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-0-DMAE0E nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an acyclic nucleic acid. In some embodiments, the acyclic nucleic is a glycol nucleic acid. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0073] In some embodiments, the modified nucleoside comprises a glycol nucleic acid (GNA). A GNA may comprise the following structure:5’ nucleotide

[0074] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:3’ nucleotide se5’ nucleotide wherein the base can be any pyrimidine or purine.

[0075] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

[0076] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:’ methylphosphonate 2’-O-Methyl Uridine).

[0077] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0078] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modifiednucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0079] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a moiety attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. Examples of moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5 ’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.

[0080] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprise a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’- O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2’ -fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’- fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least a 2’ -fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.

[0081] In some embodiments, the antisense strand is combination of 2’-fluoro and 2’-O-Methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2 ’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2 ’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.

[0082] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0083] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O- methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purinenucleosides are modified with a mixture of 2 ’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O-methyl. In some embodiments, the sense strand may include a 2 ’-deoxy nucleoside.

[0084] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’- O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’ -fluoromodified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.

[0085] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. In some embodiments, all purine nucleosides comprise 2 ’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro.

[0086] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. Thehydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0087] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof.

[0088] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N- acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N- acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages since they may target or bind a mannose receptor such as CD206.

[0089] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[0090] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0091] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’-methyl modification may be included, and vice versa.

[0092] In some embodiments, pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoroand 2’-0-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines.

[0093] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O- methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.

[0094] In some embodiments, all purines of the oligonucleotide comprise 2 ’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2 ’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -fluoro modified purines.

[0095] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine,then all purines in a strand of the oligonucleotide have a 2’0Me modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0096] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’0Me modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0097] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’0Me modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0098] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2 ’fluoromodified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modifiednucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O-methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’fluoro-modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0099] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2 ’-fluoromodified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’-fluoro-modified pyrimidines in a row.

[0100] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fIuoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and allpurines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0101] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotide.

[0102] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a targeting ligand.

[0103] In some embodiments, the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5 ’-end group. In some embodiments, the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein. The 5 ’-end group may be or include a 5’-end phosphorothioate, 5’-end phosphorodithioate, 5’-end vinylphosphonate (5’-VP), 5’- end methylphosphonate, 5’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl. The 5’-end group may comprise 5 ’-VP. In some embodiments, the 5 ’-VP comprises a trans-vinylphosphonate or cis- vinylphosphonate. The 5 ’-end group may include an extra 5’ phosphate. A combination of 5 ’-end groups may be used.

[0104] In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5’ or 3’ end (e.g. a 5’ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl. The end group may include an extra 5’ phosphate such as an extra 5’ phosphate. A combination of end groups may be used.

[0105] In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonatecomprises a trans-vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis- vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.

[0106]

[0107] 5’ vinylphosphonate 2’ O Methyl Uridine

[0108] In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

[0109] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.1. Hydrophobic moieties

[0110] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a hydrophobic moiety. An oligonucleotide comprising a hydrophobic moiety may include, or be referred to as a hydrophobic conjugate. Hydrophobic moieties may be useful for enhancing cellular uptake. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. In some embodiments, the hydrophobic moiety includes a lipid. In some embodiments, the hydrophobic moiety is used in a specific format described herein. In some embodiments, the hydrophobic moiety is attached at a 5’ end of a sense strand without any phosphorothioate groups or linkages at the 5’ end. The hydrophobic moiety may include an esterified lipid.

[0111] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof.

[0112] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g. attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g. attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

[0113] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g. a sense strand and / or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid.

[0114] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified.

[0115] In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises any aspect of the following structure:some embodiments, the oligonucleotide comprises any aspect of the following structure:some embodiments, the oligonucleotide comprises any aspect of the following structureaspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether.

[0116] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety.In some embodiments, a lipid moiety in Table 1 may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non- hepatic cell or tissue.Table 1: Hydrophobic moiety examples

[0117] In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons. In some embodiments, the lipid moiety includes 19 carbons. In some embodiments, the lipid moiety includes 20 carbons.

[0118] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g. 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g. the para, meta, or ortho phenyl configuration). In some embodiments,the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the1,4 substitution pattern (e.g. the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

[0119] The lipid moiety may comprise or consist of the following structure

[0120] In some embodiments, the lipid moiety comprises or consists of the following structure:comprises the following structure:lipid moiety comprises or consist of the following structure:some embodiments, the dotted line indicates a covalent connection. The covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. The lipid moiety may be attached at a 5’ end of the oligonucleotide. The 5’ endmay have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5 ’ end may have three phosphates linking the lipid moiety to a 5 ’ carbon of a sugar of the oligonucleotide. The 5’ end may have one phosphate connected to the 5’ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety. The 5’ end may have two phosphates connected to the 5 ’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety. The 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety. The sugar may include a ribose. The sugar may include a deoxyribose. The sugar may be modified a such as a 2’ modified sugar (e.g. a 2’-0-methyl or 2’-fluoro ribose). A phosphate of the 5’ end may include a modification such as a sulfur in place of an oxygen. Two phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen. Three phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.

[0121] In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.

[0122] Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate. A strategy for making hydrophobic conjugates may include use of a phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may be used to produce ahydrophobic conjugate are provided as follows:. In some embodiments, n is 1 -3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments, the phosphoramidite reagents is reacted to a 5’ end of a sense strand of an siRNA. The sense strand may then be hybridized to an antisense strand to form a duplex. The hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature. The temperature may be gradually reduced. The temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands. The temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands. The temperature may be below a melting temperature of the sense and antisense strands.

[0123] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g. tetraethyleneglycol).

[0124] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue.

[0125] ETL2 may be conjugated to an oligonucleotide using the following reagent:2. Sugar moieties

[0126] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N- acetyl galactose moiety (e.g. an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g. an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N-acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte.

[0127] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[0128] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g. attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g. attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

[0129] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g. oligonucleotide) represented by Formula (I) or (II):or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or if z is 1, Y is C(R6)2;Q is selected from:C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, -S(O)R7, and Ci6alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from:-O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-_ -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, - N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, -SP(O)(OR7)O-, - OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, - OP(O)(S )O-, -OP(O)(O )S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R2is independently selected from:C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7;R3and R4are each independently selected from:-OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R5is independently selected from:-OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, -N(R7)C(O)OR7, -C(O)R7, -C(O)OR7, and -C(O)N(R7)2; each R6is independently selected from: hydrogen; halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R7is independently selected from: hydrogen;Ci-6 alkyl, C2-6 alkenyl, and C2.e alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, - O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(Ci-e alkyl)2, -NH(Ci-e alkyl), C3-10 carbocycle, and 3- to 10- membered heterocycle; andC3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, - N02, -NH2, =0, =S, -O-C1-6 alkyl, -S-Ci-e alkyl, -N(Ci-e alkyl)2, -NH(Ci-e alkyl), C1-6 alkyl, C2.e alkenyl, C2.„ alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and Ci-ehaloalkyl.In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, - OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, - OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2.NR7. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, and -OP(OR7)O-. In some embodiments, R1is selected from - OP(O)(OR7)O- and -OP(OR7)O-. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR7, -OC(O)R7, -SR7, -N(R7)2, -C(O)R7, and -S(O)R7. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7, -OC(O)R7, -SR7, and -N(R7)2. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7and - OC(O)R7. In some embodiments, R3is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7In some embodiments, R3is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R3is selected from -OR7- and -OC(O)R7. In some embodiments, R4is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7In some embodiments, R4is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2 In some embodiments, R4is selected from -OR7- and -OC(O)R7. In some embodiments, R5is selected from -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, and -N(R7)C(O)OR7. In some embodiments, R5is selected from -OC(O)R7and -N(R7)C(O)R7. In some embodiments, each R7is independently selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O- C1-6 alkyl, -S-C1-6 alkyl, -N(Ci-e alkyl)2, -NH(Ci-e alkyl), C3-10 carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, - NH2, =0, =S, -O-C1.6 alkyl, -S-C1-6 alkyl, -N(CI-6 alkyl)2, and -NH(CI-6 alkyl). In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3 alkyl; R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -0P(0)(0 )0-, -OP(S)(O )0-, -OP(O)(S )0-, and - OP(OR7)O-; R2is Ci alkyl substituted with -OH or -0C(0)CH3;R3is -OH or -0C( some embodiments, the compound compriIn some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified intemucleoside linkages. In some embodiments, the one or more modified intemucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[0130] Some embodiments include the following, where J is the oligonucleotide:J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0131] Some embodiments include the following, where J is the oligonucleotide:J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0132] Some embodiments include the following, where J is the oligonucleotide:J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0133] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17”, and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0134] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0135] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to

[0136] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to

[0137] Some embodiments include the following, where J is the oligonucleotide:include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0138] Some embodiments include the following, where J is the oligonucleotide:

[0139] The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0141] Some embodiments include the following, where J is the oligonucleotide:J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0142] Some embodiments include the following, where J is the oligonucleotide:or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0143] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and isan example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0144] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g. oligonucleotide) represented by Formula (III), (IV), or (V):Formula V, or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1 ; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20;Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, - C(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, - S(O)R7, and Ci-e alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-_ -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, - SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, - OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-;each R7is independently selected from: hydrogen, Ci-6 alkyl, C2-6 alkenyl, and C2-ealkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, -SH, -NO2, -NH2, =0, =S, -O-C1.6 alkyl, -S-C1.6 alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-Ci.6alkyl, -S-C1.6 alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0145] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0146] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0147] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0148] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0149] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0150] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one ormore phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0151] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[0152] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances, 2-4 GalNAc moieties are attached to the oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in someinstances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0153] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide:

[0154] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as Hl, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0155] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0156] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O:. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0157] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:. The structure in this compound atached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0158] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:

[0159] The structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3 ’ or 5 ’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0160] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0161] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0162] Provided herein are sugar moieties comprising the following structure, where Nu is an oligonucleotide:

[0163] The structure in this compound attached to the oligonucleotide (Nu) in some instances is referred to as “L-9” and is an example of a GalNAc moiety. Nu in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. Nu in some instances comprises one or more phosphates linking to the oligonucleotide. Nu in some instances comprises a phosphate linking tothe oligonucleotide. Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide. Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0164] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0165] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Sirius GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.3. Modified siRNAs

[0166] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern IS: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3'. wherein “NT’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate. In some embodiments, the sense strand comprises modification pattern 2S: 5’-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfhNfhNfnnnnnnnnnnsnsn-3’, wherein “NT’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate. In some embodiments, the sense strand comprises modification pattern 4S: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN- moiety-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 5S: 5’-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. The moiety may include any moiety such as a lipid moiety. In some embodiments, the sense strand comprises modification pattern 6S:5’-nnnnNfNfimNfNfnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 7S: 5’- nnnnnnNfNfNfNfimnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 8S: 5’- nnnnnNfNfNfNfimnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 9S: 5’- nnnnnnNfiiNfNfimnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern IOS: 5’- nnnnnnnNfNfiiNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 1 IS: 5’- nnnnnNfnnNfimnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 12S: 5’- nnnnNfNfiiNfNfimnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 13S: 5’- nnnnNfnnnNfNfnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 14S: 5’- nnnnNfnnNfNfnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 15S: 5’- nnnnnNfNfNfNfNfnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 16S: 5’- nnnnNfNfimNfiiNfhnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 17S: 5’- nnnnnNfNfiiNfiiNfhnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 18S: 5’- nnnnNfiiNfiiNfiiNfhnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or morenucleosides. In some embodiments, the sense strand comprises modification pattern 19S: 5’- nnnnNfiiNfirNfNfimnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 20S: 5’- nnnnnnnnNfhNfimnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 21S: 5’- nnnnNfnnNfNfnNfimnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 22S: 5’- nnnnNfnnnNfiiNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 23 S: 5’- nnnnnNfnNfNfnnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 24S: 5’- nnnnnnNfnNfhNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 25 S: 5’- nnnnnNfnNfNfnNfhnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 26S: 5’- nnnnnnnnNfhnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 27S: 5’- nnnnNfnNfhNfnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 28S: 5’- nnnnnNfnnNfNfnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 29S: 5’- nnnnnNfnnNfiiNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 30S: 5’- nnnnNfNfhnNfnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 3 IS: 5’- nnnnnNfNfhNfnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 32S: 5’- nnnnnNfNfhNfNfimnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 33 S: 5’- nnnnnnnNfNfNfNfimnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 34S: 5’- nnnnnnNfNfNfNfNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 35 S: 5’- nnnnnNfiiNfNfNfNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 36S: 5’- nnnnnNfNfNfNfhNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 37S: 5’- nnnnNfnnNfNfNfNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 38S: 5’- nnnnNfiiNfNfNfNfimnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 39S: 5’- nnnnNfNfhNfNfiiNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 40S: 5’- nnnnNfNfNfNfNfnnnnnnnnnnsnsn-3 ’ , wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 4 IS: 5’- nnnnNfiiNfNfdNnnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 42S: 5’-NfsnsNfnNfnNfnNfnNfnNfnNfiiNfiiNfsnsn-3’, wherein “Nf’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 43S: 5’-snnnnNfNfimNfNfimnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, thesense strand comprises modification pattern 44S: 5’-snnnnnnNfhNfNfnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 45 S: 5’- snnnnnNfhNfNfnNfnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 46S: 5’- snnnnNfnNfNfdNnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 47S: 5’- snnnnnNfnnNfnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 48S: 5’- snnnnNfNfnNfNfimnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 49S: 5’- snnnnNfnnnNfNfimnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 50S: 5’- snnnnNfNfhNfNfiiNfnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 5 IS: 5’- snnnnNfnNfnNfNfhnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 52S: 5’- snnnnnNfNfnNfiiNfhnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 53 S: 5’- snnnnNfnNfiiNfiiNfhnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 54S: 5’- snnnnnnNfNfNfNfimnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 55 S: 5’ - snnnnnnnnNfiiNfhnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modifiednucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 56S: 5’- snnnnnnnNfNfNfNfimnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 57S: 5’- snnnnNfnnNfNfnnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 58S: 5’ - snnnnnNfhNfNfimnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 59S: 5’- snnnnNfiiNfiiNfimnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 60S: 5’- snnnnnNfimNfNfnnnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 6 IS: 5’- snnnNmnNfNfNfNfnnnNmnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, "Nm" is a 2’-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 62S: 5’- snnnNmnNfNfNfNfnnNmnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, "Nm" is a 2’-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 63 S: 5’- snnnNmnNfNfNfNfnnnnNmnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, "Nm" is a 2’-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 64S: 5’- snnnnNmNfNfNfNfnnnNmnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, "Nm" is a 2’-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 65S: 5’- snnnnNmNfNfNfNfnnNmnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, "Nm" is a 2’-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or morenucleosides. In some embodiments, the sense strand comprises modification pattern 66S: 5’- snnnnNmNfNfNfNfnnnnNmnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, "Nm" is a 2’-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 67S: 5’- snnnNmnNfNfNfNfnNmnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, "Nm" is a 2’-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 68S: 5’- snnnNmnNfNfNfNfnnnnnNmnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, "Nm" is a 2’-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the “Nm” is a 2’-O-methoxyethyl modified thymine.

[0167] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern IAS: 5’-nsNfsnNfiiNfiiNfiiNfnnnNfnNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfiiNfNfimnnNfhNfnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 3 AS: 5’-nsNfsnnnNfnnnnnnnNfiiNfnnnsnsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’-nsNfsnNfiiNfnnnnnnnNfhNfimnsnsn-3’, wherein “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 5 AS: 5’-nsNfsnNfiiNfiiNfiiNfnNfnNfhNfnNfnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 6AS:5’-nNfiiNfiiNfhNfnNfiiNfiiNfiiNfnNfimn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 7AS: 5 ’ -nsNfsnNfhNfiiNfnNfiiNfnNfiiNfiiNfiisnsn - 3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 8AS: 5’- nsnsnNfiiNfiiNfiiNfiiNfiiNfiiNfhNfhsnsn -3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate orphosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’-nsNfsnnnNfhNfimnnnNfiiNfnnnsnsn -3’, wherein “Nf’ is a 2’- fhioro -modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 10AS: 5’- nsNfsnnnNfiiNfnNfnNfiiNfiiNfiiNfnsnsn -3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 1 IAS: 5’-nsNfsnNfimNfhNfnnnnNfhNfnNfnsnsn -3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 12AS: 5’- nsNfsnNfnnNfnnNfnNfiiNfiiNfiiNfnsnsn -3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 13AS: 5’-nsNfsnNfimNfimNfnNfiiNfimnnnsnsn -3’, wherein “Nf’ is a 2’- fluoro -modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 14AS: 5’- nsNfsnnnNfhNfnNfnNfiiNfiiNfimnsnsn -3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 15AS: 5’-nsNfsnnnNfiiNfiiNfiiNfnNfnnnnnsnsn -3’, wherein “Nf’ is a 2’- fluoro -modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 16AS: 5’- nsNfsnNfnnNfnnnnNfnNfiiNfnNfiisnsn -3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the antisense strand comprises modification pattern 17AS: 5’-nsNfsnnNfiiNfiiNfnnnnNfiiNfnNfnsnsn -3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “dN” is a 2’ deoxy-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides.

[0168] In some embodiments, the sense strand comprises pattern ISand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 2Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. 14AS, 15 AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 3 Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS.14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 4Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. WAS, 15AS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 5 Sand the antisense pattern comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 6Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 7Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 8Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 9Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern lOSand the antisense pattern comprises pattern IAS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 11 Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 12Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern BSand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 14Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern BSand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 16Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern WSand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern BSand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern WSand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 20Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments, the sense strand comprises pattern 21 Sand the antisense pattern comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or WAS. In some embodiments,the sense strand comprises pattern 22Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 23 Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 24Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 25Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 26Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 27Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 28Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 29Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 30Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 31 Sand the antisense pattern comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 32Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 33Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 34Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 35Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 36Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 37Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 38Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 39Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 40Sand theantisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, WAS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises patern 41Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. HAS. 15AS, 16AS, or I 7AS. In some embodiments, the sense strand comprises patern 42Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, or I 7AS. In some embodiments, the sense strand comprises patern 43 Sand the antisense patern comprises patern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, 15AS, 16AS, or I 7AS. In some embodiments, the sense strand comprises patern 44Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, 15AS, 16AS, or I 7AS. In some embodiments, the sense strand comprises patern 45 Sand the antisense patern comprises patern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, 15AS, 16AS, or I 7AS. In some embodiments, the sense strand comprises patern 46Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 47Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 48Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 49Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 50Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 5 ISand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 52Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 53Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 54Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 55Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 56Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 57Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS, 14AS, HAS, 16AS, or WAS. In some embodiments, the sense strand comprises patern 58Sand the antisense patern comprises patern IAS, 2AS, 3AS, 4AS,5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 59Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 60Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 61 Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 62Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 63Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 64Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 65Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 1 IAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 66Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 67Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, 14AS, 15AS, 16AS, or 17AS. In some embodiments, the sense strand comprises pattern 68Sand the antisense pattern comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, or 17AS.

[0169] In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS,1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S,31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S,5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 3AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 11 S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S,53 S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 5AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 6AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 7AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 8AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 9AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 10AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 1 IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 12AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 13AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern MAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 15AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 16AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S, and the antisense strand comprises pattern 17AS.

[0170] In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, or 5 S. In some embodiments, the antisense strand comprises modification pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 1 IAS, 12AS, BAS, WAS, 15AS, 16AS, or WAS. In some embodiments, the sense strand comprises modification pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, BAS, WAS, 15AS, 16AS, or WAS. In some embodiments, the antisense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, or 68S. In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO1.

[0171] In some embodiments, purines of the sense strand comprise 2’ -fluoro modified purines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments,all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines.

[0172] In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2 ’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2’- fluoro and 2’-O-methyl modified pyrimidines.

[0173] In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’ -fluoro modified purines, and pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2 ’-fluoro modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2 ’-fluoro modified pyrimidines, and purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise 2’ -fluoro modified purines.

[0174] In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2 ’-fluoro modified purines, and all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise 2’-O-methylmodified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise 2 ’-fluoro modified purines.

[0175] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise 2 ’-fluoro modified purines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines.

[0176] In some embodiments, pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines.

[0177] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines, and purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and purines of the antisense strand comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O- methyl modified pyrimidines, and purines of the antisense strand comprise 2’-fluoro modified purines.

[0178] In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2 ’-fluoro modified purines, and all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and allpyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise 2 ’-fluoro modified purines.

[0179] Disclosed herein, in some embodiments, are modified oligonucleotides. The modified oligonucleotide may be an siRNA that includes modifications to the ribose rings, and phosphate linkages. The modifications may be in particular patterns that maximize cell delivery, stability, and efficiency. The siRNA may also include a vinyl phosphonate and a hydrophobic group. These modifications may aid in delivery to a cell or tissue within a subject. The modified oligonucleotide may be used in a method such as a treatment method or a method of reducing gene expression.

[0180] In some embodiments, the siRNA comprises a sense strand, an antisense strand, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, wherein the linker is connected to a lipid and to the end of the sense or antisense strand. In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’- fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O- methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O- methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’- O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethylmodified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O- methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’ -fluoro modified pyrimidines; all pyrimidines comprise 2’ -fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. In some embodiments, the siRNA comprises comprising a sense strand and an antisense strand; wherein the antisense strand comprises a 5’ end comprising a vinyl phosphonate and 2 phosphorothioate linkages, and a 3’ end comprising 2 phosphorothioate linkages; wherein the sense strand comprises (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O- methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O- methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines;(e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and allpyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’- O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; and wherein any one of the following is true with regard to the antisense strand: all purines comprise 2’ -fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines, or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines.

[0181] In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’- fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O- methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O- methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’- O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O- methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixtureof 2’-fluoro, 2’-0-methyl, and 2’-O-methoxyethyl modified pyrimidines. In some embodiments, a deoxy nucleoside may be included in the sense strand. In some embodiments, the sense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the sense strand. In some embodiments, the sense strand does not include a deoxy nucleoside. The deoxy nucleoside of the sense strand may be otherwise unmodified.

[0182] In some embodiments, the oligonucleotide comprises a duplex consisting of 21 nucleotide single strands with base pairing between 19 of the base pairs. In some embodiments, the duplex comprises single-stranded 2 nucleotide overhangs are at the 3’ ends of each strand. One strand (antisense strand) is complementary to a DKK2 mRNA. Each end of the antisense strand has one to two phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a DKK2 mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the DKK2 mRNA. In some embodiments, there are 1-2 phosphorothioates at the 3’ end. In some embodiments, there are 1 or no phosphorothioates at the 5’ end. In some embodiments, there is a hydrophobic conjugate of 12 to 25 carbons attached at the 5’ end via a phosphodiester bond.

[0183] In some cases, the sense strand of any of the siRNAs comprises siRNA with a particular modification pattern. In some embodiments of the modification pattern, position 9 counting from the 5’ end of the sense strand may have a 2’F modification. In some embodiments, when position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have a 2’0Me modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of the sense strand, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.

[0184] In some embodiments, when position 9 of the sense strand is a purine, then all purines in the sense strand have a 2’0Me modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with a 2’F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacentpositions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.

[0185] In some cases, position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’0Me modifications may occur at the other positions of the sense strand. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.

[0186] In some embodiments, the sense strand comprises or consists of RNA or modified RNA nucleotides. In some embodiments, the sense strand comprises a deoxy nucleoside. The deoxy nucleoside may include a DNA nucleoside. In some embodiments, the deoxy nucleoside comprises or consists of a 2’ deoxy nucleoside. The deoxy nucleoside may be at a position within the sense strand (5’ to 3’, where the 5’ position is 1). The position within the sense strand may be or include position 2, 4, 6, 8, 9, 10, 12, 14, 16, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 4, 6, 8, 10, 12, 14, 16, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 6, 9, 10, 14, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 6, 10, 14, or 18, or a combination of said positions. The position within the sense strand may be or include position 4, 8, 9, 12, or 16, or a combination of said positions. The position within the sense strand may be or include position 4, 8, 12, or 16, or a combination of said positions. The position within the sense strand may include position 9. The position within the sense strand may be position 9. The sense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides. In some embodiments, the sense strand includes 1 deoxy nucleoside. The sense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides, or a range of deoxy nucleosides defined by any two of the aforementioned numbers of deoxy nucleosides. The sense strand may include deoxy nucleosides at all even positions. The sense strand may include deoxy nucleosides at some even positions. The sense strand may include deoxy nucleosides at every other even position. The sense strand may include 1 deoxy nucleoside. The sense strand may include at least 1 deoxy nucleoside. The sense strand may include at least 2 deoxy nucleosides. The sense strand may include at least 3 deoxy nucleosides. The sense strand may include at least 4 deoxy nucleosides. The sense strand may include at least 5 deoxy nucleosides. The sense strand may include at least 6 deoxy nucleosides. The sense strand may include at least 7 deoxy nucleosides. The sense strand may include at least 8 deoxy nucleosides. The sense strand may include at least 9 deoxy nucleosides. The sense strand may include at least 10 deoxy nucleosides. The sense strand may include no greater than 2 deoxy nucleosides. The sense strand may include no greater than 3 deoxy nucleosides. The sense strand may include no greater than 4 deoxy nucleosides. The sense strand may include no greater than 5 deoxy nucleosides. The sense strand may include no greater than 6 deoxy nucleosides. The sense strand may include no greater than 7 deoxy nucleosides. The sense strand may include no greater than 8 deoxynucleosides. The sense strand may include no greater than 9 deoxy nucleosides. The sense strand may include no greater than 10 deoxy nucleosides.

[0187] In some embodiments, the antisense strand comprises or consists of RNA or modified RNA nucleotides. In some embodiments, the antisense strand comprises a deoxy nucleoside. The deoxy nucleoside may include a DNA nucleoside. In some embodiments, the deoxy nucleoside comprises or consists of a 2’ deoxy nucleoside. The antisense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides, or a range of deoxy nucleosides defined by any two of the aforementioned numbers of deoxy nucleosides.

[0188] In some embodiments in which a deoxy nucleoside is included in the sense strand (e.g. at the 9th nucleotide counting from 5’ end), nucleosides at positions 1-8 include a mixture of 2’-fluoro and 2’-O- methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 include a mixture of 2 ’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 include a mixture of 2 ’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, nucleosides at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 include a mixture of 2 ’-fluoro and 2’-O-methyl modified nucleosides, and pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides, and purines at positions 1-8 all include 2’-O-methyl modified nucleosides.

[0189] Disclosed herein, in some embodiments are compositions comprising an oligonucleotide that targets DKK2 and when administered to a cell decreases expression of DKK2, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, or an sense strand sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the oligonucleotide sequence in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, and wherein the antisense strand comprises an antisense strand sequence described herein in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the antisense strand sequence in which at least one intemucleoside linkage is modified and at least one nucleoside is modified. Some embodiments relate to methods that include administering the composition to a subject.

[0190] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence in Table 4. In some embodiments, thesense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 4. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 4, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 4, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 4. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g. a different set of modifications or modification pattern than in Table 4). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0191] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence in Table 5. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 5. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 5, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 5, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 5. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g. a different set of modifications or modification pattern than in Table 5). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0192] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence in Table 6. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strandsequence in Table 6. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 6, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 6, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 6. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g. a different set of modifications or modification pattern than in Table 6). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0193] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence in Table 13A. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 13A. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 13A, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 13A, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 13A. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g. a different set of modifications or modification pattern than in Table 13A). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0194] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence in Table 17. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 17. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 17, or a sequence thereof having 3 or 4 nucleoside substitutions,additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 17, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 17. The sense strand or antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the first 19 nucleotides of any of the aforementioned sequences. The sense strand or antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand or antisense strand may comprise an overhang. The sense strand or antisense strand may comprise any modifications described herein (e.g. a different set of modifications or modification pattern than in Table 17). The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0195] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID Nos: 7666-7717. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID Nos: 7666-7717, at least 80% identical to any one of SEQ ID Nos: 7666-7717, at least 85% identical to of any one of SEQ ID Nos: 7666-7717, at least 90% identical to any one of SEQ ID Nos: 7666-7717, or at least 95% identical to any one of SEQ ID Nos: 7666-7717. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID Nos: 7666-7717, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID Nos: 1-3636, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID Nos: 7666-7717. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety.

[0196] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID Nos: 7718-7769. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID Nos: 7718-7769, at least 80% identical to any one of SEQ ID Nos: 7718-7769, at least 85% identical to of any one of SEQ ID Nos: 7718-7769, at least 90% identical to any one of SEQ ID Nos: 7718-7769, or at least 95% identical to any one of SEQ ID Nos: 7718-7769. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID Nos: 7718-7769, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID Nos: 7718-7769, or an antisense strandsequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID Nos: 7718-7769. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety.4. ASO modification patterns

[0197] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of DKK2, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises modification pattern ASO1: 5’-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3’, wherein “dN” is any deoxynucleotide, “n” is a 2’-O-methyl or 2 ’-O-methoxyethyl -modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the ASO comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, or 17AS.D. Formulations

[0198] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0199] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises a cream. In some embodiments, the pharmaceutically acceptable carrier comprises a gel. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, a saline solution, a cream, or a gel. In some embodiments, the pharmaceutically acceptable carrier comprises contains a permeation enhancer. In some embodiments, the formulation contains pharmaceutically acceptable counterions to the oligonucleotides. In some embodiments, the pharmaceutically acceptable counterions increase membrane affinity. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof. In some embodiments, the composition is formulated for topical administration.E. Kits

[0200] Described herein, in some embodiments, are kits. The kit may include an oligonucleotide such as an siRNA described herein. The oligonucleotide may be conjugated to a lipid moiety or to a sugar moiety. The kit may include a lipid moiety. The kit may include a sugar moiety. The oligonucleotide may comprise nucleoside modifications or modified intemucleoside linkages. The oligonucleotide may include any modifications described herein, such as modifications from a base sequence. The kit may include a delivery reagent such as a needle. The kit may include instructions for use, such as methods for use in a method described herein.II. METHODS AND USES

[0201] Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject.

[0202] Some embodiments relate to a method of treating a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.

[0203] In some embodiments, the treatment comprises prevention, inhibition, or reversion of the disorder in the subject. Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder a disorder in a subject in need thereof. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject.

[0204] Some embodiments relate to a method of preventing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.

[0205] Some embodiments relate to a method of inhibiting a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.

[0206] Some embodiments relate to a method of reversing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.

[0207] The administration may be topical. For example, a composition or formulation described herein may be administered to a scalp. The topical administration may include rubbing, brushing, swabbing, dabbing, or wiping. The administration may be on a skin area of the subject. The skin area may include hair. The skin area may include hair loss. The skin area may be at risk of hair loss. The skin area may include an area of the head. The skin area may include a scalp. The skin area may include a scalp region. The skin area may include a temporal region. The skin area may include a neck region.A. Disorders

[0208] Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. In some embodiments, the disorder includes hair loss. In some embodiments, the disorder is hair loss. Non-limiting examples of hair loss include androgenetic alopecia (male pattern baldness), alopecia areata, and non-scarring hair loss. In some embodiments, the disorder includes hair discoloration or graying. In some embodiments, the hair loss comprises male pattern baldness. In some embodiments, the hair loss comprises alopecia areata. In some embodiments, the hair loss comprises scarring hair loss. In some embodiments, the hair loss comprises non-scarring hair loss.B. Subjects

[0209] Some embodiments of the methods described herein include treatment of a subject. Non-limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cattle. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human. In some embodiments, the subject is male. In some embodiments, the subject is female.

[0210] In some embodiments, the subject has a body mass index (BMI) of 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, 50, or more, or a range defined by any two of the aforementioned integers. In some embodiments, the subject is overweight. In some embodiments, the subject has a BMI of 25 or more. In some embodiments, the subject has a BMI of 25-29. In some embodiments, the subject is obese. In some embodiments, the subject has a BMI of 30 or more. In some embodiments, the subject has a BMI of 30-39. In some embodiments, the subject has a BMI of 40-50. In some embodiments, the subject has a BMI of 25-50.

[0211] In some embodiments, the subject is > 90 years of age. In some embodiments, the subject is > 85 years of age. In some embodiments, the subject is > 80 years of age. In some embodiments, the subject is > 70 years of age. In some embodiments, the subject is > 60 years of age. In some embodiments, the subject is > 50 years of age. In some embodiments, the subject is > 40 years of age. In some embodiments, the subject is > 30 years of age. In some embodiments, the subject is > 20 years of age. In someembodiments, the subject is > 10 years of age. In some embodiments, the subject is > 1 years of age. In some embodiments, the subject is > 0 years of age.

[0212] In some embodiments, the subject is < 100 years of age. In some embodiments, the subject is < 90 years of age. In some embodiments, the subject is < 85 years of age. In some embodiments, the subject is < 80 years of age. In some embodiments, the subject is < 70 years of age. In some embodiments, the subject is < 60 years of age. In some embodiments, the subject is < 50 years of age. In some embodiments, the subject is < 40 years of age. In some embodiments, the subject is < 30 years of age. In some embodiments, the subject is < 20 years of age. In some embodiments, the subject is < 10 years of age. In some embodiments, the subject is < 1 years of age.

[0213] In some embodiments, the subject is between 0 and 100 years of age. In some embodiments, the subject is between 20 and 90 years of age. In some embodiments, the subject is between 30 and 80 years of age. In some embodiments, the subject is between 40 and 75 years of age. In some embodiments, the subject is between 50 and 70 years of age. In some embodiments, the subject is between 40 and 85 years of age. In some embodiments, the subject is aging. In some embodiments, the subject is an adult.

[0214] In some embodiments, the subject has a family history of hair loss. In some embodiments, the subject has hormone levels related to hair loss. In some embodiments, the subject has a thyroid disorder. In some embodiments, the subject is malnourished. In some embodiments, the subject has been subjected to environmental factors affecting hair loss. In some embodiments, the subject has subjected to physical stress. In some embodiments, the subject has subjected to emotional stress.C. Baseline measurements

[0215] Some embodiments of the methods described herein include obtaining a baseline measurement from a subject. For example, in some embodiments, a baseline measurement is obtained from the subject prior to treating the subject. In some embodiments, the baseline measurement is a baseline hair loss measurement. In some embodiments, the baseline measurement is a baseline measurement of a symptom of hair loss. Non-limiting examples of baseline measurements include a baseline hair loss assessment score, a baseline total hair count, a baseline vellus hair count, a baseline non-vellus hair count, a baseline hair thickness measurement, a baseline hair density measurement, or a baseline number of hair follicles. The baseline measurement may include a baseline hair color measurement. The baseline measurement may include a baseline gene or protein level, a baseline DKK2 mRNA level, or a baseline DKK2 protein level.

[0216] In some embodiments, the baseline measurement is obtained non-invasively. In some embodiments, the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. In some embodiments, the baseline measurement is obtained using a photograph. In some embodiments, the baseline measurement is obtained using a phototrichogram. In some embodiments, the baseline measurement is obtained using a macrophotography analysis. In some embodiments, the baseline measurement is obtained using a questionnaire.

[0217] In some embodiments, the baseline measurement is obtained invasively. In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in a biopsy such as a scalp biopsy. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the baseline measurement is obtained by PCR.

[0218] In some embodiments, the baseline measurement is a baseline questionnaire result. In some embodiments, the baseline measurement is a baseline hair loss hair loss assessment score. In some embodiments, the baseline questionnaire result comprises a baseline score such as a baseline hair loss assessment score. In some embodiments, the baseline questionnaire result is obtained from a questionnaire. In some embodiments, the baseline questionnaire result is obtained from multiple questionnaires. In some embodiments, the questionnaire is a Men’s Hair Growth Questionnaire (MHGQ). In some embodiments, the questionnaire is a Kingsley Alopecia Profde (KAP) questionnaire. The questionnaire may include questions about hair growth that the subject rates. Non-limiting examples of such ratings may include strongly agree, agree, neither agree nor disagree, disagree, and strongly disagree, where each rating is assigned a value. The baseline score may include a sum of each value. In some embodiments, the baseline hair loss assessment score is not based on a questionnaire. In some embodiments, the baseline hair loss assessment score is assessed by a medical practitioner. In some embodiments, the baseline hair loss assessment score includes a semi-quantitative hair visual hair score on a numerical scale such as 1-10.

[0219] In some embodiments, the baseline measurement is a baseline hair count. In some embodiments, the baseline hair count is a baseline total hair count. The baseline total hair count may include a baseline vellus hair count and a baseline non-vellus hair count. In some embodiments, the baseline hair count is a baseline vellus hair count. In some embodiments, the baseline hair count is a baseline non-vellus hair count. In some embodiments, the baseline hair count is determined in an area of skin. In some embodiments, the baseline hair count is normalized based on the area of skin. In some embodiments, the baseline hair count is assessed using photography. In some embodiments, the baseline hair count is assessed by phototrichogram. In some embodiments, the baseline hair count is assessed by a macrophotography analysis.

[0220] In some embodiments, the baseline measurement is a baseline hair thickness measurement. In some embodiments, the baseline hair thickness measurement is determined in an area of skin. In some embodiments, the baseline hair thickness measurement comprises a width of an individual hair. In some embodiments, the baseline hair thickness measurement comprises widths of multiple individual hairs. In some embodiments, the baseline hair thickness measurement comprises an average of the widths of the multiple individual hairs. In some embodiments, the baseline hair thickness measurement comprises a median of the widths of the multiple individual hairs. The baseline hair thickness measurement mayinclude a baseline vellus hair thickness measurement. The baseline hair thickness measurement may include a baseline non-vellus hair thickness measurement. In some embodiments, the baseline hair thickness measurement is assessed using photography. In some embodiments, the baseline hair thickness measurement is assessed by phototrichogram. In some embodiments, the baseline hair thickness measurement is assessed by a macrophotography analysis.

[0221] In some embodiments, the baseline measurement is a baseline hair density measurement. In some embodiments, the baseline hair density measurement is determined in an area of skin. In some embodiments, the baseline hair density measurement comprises a number of hair in the area of skin. In some embodiments, the baseline hair density measurement comprises the number of hair in the area of skin divided by the area of skin. The baseline hair density measurement may include a baseline vellus hair density measurement. The baseline hair density measurement may include a baseline non-vellus hair density measurement. In some embodiments, the baseline hair density measurement is assessed using photography. In some embodiments, the baseline hair density measurement is assessed by phototrichogram. In some embodiments, the baseline hair density measurement is assessed by a macrophotography analysis.

[0222] In some embodiments, the baseline measurement is a baseline number of hair follicles. In some embodiments, the baseline number of hair follicles is a baseline total number of hair follicles. In some embodiments, the baseline number of hair follicles include a baseline number of terminal hair follicles. In some embodiments, the baseline number of hair follicles include a baseline number of anagen hair follicles. In some embodiments, the baseline number of hair follicles include a baseline number of telogen hair follicles. In some embodiments, the baseline number of hair follicles include a baseline number of catagen hair follicles. In some embodiments, the baseline number of hair follicles include a baseline number of miniaturized hair follicles. In some embodiments, the baseline number of hair follicles include a baseline number of vellus miniaturized hair follicles. In some embodiments, the baseline number of hair follicles include a baseline number of vellus-like miniaturized hair follicles. In some embodiments, the baseline number of hair follicles include a baseline number of indeterminate hair follicles. In some embodiments, the baseline number of hair follicles is determined in an area of skin. In some embodiments, the baseline number of hair follicles is normalized based on the area of skin. In some embodiments, the baseline number of hair follicles is assessed in a biopsy, such as a scalp biopsy. In some embodiments, the baseline number of hair follicles is assessed using photography.

[0223] In some embodiments, the baseline measurement is a baseline hair color measurement. In some embodiments, the baseline hair color measurement is determined in an area of skin. In some embodiments, the baseline hair color measurement comprises a color of an individual hair. In some embodiments, the baseline hair color measurement comprises colors of multiple individual hairs. In some embodiments, the baseline hair color measurement comprises an average of the colors of the multiple individual hairs. In some embodiments, the baseline hair color measurement comprises a median of the colors of the multiple individual hairs. The baseline hair color measurement may include a baseline measurement of how gray the hair is, or how gray the hairs are. The baseline hair color measurement mayinclude a baseline measurement of how much color is in the hair, or how much color is in the hairs. The baseline hair color measurement may include a baseline measurement of how white the hair is, or how white the hairs are. The baseline hair color measurement may include a hair pigmentation measurement. The baseline hair color measurement may include a hair contrast measurement. The baseline hair color measurement may include a baseline vellus hair color measurement. The baseline hair color measurement may include a baseline non-vellus hair color measurement. In some embodiments, the baseline hair color measurement is assessed using photography. In some embodiments, the baseline hair color measurement is assessed by phototrichogram. In some embodiments, the baseline hair color measurement is assessed by a macrophotography analysis. The baseline hair color measurement may be a qualitative measurement. The baseline hair color measurement may be a quantitative measurement. The baseline hair color measurement may be a number, such as an amount of hair color. The baseline hair color measurement may be a rate, such as a rate of hair color loss.

[0224] In some embodiments, the baseline measurement is a baseline protein level. In some embodiments, the baseline protein level is a baseline [3-catenin protein level. In some embodiments, the baseline protein level is a baseline a-SMA protein level. In some embodiments, the baseline protein level is a baseline collagen protein level. In some embodiments, the collagen of the baseline collagen protein level is collagen I. In some embodiments, the collagen of the baseline collagen protein level is collagen III. In some embodiments, the baseline protein level is assessed in a baseline sample such as a baseline skin sample. In some embodiments, the baseline protein level is indicated as a mass or percentage of protein per sample weight. In some embodiments, the baseline protein level is indicated as a mass or percentage of protein per sample volume. In some embodiments, the baseline protein level is indicated as a mass or percentage of protein per total protein within the sample. In some embodiments, the baseline protein measurement is a baseline circulating protein measurement. In some embodiments, the baseline protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.

[0225] In some embodiments, the baseline measurement is a baseline mRNA level. In some embodiments, the baseline mRNA level is a baseline [3-catenin mRNA level. In some embodiments, the baseline mRNA level is a baseline a-SMA mRNA level. In some embodiments, the baseline mRNA level is a baseline collagen mRNA level. In some embodiments, the collagen of the baseline collagen mRNA level is collagen I. In some embodiments, the collagen of the baseline collagen mRNA level is collagen III. In some embodiments, the baseline mRNA level is assessed in a baseline sample such as a baseline skin sample. In some embodiments, the baseline mRNA level is indicated as a mass or percentage of mRNA per sample weight. In some embodiments, the baseline mRNA level is indicated as a mass or percentage of mRNA per sample volume. In some embodiments, the baseline mRNA level is indicated as a mass or percentage of mRNA per total mRNA within the sample. In some embodiments, the baseline mRNA level is indicated as a mass or percentage of mRNA per total nucleic acids within the sample. In some embodiments, the baseline mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline mRNAmeasurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the mRNA.

[0226] In some embodiments, the baseline measurement is a baseline DKK2 protein measurement. In some embodiments, the baseline DKK2 protein measurement comprises a baseline DKK2 protein level. In some embodiments, the baseline DKK2 protein level is assessed in a baseline sample such as a baseline skin sample or a baseline fluid sample (e.g. blood, serum, or plasma). In some embodiments, the baseline DKK2 protein level is indicated as a mass or percentage of DKK2 protein per sample weight. In some embodiments, the baseline DKK2 protein level is indicated as a mass or percentage of DKK2 protein per sample volume. In some embodiments, the baseline DKK2 protein level is indicated as a mass or percentage of DKK2 protein per total protein within the sample. In some embodiments, the baseline DKK2 protein measurement is a baseline circulating DKK2 protein measurement. In some embodiments, the baseline DKK2 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.

[0227] In some embodiments, the baseline measurement is a baseline DKK2 mRNA measurement. In some embodiments, the baseline DKK2 mRNA measurement comprises a baseline DKK2 mRNA level. In some embodiments, the baseline DKK2 mRNA level is assessed in a baseline sample such as a baseline skin sample. In some embodiments, the baseline DKK2 mRNA level is indicated as a mass or percentage of DKK2 mRNA per sample weight. In some embodiments, the baseline DKK2 mRNA level is indicated as a mass or percentage of DKK2 mRNA per sample volume. In some embodiments, the baseline DKK2 mRNA level is indicated as a mass or percentage of DKK2 mRNA per total mRNA within the sample. In some embodiments, the baseline DKK2 mRNA level is indicated as a mass or percentage of DKK2 mRNA per total nucleic acids within the sample. In some embodiments, the baseline DKK2 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline DKK2 mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the DKK2 mRNA.

[0228] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject. In some embodiments, the sample is obtained from the subject in a fasted state. In some embodiments, the sample is obtained from the subject after an overnight fasting period. In some embodiments, the sample is obtained from the subject in a fed state.

[0229] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, thesample is a whole-blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample.

[0230] In some embodiments, the sample comprises a tissue. The tissue may be or include skin. The skin may comprise or consist of a skin layer. The skin layer may be or include a dermal layer or an epidermal layer. The skin may include epidermis. The skin may include epidermis. The skin may include scalp skin. The skin may eyebrow skin. The skin may pubic skin. The skin may include skin from a leg of the subject. The skin may include skin from an arm of the subject. The skin may include one or more hairs. The hairs may be any of scalp hairs, eyebrow hairs, pubic hairs, arm hairs, or leg hairs.

[0231] In some embodiments, the sample is a tissue sample. In some embodiments, the sample comprises skin. In some embodiments, the sample is a skin sample. For example, the baseline DKK2 mRNA measurement, or the baseline DKK2 protein measurement, may be obtained in a skin sample from the patient prior to administration of a compound or oligonucleotide disclosed herein. In some embodiments, the sample is a biopsy. In some embodiments, the biopsy is a skin biopsy. In some embodiments, the skin biopsy includes a scalp biopsy.D. Effects

[0232] In some embodiments, the composition or administration of the composition affects a measurement such as a hair loss measurement or a measurement of a symptom of hair loss. In some embodiments, the measurement is a hair loss assessment score, a total hair count, a vellus hair count, a non-vellus hair count, a hair thickness measurement, a hair density measurement, a number of hair follicles, a hair color measurement, a gene or protein level, a DKK2 protein measurement (for example, circulating or tissue DKK2 protein levels), or a DKK2 mRNA measurement, relative to the baseline measurement.

[0233] Some embodiments of the methods described herein include obtaining the measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement indicates that the disorder has been treated.

[0234] In some embodiments, the measurement is obtained non-invasively. In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the measurement is obtained noninvasively using an imaging device. In some embodiments, the measurement is obtained using a photograph. In some embodiments, the measurement is obtained using a phototrichogram. In some embodiments, the measurement is obtained using a macrophotography analysis. In some embodiments, the measurement is obtained using a questionnaire.

[0235] In some embodiments, the measurement is obtained invasively. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in a biopsy such as a scalp biopsy. In some embodiments, the measurement is obtained in one ormore histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescence assay, or a PCR assay. In some embodiments, the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the measurement is obtained by PCR. In some embodiments, the measurement is obtained by histology. In some embodiments, the measurement is obtained by observation. In some embodiments, additional measurements are made, such as in a 3rd sample, a 4th sample, or a fifth sample.

[0236] In some embodiments, the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition. In some embodiments, the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition. In some embodiments, the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the composition. In some embodiments, the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition.

[0237] In some embodiments, the composition reduces the measurement relative to the baseline measurement. In some embodiments, the reduction is measured in a second tissue sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In someembodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0238] In some embodiments, the composition increases the measurement relative to the baseline measurement. In some embodiments, the increase is measured in a second tissue sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement. In some embodiments, the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0239] In some embodiments, the measurement is a questionnaire result. In some embodiments, the measurement is a hair loss assessment score. In some embodiments, the questionnaire result comprises a score such as a hair loss assessment score. In some embodiments, the questionnaire result is obtained from a questionnaire. In some embodiments, the questionnaire result is obtained from multiple questionnaires. In some embodiments, the questionnaire is a Men’s Hair Growth Questionnaire (MHGQ). In some embodiments, the questionnaire is a Kingsley Alopecia Profile (KAP) questionnaire. The questionnaire may include questions about hair growth that the subject rates. Non-limiting examples of such ratings may include strongly agree...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount increases a hair count in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821.

2. The composition of claim 1, wherein the hair count is increased by about 10% or more, as compared to prior to administration.

3. The composition of claim 1, wherein the hair count includes a vellus hair count, a non- vellus hair count, or a total hair count.

4. A composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount increases a hair thickness measurement in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770- 7821.

5. The composition of claim 4, wherein the hair thickness measurement is increased by about 10% or more, as compared to prior to administration.

6. A composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount increases a hair density measurement in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821.

7. The composition of claim 6, wherein the hair density measurement is increased by about 10% or more, as compared to prior to administration.

8. A composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount increases a number of hair follicles in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770- 7821.

9. The composition of claim 8, wherein the number of hair follicles is increased by about 10% or more, as compared to prior to administration.

10. The composition of claim 8, wherein the number of hair follicles includes a number of terminal hair follicles, a number of anagen hair follicles, a number of telogen hair follicles, a number of catagen hair follicles, a number of vellus-like miniaturized hair follicles, a number of indeterminate hair follicles, or a total number of hair follicles.

11. A composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount changes a hair loss assessment score in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821.

12. The composition of claim 11, wherein the hair loss assessment score is changed by about 10% or more, as compared to prior to administration.

13. A composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a subject in an effective amount changes a protein or mRNA level of P-catenin, a-SMA, collagen I, or collagen III, in the subject wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821.

14. The composition of claim 13, wherein the protein or mRNA level of P-catenin, a-SMA, collagen I, or collagen III is changed by about 10% or more, as compared to prior to administration.

15. A composition comprising an oligonucleotide that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to the skin of a subject in an effective amount decreases a level of DKK2 mRNA or DKK2 protein wherein the oligonucleotide is selected from SEQ ID NO: 7770-7821.

16. The composition of claim 15, wherein the skin comprises scalp skin.

17. The composition of claim 15, wherein the level of DKK2 mRNA or DKK2 protein decreased by about 10% or more, as compared to prior to administration.

18. The composition of any one of claims 1-17, wherein the oligonucleotide comprises a modified intemucleoside linkage.

19. The composition of claim 18, wherein the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

20. The composition of claim 18, wherein the modified intemucleoside linkage comprises one or more phosphorothioate or phosphate linkages.

21. The composition of any one of claims 1-17, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages.

22. The composition of any one of claims 1-17, wherein the oligonucleotide comprises 2 or more modified intemucleoside linkages, 3 or more modified intemucleoside linkages, 4 or more modified intemucleoside linkages, 5 or more modified intemucleoside linkages, 6 or more modified intemucleosidelinkages, 7 or more modified intemucleoside linkages, 8 or more modified intemucleoside linkages, 9 or more modified intemucleoside linkages, 10 or more modified intemucleoside linkages, 11 or more modified intemucleoside linkages, 12 or more modified intemucleoside linkages, 13 or more modified intemucleoside linkages, 14 or more modified intemucleoside linkages, 15 or more modified intemucleoside linkages, 16 or more modified intemucleoside linkages, 17 or more modified intemucleoside linkages, 18 or more modified intemucleoside linkages, 19 or more modified intemucleoside linkages, or 20 or more modified intemucleoside linkages.

23. The composition of any one of claims 1-17, wherein the oligonucleotide comprises a modified nucleoside.

24. The composition of claim 23, wherein the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof.

25. The composition of claim 23, wherein the modified nucleoside comprises an LNA.

26. The composition of claim 23, wherein the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid.

27. The composition of claim 23, wherein the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-0-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.

28. The composition of claim 23, wherein the modified nucleoside comprises one or more 2’- fluoro modified nucleosides.

29. The composition of claim 23, wherein the modified nucleoside comprises a 2'-O-alkyl modified nucleoside.

30. The composition of claim 23, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.

31. The composition of claim 30, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a- tocopherol, or a combination thereof.

32. The composition of any one of claims 1-31, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides.

33. The composition of any one of claims 1-32, wherein the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

34. The composition of any one of claims 1-33, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

35. The composition of claim 34, wherein the sense strand is 14-30 nucleosides in length.

36. The composition of claim 34, wherein the antisense strand is 14-30 nucleosides in length.

37. A composition comprising an oligonucleotide that inhibits the expression of dickkopf WNT signaling pathway inhibitor 2 (DKK2) wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of SEQ ID NO: 1 wherein the sense strand is selected from SEQ ID NO: 7770-7821, and wherein the antisense strand is selected from SEQ ID NO: 7822-7873.

38. A composition comprising an oligonucleotide that inhibits the expression of dickkopf WNT signaling pathway inhibitor 2 (DKK2), wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of a full-length human DKK2 pre-mRNA sequence wherein the sense strand is selected from SEQ ID NO: 7770-7821 and wherein the antisense strand is selected from SEQ ID NO: 7822-7873.

39. The composition of any one of claims 1-38, wherein the sense strand is selected from the group consisting of SEQ ID NO: 7787, SEQ ID NO: 7799, and SEQ ID NO: 7804; wherein the antisense strand is selected from the group consisting of SEQ ID NO: 7839, SEQ ID NO: 7821, and SEQ ID NO: 7856.

40. The composition of claim 39, wherein the sense strand is selected from the group consisting of: SEQ ID NO: 7684, SEQ ID NO: 7874, and SEQ ID NO: 7875; wherein the antisense strand is selected from the group consisting of: SEQ ID NO: 7328, SEQ ID NO: 7747, and SEQ ID NO: 7752.41 The composition of any one of claims 1- 39, wherein the oligonucleotide further comprises a modification pattern.

42. The composition of claim 41, wherein the modification pattern is selected from the group consisting of: 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, and 17AS, wherein "N" is any nucleotide, “dN” is a 2’ deoxy-modified nucleoside, “NT’ is a 2’- fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside and “s” is a phosphorothioate or phosphate linkage.

43. A composition comprising a small interfering RNA (siRNA) that targets dickkopf WNT signaling pathway inhibitor 2 (DKK2) and when administered to a cell decreases expression of DKK2, wherein the siRNA comprises a sense strand and an antisense strand; and wherein the antisense strand comprises modification pattern 6AS, 7AS, 8AS, 9AS, 10AS, 1 IAS, 12AS, HAS. 14AS, 15AS, 16AS, and 17AS ; or wherein the sense strand comprises a modification pattern selected from the group consisting of: 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, and 68S, wherein “Nf’ is a 2’- fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside and “s” is a phosphorothioate or phosphate linkage.

44. A method of treating hair loss in a subject in need thereof comprising administering to the subject a composition according to any one of the aforementioned claims.

45. The method of claim 44, wherein the hair loss comprises any one or more of male pattern baldness, female pattern baldness, alopecia areata, or non-scarring hair loss.

46. The method of claim 44 or 45, wherein the administration is topical.

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