Chi3l1-targeting oligonucleotides and methods of using the same

Abstract

Among other things, the present disclosure provides oligonucleotides (e.g., antisense oligonucleotides) targeting CHI3L1 and compositions thereof. In some aspects, the present disclosure provides methods for preventing or treating a brain cancer, for example, glioblastoma.

Description

CHI3L1 -TARGETING OLIGONUCLEOTIDES AND METHODS OF USINGTHE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 728,942, filed December 6, 2024, which is incorporated herein by reference in its entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the electronically submitted Sequence Listing XML (File Name 5389.005PC01_SequenceListing_ST26.xml; Size: 77,192 bytes; and Date of Creation: November 18, 2025) filed with the application is incorporated herein by reference in its entirety.FIELD OF DISCLOSURE

[0003] The present disclosure pertains generally to the fields of molecular biology and medicine. More particularly it relates to oligonucleotides, e.g., antisense oligonucleotides (ASOs), and methods of using the same.BACKGROUND

[0004] Glioblastoma is the most prevalent and aggressive primary brain tumor in the United States (see, e.g., Ostrom QT et al. Neuro. Oncol. 2020; 22(12 Suppl 2):ivl-iv96). Standard treatment for glioblastoma includes surgical resection followed by radiation in the vicinity of the resection cavity and administration of temozolomide (see, e.g., Stupp R et al. N. Engl. J. Med. 2005; 352:987-96). Even with this therapeutic approach, tumor recurrence is inevitable mainly due to the presence of glioma stem cells (GSC), which are characterized by high migratory potential, resistance to chemotherapy and radiation and the ability to form recurrent tumors (see, e.g., Soni P et al. Asian Pac. J. Cancer Prev. 2017; 18:2215-9). Although each glioblastoma contains cells in multiple states, plasticity between states and the potential of a single cell to generate multiple transcriptomic and phenotypic states has been demonstrated (Neftel C et al. Cell. 2019; 178:835-49).

[0005] From all glioma cell phenotypes, the mesenchymal state is associated with worst clinical outcomes and the main phenotypic markers expressed in mesenchymal GSCs are CD44 and chitinase 3— like protein 1 (CHI3L1). CHI3L1, also known as YKL-40 or human cartilage glycoprotein 39 (HC-gp39), is a chitin-binding lectin that belongs to the glycosyl hydrolasefamily. CHI3L1, commonly referred to as YKL-40, is a secreted glycoprotein encoded by the CHI3L1 gene. CHI3L1 is expressed in astrocytes in the brain, in macrophages in the periphery, and is induced in the setting of inflammation. YKL-40 levels increase in parallel with tau protein and other markers of inflammation and neurodegeneration.

[0006] YKL-40 is secreted from a variety of cells including macrophages, neutrophils, epithelial, endothelial, synovial cells as well as cancer cells. Studies have demonstrated that circulating levels of YKL-40 are increased in many malignancies, including prostate, colon, ovary, kidney, breast, glioblastoma, malignant melanoma, and lung cancer. High levels of YKL-40 are frequently associated with poor prognosis and mortality in these cancers (see, e.g., Iwamoto FM et al. Neuro. Oncol. 2011; 13: 1244-51; Schmidt H et al. Cancer. 2006; 106:1130- 9; Vom Dorp F et al. J Urol. 2016; 195: 1120-5; Bi J et al. Hum. Pathol. 2009; 40: 1790-7; and Johansen JS et al. Lung Cancer. 2004; 46: 333-40). CHI3L1 mRNA expression has been found to be significantly increased in glioma tumor samples compared to healthy control brain samples, and elevated levels of CHI3L1 expression were shown to be correlated with reduced survival across two independent glioma cohorts (Zhou J et al. Int. J. Mol. Sci. 2024; 25(13): 7094). YKL-40 has recently been identified as a targetable vulnerability in glioblastoma (Guetta-Terrier C et al. Cancer Res. 2023; 83(12): 1984-1999). YKL-40 has been shown to play a role in VEGF expression, tumor angiogenesis, and radioresistance of glioblastoma (Francescone RA et al. J. Biol. Chem. 2011; 286(17): 15332-15343), and targeting CHI3L1 has also been shown to restore glioblastoma sensitivity to temozolomide treatment (Akiyama Y et al. Oncol. Rep. 2014; 32(1): 159-66).

[0007] Monoclonal antibodies (mAb) against YKL-40 are being developed as potential therapeutic agents that neutralize it or prevent its binding to receptors, thus inhibiting its pro- tumorigenic effects (Kang K et al. Int. J. Mol. Sci. 2020; 21(17): 6354). In an ovarian cancer xenograft mouse model, radiolabeled anti-YKL-40 antibodies were shown to significantly inhibit tumor growth (Chang MC et al. Biomed. Pharmacother. 2022; 155: 113668). However, the safety, efficacy, and long-term effects of these YKL-40-targeted antibody therapies in cancer patients are still being assessed. There remains a need for compositions and methods for treating subjects suffering from (77 / 3 / . / -associated diseases or disorders, including a need for therapies for subjects suffering from a disease or disorder, e.g., glioblastoma.SUMMARY

[0008] Among other things, the present disclosure provides oligonucleotides, compositions, and methods for treating conditions, disorders, or diseases (e.g., glioblastoma) associated with CHI3L1. In some aspects, the present disclosure provides oligonucleotides (e.g., antisense oligonucleotides) that comprise various modifications, e.g., nucleobase modifications, sugar modifications, internucleotidic linkage modifications, etc., and that can hybridize to a CHI3L1 RNA transcript. In some aspects, the present disclosure provides oligonucleotides (e.g., antisense oligonucleotides) and compositions thereof that when administered or delivered to a system comprising or expressing a CHI3L1 transcript can reduce the level of the CHI3L1 transcript in the system.

[0009] Certain aspects of the disclosure are directed to an oligonucleotide, wherein: the oligonucleotide comprises a base sequence of 20 or more contiguous nucleobases comprising CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11), TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13), ATAATTAGTATGGTCACTGT (SEQ ID NO: 15),TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17), or AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19), wherein each T is optionally replaced with U; and wherein the oligonucleotide comprises one or more of a modified nucleobase, a modified sugar, and a modified internucleotidic linkage.

[0010] In some aspects, the base sequence of the oligonucleotide is CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11), TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13), ATAATTAGTATGGTCACTGT (SEQ ID NO: 15),TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17), or AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19).

[0011] In some aspects, the base sequence of the oligonucleotide is TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13) or TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17).

[0012] In some aspects, the base sequence of the oligonucleotide isCCCATGTGCCTGTACCTGCT (SEQ ID NO: 11).

[0013] In some aspects, the base sequence of the oligonucleotide isTTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13).

[0014] In some aspects, wherein the base sequence of the oligonucleotide isATAATTAGTATGGTCACTGT (SEQ ID NO: 15).

[0015] In some aspects, the base sequence of the oligonucleotide is TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17).

[0016] In some aspects, the base sequence of the oligonucleotide is AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19).

[0017] In some aspects, each T is replaced with U such that the base sequence of the oligonucleotide comprises CCCAUGUGCCUGUACCUGCU (SEQ ID NO: 12), UUGGCCCUGCUUAGCUUCUU (SEQ ID NO: 14), AUAAUUAGUAUGGUCACUGU (SEQ ID NO: 16), UUGUACUUUAUUGAGCAGCU (SEQ ID NO: 18), or AAGCUCUUGUACUUUAUUGA (SEQ ID NO: 20).

[0018] In some aspects, each T is replaced with U such that the base sequence of the oligonucleotide is CCCAUGUGCCUGUACCUGCU (SEQ ID NO: 12), UUGGCCCUGCUUAGCUUCUU (SEQ ID NO: 14), AUAAUUAGUAUGGUCACUGU (SEQ ID NO: 16), UUGUACUUUAUUGAGCAGCU (SEQ ID NO: 18), or AAGCUCUUGUACUUUAUUGA (SEQ ID NO: 20)

[0019] In some aspects, each T is replaced with U such that the base sequence of the oligonucleotide is UUGGCCCUGCUUAGCUUCUU (SEQ ID NO: 14) or UUGUACUUUAUUGAGCAGCU (SEQ ID NO: 18).

[0020] In some aspects, the oligonucleotide comprises a 5 ’-wing-gap-wing-3’ structure.

[0021] In some aspects, there are about 3-10 nucleosides in the 5’-wing, optionally wherein there are 5 nucleosides in the 5 ’-wing.

[0022] In some aspects, each sugar in the 5’-wing is independently a modified sugar.

[0023] In some aspects, a sugar in the 5’-wing is a 2’-ORsmodified sugar wherein Rsis Ci- 6 aliphatic; wherein a sugar in the 5 ’-wing is a 2’ -MOE modified sugar; wherein a sugar in the 5 ’-wing is a 2’-OMe modified sugar; and / or wherein a sugar in the 5 ’-wing is a bicyclic sugar, optionally wherein the bicyclic sugar is a LNA sugar or cEt sugar.

[0024] In some aspects, each sugar in the 5 ’-wing is independently a 2’-ORsmodified sugar, wherein Rsis Ci-6 aliphatic, or wherein each sugar in the 5 ’-wing is independently a 2’- MOE modified sugar.

[0025] In some aspects, there are about 8-15 nucleosides in the gap, optionally wherein there are 10 nucleosides in the gap.

[0026] In some aspects, each sugar in the gap is independently a natural DNA sugar.

[0027] In some aspects, the gap contains no cytosine and / or wherein the gap comprises one or more 5-methylcytosine.

[0028] In some aspects, there are about 3-10 nucleosides in the 3 ’-wing, optionally wherein there are 5 nucleosides in the 3 ’-wing.

[0029] In some aspects, each sugar in the 3 ’-wing is independently a modified sugar.

[0030] In some aspects, a sugar in the 3 ’-wing is a 2’-ORsmodified sugar, wherein RsisCi-6 aliphatic; wherein a sugar in the 3’-wing is a 2’-M0E modified sugar; wherein a sugar in the 3’-wing is a 2’-OMe modified sugar; and / or wherein a sugar in the 3’-wing is a bicyclic sugar, optionally wherein the bicyclic sugar is a LNA sugar or cEt sugar.

[0031] In some aspects, each sugar in the 3 ’-wing is independently a 2’-ORsmodified sugar, wherein Rsis Ci-6 aliphatic or wherein each sugar in the 3’-wing is independently a 2’- MOE modified sugar.

[0032] In some aspects, the oligonucleotide comprises a modified internucleotidic linkage, optionally wherein the modified internucleotidic linkage is a phosphorothioate internucleotidic linkage.

[0033] In some aspects, each internucleotidic linkage is independently a modified internucleotidic linkage and / or wherein each internucleotidic linkage is independently a phosphorothioate internucleotidic linkage.

[0034] In some aspects, provided herein is an oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to: an equal length portion within nucleobases 6412-6431 of SEQ ID NO: 29; an equal length portion within nucleobases 6613- 6632 of SEQ ID NO: 29; an equal length portion within nucleobases 7641-7660 of SEQ ID NO: 29; an equal length portion within nucleobases 7742-7761 of SEQ ID NO: 29; or an equal length portion within nucleobases 7748-7767 of SEQ ID NO: 29; wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.

[0035] Certain aspects of the disclosure are directed to an oligonucleotide comprising or having the structure of: / 52MOErC / * / i2MOErC / * / i2MOErC / * / i2MOErA / * / i2MOErT / *dG*dT*dG*iMe-dC*iMe- dC*dT*dG*dT*dA*iMe-dC* / i2MOErC / * / i2MOErT / * / i2MOErG / * / i2MOErC / * / 32MOErT / (SEQ ID NO: 43), / 52MOErT / * / i2MOErT / * / i2MOErG / * / i2MOErG / * / i2MOErC / *iMe- dC*iMe-dC*dT*dG*iMe-dC*dT*dT*dA*dG*iMe- dC* / i2MOErT / * / i2MOErT / * / i2MOErC / * / i2MOErT / * / 32MOErT / (SEQ ID NO: 47), / 52MOErA / * / i2MOErT / * / i2MOErA / * / i2MOErA / * / i2MOErT / *dT*dA*dG*dT*dA*dT*dG* dG*dT*iMe-dC* / i2MOErA / * / i2MOErC / * / i2MOErT / * / i2MOErG / * / 32MOErT / (SEQ ID NO: 52), / 52MOErT / * / i2MOErT / * / i2MOErG / * / i2MOErT / * / i2MOErA / *iMe- dC*dT*dT*dT*dA*dT*dT*dG*dA*dG* / i2MOErC / * / i2MOErA / * / i2MOErG / * / i2MOErC / * / 32MOErT / (SEQ ID NO: 53), / 52MOErA / * / i2MOErA / * / i2MOErG / * / i2MOErC / * / i2MOErT / *iMe- dc * dT * dT * dG* dT * d A* iMe- dC*dT*dT*dT* / i2MOErA / * / i2MOErT / * / i2MOErT / * / i2MOErG / * / 32MOErA / (SEQ ID NO:54), or a salt thereof, wherein: /

[0037] In some aspects, the oligonucleotide / 52MOErA / * / i2MOErT / * / i2MOErA / * / i2MOErA / * / i2MOErT / *dT*dA*dG*dT*dA*dT*dG* dG*dT*iMe-dC* / i2MOErA / * / i2MOErC / * / i2MOErT / * / i2MOErG / * / 32MOErT / (SEQ ID NO:52), or a salt thereof, wherein: / 52MOErA / is* is

[0039] In some aspects, the oligonucleotide is / 52MOErA / * / i2MOErA / * / i2MOErG / * / i2MOErC / * / i2MOErT / *iMe- dc * dT * dT * dG* dT * d A* iMe-dC*dT*dT*dT* / i2MOErA / * / i2MOErT / * / i2MOErT / * / i2MOErG / * / 32MOErA / (SEQ ID NO:54), or a salt thereof, wherein: / 52MOErA / is* is

[0040] In some aspects, the oligonucleotide is a pharmaceutically acceptable salt, optionally wherein the oligonucleotide is a sodium salt.

[0041] In some aspects, wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a portion of SEQ ID NO: 29.

[0042] In some aspects, the oligonucleotide is an antisense oligonucleotide (ASO).

[0043] Certain aspects of the disclosure are directed to a composition comprising an oligonucleotide disclosed herein and a pharmaceutically acceptable carrier. In some aspects, the composition comprises one or more pharmaceutically acceptable salts of anoligonucleotide. In some aspects, the composition is a liquid composition. In some aspects, the pharmaceutically acceptable carrier is a buffer, buffered saline, or artificial cerebrospinal fluid.

[0044] Certain aspects of the disclosure are directed to a method for reducing CHI3L1 mRNA levels, YKL-40 polypeptide levels, and / or YKL-40 activity in a system, comprising administering or delivering to the system an oligonucleotide or composition disclosed herein.

[0045] In some aspects, the system expresses CHI3L1 mRNA.

[0046] In some aspects, the system is or comprises a cell, a tissue, an organ, brain or a portion thereof, an organism, a subject, or a human.

[0047] In some aspects, the level of CHI3L1 mRNA in the system is reduced by about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% compared to absence of the oligonucleotide or composition. In some aspects, the level of YKL-40 polypeptide in the system is reduced by about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, or 90% compared to absence of the oligonucleotide or composition. In some aspects, the level of YKL- 40 activity in the system is reduced by about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, or 90% compared to absence of the oligonucleotide or composition.

[0048] In some aspects, the reduction is assessed in iPSC-derived astrocytes and / or glioblastoma patient-derived cell lines with oligonucleotide delivered via gymnosis, optionally at a concentration of about 10 pM.

[0049] Certain aspects of the disclosure are directed to a method for preventing or treating a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an oligonucleotide or composition disclosed herein. In some aspects, the onset of the condition, disorder or disease is delayed or prevented. In some aspects, the condition, disorder or disease is a brain cancer, e.g., glioblastoma.

[0050] Certain aspects of the disclosure are directed to a method for treating a condition, disorder or disease, comprising administering or delivering to a subject suffering therefrom an oligonucleotide or composition disclosed herein. In some aspects, the severity of a symptom of the condition, disorder or disease is reduced. In some aspects, the condition, disorder or disease is a brain cancer. In some aspects, the brain cancer is glioblastoma.

[0051] Certain aspects of the disclosure are directed to a method for treating a glioblastoma in a subject in need thereof comprising administering to said subject an oligonucleotide or composition disclosed herein.

[0052] In some aspects, the method comprises administering a therapeutically effective amount of the oligonucleotide or composition disclosed herein. In some aspects, after administration one or more clinical assessment results (e.g., size of the cancer or tumor, symptoms associated with the cancer, and / or survival) in the subject are independently improved.

[0053] In some aspects, the oligonucleotide or composition is administered or delivered intratumorally, intrathecally, intracerebrally, intracerebroventricularly, intranasally, intraocularly, intravenously, and / or intraci sternally.BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIG. 1 is a graph showing CHI3L1 knockdown following gymnotic uptake of ASO68 or ASO78 by three different glioblastoma patient-derived cell lines (PDCLs), referred to as PDCL1, PDCL2, and PDCL3. Fold change of CHI3L1 is presented based on the deltadelta CT method using SRSF9 as the housekeeping gene.

[0055] FIG. 2 is a graph showing CHI3L1 knockdown following treatment of sixteen different glioblastoma PDCLs (PDCL1-16) with ASO68 or ASO78. The PDCLs were selected as having differing characteristics (e.g., MGMT methylation status, recurrent tumor, and primary tumor) and were cultured for 24 hours in 96-well plates prior to a 5-day incubation with ASOs. The fold change in CHI3L1 mRNA expression, as determined by qPCR analysis, is shown for each glioblastoma PDCL. “TN” refers to treatment naive, and “PT” refers to previously treated.DETAILED DESCRIPTION

[0056] Technologies of the present disclosure can be understood more readily by reference to the following detailed description of certain aspects. The present disclosure provides oligonucleotides (e.g., antisense oligonucleotides), compositions comprising an oligonucleotide (e.g., an antisense oligonucleotide) of the disclosure, and methods of using the same to reduce the levels of RNA transcripts of a CHI3L1 gene. The CHI3L1 gene can be within a cell, e.g., a cell within a subject, such as a human. The present disclosure also provides methods of using the oligonucleotide (e.g., the antisense oligonucleotide) and compositions thereof of the disclosure for inhibiting the expression of a CHI3L1 gene and / or for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of a CHI3L1 gene, e.g., a C7 / / 3 / . / -associated disease (e.g., glioblastoma).Definitions

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0058] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” can be understood to mean “at least one”; (ii) the term “or” can be understood to mean “and / or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) can be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” can be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” can be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included.

[0059] Unless otherwise specified, description of oligonucleotides and elements thereof (e.g., base sequence, sugar modifications, internucleotidic linkages, linkage phosphorus stereochemistry, patterns thereof, etc.) is from 5’ to 3’. As those skilled in the art will appreciate, in some aspects, oligonucleotides (e.g., antisense oligonucleotides) can be provided and / or utilized as various forms, e.g., salt forms, particularly pharmaceutically acceptable salt forms, e.g., sodium salts. As those skilled in the art will also appreciate, in some aspects, individual oligonucleotides (e.g., antisense oligonucleotides) within a composition can be considered to be of the same constitution and / or structure even though, within such composition (e.g., a liquid composition), particular oligonucleotides (e.g., antisense oligonucleotides) might be in different forms, e.g., salt form(s) (and can be dissolved and the oligonucleotide chain can exist as an anion form when, e.g., in a liquid composition) at a particular moment in time. For example, those skilled in the art will appreciate that, at a given pH, individual internucleotidic linkages along an oligonucleotide chain can be in an acid (H) form, or in one of a plurality of possible salt forms (e.g., a sodium salt, or a salt of a different cation, depending on which ions might be present in the preparation or composition), and willunderstand that, so long as their acid forms (e.g., replacing all cations, if any, with H+) are of the same constitution and / or structure, such individual oligonucleotides can properly be considered to be of the same constitution and / or structure.

[0060] Aliphatic: As used herein, “aliphatic” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or combinations thereof. In some aspects, aliphatic groups contain 1-50 aliphatic carbon atoms. In some aspects, aliphatic groups contain 1-20 aliphatic carbon atoms. In other aspects, aliphatic groups contain 1-10 aliphatic carbon atoms. In other aspects, aliphatic groups contain 1-9 aliphatic carbon atoms. In other aspects, aliphatic groups contain 1-8 aliphatic carbon atoms. In other aspects, aliphatic groups contain 1-7 aliphatic carbon atoms. In other aspects, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other aspects, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other aspects, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0061] Alkyl: As used herein, the term “alkyl” is given its ordinary meaning in the art and can include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some aspects, an alkyl can have 1-100 carbon atoms. In certain aspects, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20 for straight chain, C2-C20 for branched chain), and alternatively, about 1-10. In some aspects, cycloalkyl rings can have from about 3-10 carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some aspects, an alkyl group can be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C1-C4 for straight chain lower alkyls).

[0062] Characteristic portion: As used herein, the term “characteristic portion”, in the broadest sense, refers to a portion of a substance whose presence (or absence) correlates with presence (or absence) of a particular feature, attribute, or activity of the substance. In some aspects, a characteristic portion of a substance is a portion that is found in the substance and in related substances that share the particular feature, attribute or activity, but not in those that donot share the particular feature, attribute or activity. In certain aspects, a characteristic portion shares at least one functional characteristic with the intact substance. For example, in some aspects, a “characteristic portion” of a nucleic acid is one that contains a number of, in some aspects, a continuous stretch of, nucleobases that are characteristic of that nucleic acid.

[0063] Heteroatom: The term “heteroatom", as used herein, means an atom that is not carbon or hydrogen. In some aspects, a heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, and / or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (e.g., quaternized forms, forms as in iminium groups, etc.), phosphorus, sulfur, oxygen; etc.). In some aspects, a heteroatom is silicon, phosphorus, oxygen, sulfur and / or nitrogen. In some aspects, a heteroatom is silicon, oxygen, sulfur and / or nitrogen. In some aspects, a heteroatom is oxygen, sulfur and / or nitrogen.

[0064] Hybridize: As used herein, the term “hybridize,” or “hybridization,” refers to the annealing of oligonucleotides and / or nucleic acids.

[0065] Identity: As used herein, the term “identity” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., oligonucleotides, DNA, RNA, etc.) and / or between polypeptide molecules. In some aspects, polymeric molecules are considered to be “substantially identical” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. Calculation of the percent identity of two nucleic acid or polypeptide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain aspects, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of a reference sequence. The nucleotides at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4: 11-17), which has been incorporated into the ALIGNprogram (version 2.0). In some exemplary aspects, nucleic acid sequence comparisons made with the ALIGN program use a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix.

[0066] Linkage phosphorus: The phrase “linkage phosphorus” is used to indicate that the particular phosphorus atom being referred to is the phosphorus atom present in the internucleotidic linkage, which phosphorus atom corresponds to the phosphorus atom of a phosphodiester internucleotidic linkage as occurs in naturally occurring DNA and RNA. In some aspects, a linkage phosphorus atom is in a modified internucleotidic linkage, wherein each oxygen atom of a phosphodiester linkage is optionally and independently replaced by an organic or inorganic moiety. In some aspects, a linkage phosphorus atom is chiral (e.g., as in phosphorothioate internucleotidic linkages). In some aspects, a linkage phosphorus atom is achiral (e.g., as in natural phosphate linkages).

[0067] Modified nucleobase: The terms “modified nucleobase,” “modified base” and the like refer to a chemical moiety which is chemically distinct from a nucleobase, but which is capable of performing at least one function of a nucleobase. In some aspects, a modified nucleobase is a nucleobase which comprises a modification. In some aspects, a modified nucleobase is capable of at least one function of a nucleobase, e.g., forming a moiety in a polymer capable of base-pairing to a nucleic acid comprising an at least complementary sequence of bases. In some aspects, a modified nucleobase is substituted A, T, C, G, or U, or a substituted tautomer of A, T, C, G, or U. In some aspects, a modified nucleobase in the context of oligonucleotides refer to a nucleobase that is not A, T, C, G or U.

[0068] Modified nucleoside: The term “modified nucleoside” refers to a moiety derived from or chemically similar to a natural nucleoside, but which comprises a chemical modification which differentiates it from a natural nucleoside. Non-limiting examples of modified nucleosides include those which comprise a modification at the base and / or the sugar. Non-limiting examples of modified nucleosides include those with a 2’ modification at a sugar. Non-limiting examples of modified nucleosides also include abasic nucleosides (which lack a nucleobase). In some aspects, a modified nucleoside is capable of at least one function of a nucleoside, e.g., forming a moiety in a polymer capable of base-pairing to a nucleic acid comprising an at least complementary sequence of bases.

[0069] Modified nucleotide: The term “modified nucleotide” includes any chemical moiety which differs structurally from a natural nucleotide but is capable of performing at least onefunction of a natural nucleotide. In some aspects, a modified nucleotide comprises a modification at a sugar, base and / or internucleotidic linkage. In some aspects, a modified nucleotide comprises a modified sugar, modified nucleobase and / or modified internucleotidic linkage. In some aspects, a modified nucleotide is capable of at least one function of a nucleotide, e.g., forming a subunit in a polymer capable of base-pairing to a nucleic acid comprising an at least complementary sequence of bases.

[0070] Modified sugar: The term “modified sugar” refers to a moiety that can replace a sugar. A modified sugar mimics the spatial arrangement, electronic properties, or some other physicochemical property of a sugar. In some aspects, as described in the present disclosure, a modified sugar is substituted ribose or deoxyribose. In some aspects, a modified sugar comprises a 2’-modification. Examples of useful 2’ -modification are widely utilized in the art and described herein. In some aspects, a 2’ -modification is 2’-F. In some aspects, a 2’- modification is 2’ -OR, wherein R is optionally substituted Ci-io aliphatic. In some aspects, a 2’ -modification is 2’-0Me. In some aspects, a 2’ -modification is 2’ -MOE. In some aspects, a modified sugar is a bicyclic sugar (e.g., a sugar used in LNA, BNA, etc.). In some aspects, in the context of oligonucleotides, a modified sugar is a sugar that is not ribose or deoxyribose as typically found in natural RNA or DNA.

[0071] Monocyclic nucleosides: As used herein, “monocyclic nucleotides” refer to nucleosides comprising modified sugar moieties that are not bicyclic sugar moieties. In certain embodiments, the sugar moiety, or sugar moiety analogue, of a nucleoside may be modified or substituted at any position.

[0072] Bicyclic nucleosides: As used herein, “bicyclic nucleosides” refer to modified nucleosides comprising a bicyclic sugar moiety. Examples of bicyclic nucleic acids (BNAs) include without limitation nucleosides comprising a bridge between the 4' and the 2' ribosyl ring atoms. In certain aspects, antisense oligonucleotides provided herein include one or more BNA nucleosides wherein the bridge comprises one of the formulas: 4'-(CH2)-O-2' (LNA); 4'- (CH2)-S-2'; 4'-(CH2)2-O-2' (ENA); 4'-CH(CH3)-O-2' and 4'-CH(CH2OCH3)-O-2' (and analogs thereof see U.S. Patent 7,399,845); 4'-C(CH3)(CH3)-O-2' (and analogs thereof see WO / 2009 / 006478); 4'-CH2- N(OCH3)-2' (and analogs thereof see WO / 2008 / 150729); 4'-CH2- O-N(CH3)-2' (see U.S. Patent Application US2004-0171570); 4'-CH2-N(R)-O-2', wherein R is H, C1-C12 alkyl, or a protecting group (see U.S. Patent 7,427,672); 4'-CH2-C(H)(CH3)-2' (see Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134); and 4'-CH2-C-(=CH2)-2' (and analogs thereof see WO 2008 / 154401). As used herein, “4’-2’ bicyclic nucleoside” or “4’ to 2’ bicyclic nucleoside” refers to a bicyclic nucleoside comprising a furanose ring comprising abridge connecting two carbon atoms of the furanose ring connects the 2’ carbon atom and the 4’ carbon atom of the sugar ring. Further bicyclic nucleosides have been reported in published literature (see for example: Srivastava et al., J. Am. Chem. Soc., 2007, 129(26) 8362-8379; Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372; Elayadi et al, Curr. Opinion Invens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. BioL, 2001, 8, 1-7; (Drum et al., Curr. Opinion Mol. Ther., 2001, 3, 239- 243; Wahlestedt et al., Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 5633-5638; Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; U.S. Patents Nos.: 7,399,845; 7,053,207; 7,034,133; 6,794,499; 6,770,748; 6,670,461; 6,525,191; 6,268,490; U.S. Patent Publication Nos.: US2008-0039618; US2007-0287831 ; US2004-0171570; U. S. Patent Applications, Serial Nos. : 12 / 129,154; 61 / 099,844; 61 / 097,787; 61 / 086,231; 61 / 056,564; 61 / 026,998; 61 / 026,995; 60 / 989,574; International applications WO 2007 / 134181; WO 2005 / 021570; WO 2004 / 106356; WO 94 / 14226; and PCT International Applications Nos.: PCT / US2008 / 068922; PCT / US2008 / 066154; and PCT / US2008 / 064591). Each of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example a-L-ribofuranose and P-D-ribofuranose (see PCT international application PCT / DK98 / 00393, published on March 25, 1999 as WO 99 / 14226).

[0073] Nucleic acid: The term “nucleic acid” includes any nucleotides and polymers thereof. The term “polynucleotide”, as used herein, refers to a polymeric form of nucleotides of any length, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) or a combination thereof. These terms include, as equivalents, analogs of either RNA or DNA comprising modified nucleotides and / or modified polynucleotides, such as, though not limited to, methylated, protected and / or capped nucleotides or polynucleotides. The term encompasses nucleic acids containing any combinations of nucleobases, modified nucleobases, sugars, modified sugars, phosphate bridges or modified internucleotidic linkages.

[0074] Nucleobase: The term “nucleobase” refers to the parts of nucleic acids that are involved in the hydrogen-bonding that binds one nucleic acid strand to another complementary strand in a sequence specific manner. In some aspects, a nucleobase is a “modified nucleobase,” a nucleobase other than adenine (A), guanine (G), uracil (U), cytosine (C), and thymine (T). As used herein, the term “nucleobase” also encompasses structural analogs used in lieu of natural or naturally-occurring nucleotides, such as modified nucleobases and nucleobase analogs.

[0075] Nucleoside: The term “nucleoside” refers to a moiety wherein a nucleobase or a modified nucleobase is covalently bound to a sugar or a modified sugar.

[0076] Nucleotide: The term “nucleotide” as used herein refers to a monomeric unit of a polynucleotide that consists of a nucleobase, a sugar, and one or more internucleotidic linkages (e.g., phosphate linkages in natural DNA and RNA).

[0077] Oligonucleotide: The term “oligonucleotide” refers to a polymer or oligomer of nucleotides, and can contain any combination of natural and non-natural nucleobases, sugars, and internucleotidic linkages. In some aspects, the oligonucleotide is an antisense oligonucleotide (also referred to as an “ASO”).

[0078] Antisense oligonucleotide: “Antisense oligonucleotide” or “ASO” refers to a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid. Antisense oligonucleotides may be chemically modified or unmodified. In some aspects, an antisense oligonucleotide can hybridize to a target nucleic acid and modulate (e.g., increase or decrease) its expression.

[0079] Gapmer: As described herein, “gapmer” means a chimeric antisense oligonucleotide in which an internal region having a plurality of nucleosides that support RNase H cleavage is positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region can be referred to as a “gap” and the external regions can be referred to as the “wings.”

[0080] Gap-narrowed: “Gap-narrowed” means a chimeric antisense oligonucleotide having a gap segment of 9 or fewer contiguous 2 ' -deoxyribonucleosides positioned between and immediately adjacent to 5’ and 3’ wing segments having from 1 to 6 nucleosides.

[0081] Gap-widened: “Gap-widened” means a chimeric antisense oligonucleotide having a gap segment of 12 or more contiguous 2’-deoxyribonucleosides positioned between and immediately adjacent to 5’ and 3’ wing segments having from 1 to 6 nucleosides.

[0082] Wing segment: “Wing segment” means a plurality of nucleosides modified to impart to an oligonucleotide property such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases.

[0083] Optionally Substituted: As described herein, compounds, e.g., oligonucleotides, of the disclosure can contain optionally substituted and / or substituted moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. In some aspects, an optionally substituted group is unsubstituted. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein. Certain substituents are described below.

[0084] Suitable monovalent substituents on a substitutable atom, e.g., a suitable carbon atom, are independently halogen; -(CH2)o4R°; -(CH2)o-4OR°; -0(CH2)o-4R°, -0-(CH2)o- 4C(O)OR°; -(CIhjo4CH(ORO)2; -(Clhjo4Ph, which can be substituted with R°; -(CH2)o-40(CH2)o iPh which can be substituted with R°; -CH=CHPh, which can be substituted with R°; -(CH2)o40(CH2)o i -pyridyl which can be substituted with R°; -NO2; -CN; -N3; -(CH2)o-4N(R°)2; -(CH2)O 4N(RO)C(O)R°; -N(R°)C(S)R°; -(CH2)O4N(RO)C(O)NR°2;-N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; -C(S)R°; -(CH2)O-IC(0)OR0; -(CH2)o-4C(O)SR°; -(CH2)O4C(O)OSiR°3; -(CH2)o4OC(O)R°; -OC(0)(CH2)o4SR°, -SC(S)SR°; -(CH2)O 4SC(O)RC; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; -(CH2)O4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O4SSRO; -(CH2)O4S(O)2RO; -(CH2)O4S(O)2ORO; -(CH2)O ^OS(O)2RO; -S(O)2NRO2; -(CH2)O4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(0R°)R°; -C(NH)NRO2; -Si(R°)3; - OSi(R°)3; -B(R°)2; -OB(RO)2; -OB(ORO)2; -P(RO)2; -P(ORO)2; -P(R°)(OR°); -OP(R°)2; -OP(OR°)2; -OP(R°)(OR°); -P(O)(RO)2; -P(O)(ORO)2; -OP(O)(RO)2; -OP(O)(ORO)2; -OP(O)(OR°)(SR°); -SP(O)(R°)2; -SP(O)(ORO)2; -N(RO)P(O)(R°)2; -N(RO)P(O)(OR°)2; -P(RO)2[B(RO)3]; -P(ORO)2[B(RO)3]; -OP(RO)2[B(RO)3]; -OP(ORO)2[B(RO)3]; -(C1-1 straight or branched alkylene)O-N(R°)2; or -(Ci-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° can be substituted as defined herein and is independently hydrogen, C1-20 aliphatic, C1-20 heteroaliphatic having 1-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, -CH2-(C6-i4 aryl), -0(CH2)o-i(Ce-i4aryl), -CH2-(5- 14 membered heteroaryl ring), a 5-20 membered, monocyclic, bicyclic, or polycyclic,saturated, partially unsaturated or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 5-20 membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which can be substituted as defined below.

[0085] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o2R*, -(haloR*), -(CH2)o2OH, -(CH2)o-2OR*, -(CH2)o-2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)o2C(O)R*, -(CH2)o2C(O)OH, -(CH2)o2C(O)OR*, -(CH2)o- 2SR*, -(CH2)O2SH, -(CH2)O2NH2, -(CH2)O2NHR*, -(CH2)O2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4 aliphatic, -CH2Ph, -0(CH2)o iPh, and a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0086] Suitable divalent substituents, e.g., on a suitable carbon atom, are independently the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*,wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which can be substituted as defined below, and an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: - O(CR*2)23O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which can be substituted as defined below, and an unsubstituted 5-6-membered saturated, partially unsaturated, and aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] Suitable substituents on the aliphatic group of R* are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0088] In some aspects, suitable substituents on a substitutable nitrogen are independentlywherein each R1' is independently hydrogen, Ci- 6 aliphatic which can be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0089] Suitable substituents on the aliphatic group of:are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0091] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.

[0092] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, and / or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.

[0093] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0094] Protecting group: The term “protecting group,” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Also included are those protecting groups specially adapted for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al. 06 / 2012, the entirety of Chapter 2 is incorporated herein by reference. Suitable amino-protecting groups include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9- (2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(l 0, 10-dioxo-l 0, 10,10,10— tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), 1,1— dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2, 2, 2— tri chloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t- butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4- nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p- nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4- di chlorobenzyl carbamate, 4-methylsulfmylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1— dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)- 6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o- nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivative, N’-p-toluenesulfonylaminocarbonyl derivative, N’-phenylaminothiocarbonyl derivative, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1 , l-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2- furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-l-cyclopropylmethyl carbamate, 1- methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, l-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l-phenylethyl carbamate, l-methyl-l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, tri chloroacetamide, trifluoroacetamide, phenylacetamide, 3- phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenyl acetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxycarbonylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin- 2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N- allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N- (l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N- benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N- triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9- phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N- ferrocenylmethylamino (Fem), N-2-picolylamino N’-oxide, N-1,1- dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N- diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’,N’- dimethylaminomethylene)amine, N,N’-isopropylidenediamine, N-p-nitrobenzylideneamine,N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo- l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl (pentacarbonyl chromium- or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys), p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 4-(4’,8’-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0095] Suitably protected carboxylic acids further include, but are not limited to, silylalkyl-, alkenyl-, aryl-, and arylalkyl-protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, tetrahydropyran-2-yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O- nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl), and 2- and 4- picolyl.

[0096] Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4- methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4- pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl(SEMOR), tetrahydropyranyl (TEIP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1-methyl-l-methoxyethyl, 1-methyl-l-benzyloxyethyl, 1- methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxy phenyl, 2,4-dinitrophenyl, benzyl, p-m ethoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2- picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p— methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4’,4”-tris(4,5- dichlorophthalimidophenyl)methyl, 4, 4’, 4’ ’-tris(levulinoyloxyphenyl)methyl, 4, 4’, 4’ tris(benzoyloxyphenyl)methyl, 3-(imidazol-l-yl)bis(4’,4”-dimethoxyphenyl)methyl, 1,1— bis(4-methoxyphenyl)-l’-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethyl silyl (TMS), triethylsilyl (TES), triisopropyl silyl (TIPS), dimethylisopropyl silyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri— p— xylylsilyl, triphenylsilyl, diphenylmethyl silyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, di chloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenyl sulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2- iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro- 4-(l,l,3,3-tetramethylbutyl)phenoxyacetate, 2, 4-bis(l,l-dimethylpropyl)phenoxy acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxycarbonyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1,2- or 1 ,3— diols, the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4- methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p- methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1 -methoxy ethylidene ortho ester, 1-ethoxyethylidine ortho ester, 1,2-dimethoxy ethylidene ortho ester, a-methoxybenzylidene ortho ester, 1-(N,N- dimethylamino)ethylidene derivative, a-(N,N’-dimethylamino)benzylidene derivative, 2- oxacyclopentylidene ortho ester, di-t-butyl silylene group (DTBS), 1,3— (1, 1,3,3— tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra-t-butoxydisiloxane-l,3-diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and / or phenyl boronate.

[0097] In some aspects, a hydroxyl protecting group is acetyl, t-butyl, tbutoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 2- trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6- di chlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4,4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifiuoroacetyl, pivaloyl, 9- fluorenylmethyl carbonate, mesylate, tosylate, tritiate, trityl, monomethoxytrityl (MMTr), 4,4'- dimethoxytrityl, (DMTr) and 4,4',4"-trimethoxytrityl (TMTr), 2-cyanoethyl (CE or Cne), 2- (trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl 2-(4- nitrophenyl)ethyl (NPE), 2-(4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4- dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4,6-trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4',4"-tris(benzoyloxy)trityl, diphenylcarbamoyl, levulinyl, 2- (dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9- phenylxanthen-9-yl (pixyl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX). In some aspects, each of the hydroxyl protecting groups is, independently selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and 4,4'-dimethoxytrityl. In some aspects, the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl and / or 4,4'- dimethoxytrityl group. In some aspects, a phosphorous linkage protecting group is a group attached to the phosphorous linkage (e.g., an internucleotidic linkage) throughout oligonucleotide synthesis. In some aspects, a protecting group is attached to a sulfur atom of an phosphorothioate group. In some aspects, a protecting group is attached to an oxygen atom of an internucleotide phosphorothioate linkage. In some aspects, a protecting group is attached to an oxygen atom of the internucleotide phosphate linkage. In some aspects a protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert- buty 1 carb oxami do)- 1 -propyl, 4-oxopentyl, 4-methylthio-l-butyl, 2-cyano- 1,1 -dimethylethyl, 4-N-methylaminobutyl, 3 -(2-pyridyl)-l -propyl, 2-[N-methyl-N-(2-pyridyl)]aminoethyl, 2-(N- formyl,N-methyl)aminoethyl, and / or 4-[N-methyl-N-(2,2,2-trifluoroacetyl)amino]butyl.

[0098] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a compound (e.g., an oligonucleotide) or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes. In some aspects, a subject is a human.

[0099] (W / 3 / . / / YKL-40-associated disease: As used herein, the terms “CHI3L1- associated disease” and “YKL-40-associated disease” can be used interchangeably to refer to a disease or disorder that is caused by, or associated with, CHI3L1 gene expression or YKL- 40 protein production and would benefit from a decrease in CHI3L1 gene expression and / or replication and / or YKL-40 protein activity. Non-limiting examples of (77 / 3 / . / -associated diseases include, e.g., glioblastoma.

[0100] Susceptible to: An individual who is “susceptible to” a disease, disorder and / or condition is one who has a higher risk of developing the disease, disorder and / or condition than does a member of the general public. In some aspects, an individual who is susceptible to a disease, disorder and / or condition is predisposed to have that disease, disorder and / or condition.

[0101] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some aspects, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to adisease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition (e.g., glioblastoma).Antisense oligonucleotides (ASOs) targeting CHI3L1

[0102] Among other things, the present disclosure provides various oligonucleotides (e.g., antisense oligonucleotides) and compositions thereof. In some aspects, the oligonucleotide of the disclosure is an antisense oligonucleotide (ASO). In some aspects, oligonucleotides (e.g., antisense oligonucleotides) of the present disclosure target CHI3L1 and can hybridize with a CHI3L1 transcript, e.g., a CHI3L1 mRNA. In some aspects, provided technologies, e.g., oligonucleotides (e.g., antisense oligonucleotides), compositions, methods, etc., reduce levels of CHI3L1 transcripts and / or products thereof. Use of naturally occurring nucleic acids is limited, for example, by their susceptibility to endonucleases and exonucleases. As such, various synthetic counterparts have been developed to circumvent these shortcomings and / or to further improve various properties and activities. In some aspects, provided oligonucleotides (e.g., antisense oligonucleotides) comprise one or more chemical modifications, e.g., nucleobase modifications, sugar modifications, intemucleotidic linkage modifications, etc., which, among other things, render these molecules less susceptible to degradation and improve other properties and / or activities. In some aspects, an oligonucleotide (e.g., antisense oligonucleotide) comprises one or more features described herein, e.g., base sequence, length, wing, gap, activity, etc. In some aspects, an oligonucleotide has a base sequence described herein, and / or a wing-gap-wing structure as described herein.Base Sequences

[0103] In certain aspects of the disclosure, oligonucleotides (e.g., antisense oligonucleotides) comprise a base sequence. In some aspects, the base sequences of the oligonucleotides (e.g., antisense oligonucleotides) of the disclosure are of sufficient lengths so that they can form duplexes with complementary sequences in target nucleic acids for one or more biological functions. In some aspects, oligonucleotides (e.g., antisense oligonucleotides) specifically target their target nucleic acids. In some aspects, the base sequence of a provided oligonucleotide (e.g., antisense oligonucleotides) is or comprises a sequence that is complementary to a portion in a target nucleic acid (a “target portion”), e.g., a CHI3L1 gene or a transcript thereof. In some aspects, such a sequence complementary to a target portion (i.e., a base sequence) is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or morenucleobases in length. In some aspects, such a sequence complementary to a target portion (i.e., a base sequence) is about 20 nucleobases in length.

[0104] In some aspects, a target portion is or comprises a characteristic portion of a nucleic acid sequence (e.g., of a CHI3L1 gene or a transcript thereof) which characteristic portion defines the nucleic acid sequence over others in a relevant organism; for example, the characteristic portion is not in other genomic nucleic acid sequences (e.g., genes) or transcripts thereof in a relevant organism (e.g., for human CHI3L1, its characteristic portion is not in other human nucleic acid sequences or transcripts thereof). In some aspects, a characteristic portion of a transcript defines that transcript over other transcripts in a relevant organism; for example, in some aspects, the characteristic portion is not in transcripts that are transcribed from a different nucleic acid sequence (e.g., a different gene). In some aspects, transcript variants from a nucleic acid sequence (e.g., mRNA variants of a gene) can share a common characteristic portion that defines them from transcripts of other nucleic acids, e.g., transcripts of other genes. In some aspects, a characteristic portion in a transcript defines the transcript from other transcript(s) of the same nucleic acid sequence (e.g., a gene) and / or other alleles of the nucleic acid sequence. In some aspects, a characteristic portion defines a particular allele (and / or transcripts thereof) over other allele(s) (and / or transcripts thereof). In some aspects, a characteristic portion comprises sequences that are separated in a nucleic acid. In some aspects, a characteristic portion is a contiguous stretch of nucleobases in a nucleic acid (a “characteristic sequence”). A characteristic portion or sequence can have various numbers of nucleobases. In some aspects, there are about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more nucleobases in a characteristic portion or sequence; in some aspects, there are about 10; in some aspects, there are about 11; in some aspects, there are about 12; in some aspects, there are about 13; in some aspects, there are about 14; in some aspects, there are about 15; in some aspects, there are about 16; in some aspects, there are about 17; in some aspects, there are about 18; in some aspects, there are about 19; in some aspects, there are about 20; in some aspects, there are about 21; in some aspects, there are about 22; in some aspects, there are about 23; in some aspects, there are about 24; in some aspects, there are about 25; in some aspects, there are about 25 or more nucleobases in a characteristic portion or sequence.

[0105] Suitable target portions can be found within a 5’ UTR, a coding region, a 3’ UTR, an intron, an exon, or an exon / intron junction. Target portions containing a start codon or a stop codon are also suitable target portions. A suitable target portion can specifically exclude a certain structurally defined region such as the start codon or stop codon.

[0106] The determination of suitable target portions can include a comparison of the sequence of a target nucleic acid to other sequences throughout the genome. For example, the BLAST algorithm can be used to identify regions of similarity amongst different nucleic acids. This comparison can prevent the selection of antisense oligonucleotide sequences that can hybridize in a non-specific manner to sequences other than a selected target nucleic acid (i.e., non-target or off-target sequences).

[0107] In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) comprises a sequence (e.g., base sequence) that is identical or complementary to a characteristic portion of a CHI3L1 nucleic acid sequence or portion thereof. In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) comprises a sequence (e.g., base sequence) that is identical or complementary to a characteristic portion of a CHI3L1 transcript. In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) comprises a sequence that is complementary to a characteristic portion of a CHI3L1 transcript. In some aspects, the base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) is identical or complementary to a characteristic portion of a CHI3L1 transcript. In some aspects, a characteristic portion is a characteristic sequence.

[0108] In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) comprises a base sequence that is complementary or identical to a characteristic sequence of a CHI3L1 transcript. In some aspects, a characteristic sequence is or comprises AGCAGGUACAGGCACAUGGG (SEQ ID NO: 1), wherein the U can be independently replaced with T (i.e., AGCAGGTACAGGCACATGGG (SEQ ID NO: 2)). In some aspects, a characteristic sequence of a CHI3L1 transcript is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to AGCAGGUACAGGCACAUGGG (SEQ ID NO: 1), wherein the U can be replaced with T (i.e., AGCAGGTACAGGCACATGGG (SEQ ID NO: 2)).

[0109] In some aspects, a characteristic sequence is or comprises AAGAAGCUAAGCAGGGCCAA (SEQ ID NO: 3), wherein the U can be replaced with T (i.e., AAGAAGCTAAGCAGGGCCAA (SEQ ID NO: 4)). In some aspects, a characteristic sequence of a CHI3L1 transcript is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to AAGAAGCUAAGCAGGGCCAA (SEQ ID NO: 3), wherein the U can be replaced with T (i.e., AAGAAGCTAAGCAGGGCCAA (SEQ ID NO: 4)).

[0110] In some aspects, a characteristic sequence is or comprises ACAGUGACCAUACUAAUUAU (SEQ ID NO: 5), wherein the U can be replaced with T (i.e., ACAGTGACCATACTAATTAT (SEQ ID NO: 6)). In some aspects, a characteristic sequence of a CHI3L1 transcript is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to ACAGUGACCAUACUAAUUAU (SEQ ID NO:5), wherein the U can be replaced with T (i.e., ACAGTGACCATACTAATTAT (SEQ ID NO:6))-

[0111] In some aspects, a characteristic sequence is or comprises AGCUGCUCAAUAAAGUACAA (SEQ ID NO: 7), wherein the U can be replaced with T (i.e., AGCTGCTCAATAAAGTACAA (SEQ ID NO: 8)). In some aspects, a characteristic sequence of a CHI3L1 transcript is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to AGCUGCUCAAUAAAGUACAA (SEQ ID NO:7), wherein the U can be replaced with T (i.e., AGCTGCTCAATAAAGTACAA (SEQ ID NO:8))-

[0112] In some aspects, a characteristic sequence is or comprises UCAAUAAAGUACAAGAGCUU (SEQ ID NO: 9), wherein the U can be replaced with T (i.e., TCAATAAAGTACAAGAGCTT (SEQ ID NO: 10)). In some aspects, a characteristic sequence of a CHI3L1 transcript is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to UCAAUAAAGUACAAGAGCUU (SEQ ID NO:9), wherein the U can be replaced with T (i.e., TCAATAAAGTACAAGAGCTT (SEQ ID NO:10)).

[0113] In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) can hybridize to a region of a nucleic acid (e.g., a CHI3L1 nucleic acid sequence). In some aspects, oligonucleotides (e.g., antisense oligonucleotides) that can specifically hybridize (e.g., through sequence complementarity) to certain region(s) of a target nucleic acid can more effectively reduce levels of the nucleic acid than oligonucleotides that specifically hybridize (e.g., through sequence complementarity) to one or more reference regions of the target nucleic acid. In some aspects, a region has a length of about 20-200 (e.g., about 20-150, 20-100, 30-200, 30-150, 40- 200, 40-150, 50-100, or about 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200) nucleobases.

[0114] In some aspects, a region comprises a sequence complementary to a base sequence of an oligonucleotide in Table 1, which in some aspects, the complementary portion is in the approximate middle of a region. For example, in some aspects, a region is or comprisesAGCAGGUACAGGCACAUGGG (SEQ ID NO: 1). In some aspects, a region is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to AGCAGGUACAGGCACAUGGG (SEQ ID NO: 1). In some aspects, a region is or comprises AAGAAGCUAAGCAGGGCCAA (SEQ ID NO: 3). In some aspects, a region is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to AAGAAGCUAAGCAGGGCCAA (SEQ ID NO: 3). In some aspects, a region is or comprises ACAGUGACCAUACUAAUUAU (SEQ ID NO: 5). In some aspects, a region is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to ACAGUGACCAUACUAAUUAU (SEQ ID NO: 5). In some aspects, a region is or comprises AGCUGCUCAAUAAAGUACAA (SEQ ID NO: 7). In some aspects, a region is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to AGCUGCUCAAUAAAGUACAA (SEQ ID NO: 7). In some aspects, a region is or comprises UCAAUAAAGUACAAGAGCUU (SEQ ID NO: 9). In some aspects, a region is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to UCAAUAAAGUACAAGAGCUU (SEQ ID NO: 9).

[0115] In some aspects, base sequences of oligonucleotides (e.g., antisense oligonucleotides) comprise or consist of about 10-50 (e.g., in some aspects, at least about 15; in some aspects, at least about 16; in some aspects, at least about 17; in some aspects, at least about 18; in some aspects, at least about 19; in some aspects, at least about 20) contiguous bases that are identical to or complementary to a target sequence (e.g., a region) of equal length in a CHI3L1 gene or a transcript (e.g., mRNA) thereof. In some aspects, the base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) is complementary to a target sequence (e.g., region) of equal length in a CHI3L1 transcript.

[0116] In some aspects, a base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) is at least about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a target sequence in a CHI3L1 transcript. In some aspects, a base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a target sequence in a CHI3L1 transcript. In some aspects, a base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) is at least about 95%, 96%, 97%, 98%, 99%, or 100% complementary to a target sequence in a CHI3L1 transcript. In some aspects, a base sequence of an oligonucleotide is fully complementary to a target sequence in a CHI3L1 transcript.

[0117] In some aspects, the base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) has about 80% or more identity with the base sequence of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide has about 85% or more identity with the base sequence of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide has about 90% or more identity with the base sequence of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide has about 95% or more identity with the base sequence of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa.

[0118] In some aspects, the base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) comprises a continuous span of about 15 or more bases of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide comprises a continuous span of about 16 or more bases of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide comprises a continuous span of about 17 or more bases of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide comprises a continuous span of about 18 or more bases of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide comprises a continuous span of about 19 or more bases of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide comprises a continuous span of about 20 or more bases of an oligonucleotide disclosed in Table 1, wherein in some aspects each T can be replaced with U and vice versa.

[0119] In some aspects, the base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) comprises the base sequence of an oligonucleotide in Table 1, wherein optionally each T can be replaced with U and vice versa. In some aspects, the base sequence of an oligonucleotide is the base sequence of an oligonucleotide in Table 1, wherein optionally each T can be replaced with U and vice versa.

[0120] For example, in some aspects, the base sequence of an oligonucleotide comprises CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11), optionally wherein each T can be replaced with U (i.e., CCCAUGUGCCUGUACCUGCU (SEQ ID NO: 12)). In some aspects, the base sequence for an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11), optionally wherein each T can be replaced with U (i.e., CCCAUGUGCCUGUACCUGCU (SEQ ID NO: 12)).

[0121] In some aspects, the base sequence of an oligonucleotide comprises TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13), optionally wherein each T can be replaced with U (i.e., UUGGCCCUGCUUAGCUUCUU (SEQ ID NO: 14)). In some aspects, the base sequence for an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13), optionally wherein each T can be replaced with U (i.e., UUGGCCCUGCUUAGCUUCUU (SEQ ID NO: 14)).

[0122] In some aspects, the base sequence of an oligonucleotide comprises ATAATTAGTATGGTCACTGT (SEQ ID NO: 15), optionally wherein each T can be replaced with U (i.e., AUAAUUAGUAUGGUCACUGU (SEQ ID NO: 16)). In some aspects, the base sequence for an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to ATAATTAGTATGGTCACTGT (SEQ ID NO: 15), optionally wherein each T can be replaced with U (i.e., AUAAUUAGUAUGGUCACUGU (SEQ ID NO: 16)).

[0123] In some aspects, the base sequence of an oligonucleotide comprises TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17), optionally wherein each T can be replaced with U (i.e., UUGUACUUUAUUGAGCAGCU (SEQ ID NO: 18)). In some aspects, the base sequence for an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% complementary to TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17), optionally wherein each T can be replaced with U (i.e., UUGUACUUUAUUGAGCAGCU (SEQ ID NO: 18)).

[0124] In some aspects, the base sequence of an oligonucleotide comprises AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19), optionally wherein each T can be replaced with U (i.e., AAGCUCUUGUACUUUAUUGA (SEQ ID NO: 20)). In some aspects, the base sequence for an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99%, or 100% complementary to AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19), optionally wherein each T can be replaced with U (i.e., AAGCUCUUGUACUUUAUUGA (SEQ ID NO: 20)).

[0125] In some aspects, the base sequence of an oligonucleotide (e.g., an antisense oligonucleotide) comprises CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11). In some aspects, the base sequence of an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% identical or complementary to CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11). In some aspects, the base sequence of an oligonucleotide comprises TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13). In some aspects, the base sequence of an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% identical or complementary to TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13). In some aspects, the base sequence of an oligonucleotide comprises ATAATTAGTATGGTCACTGT (SEQ ID NO: 15). In some aspects, the base sequence of an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% identical or complementary to ATAATTAGTATGGTCACTGT (SEQ ID NO: 15). In some aspects, the base sequence of an oligonucleotide comprises TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17). In some aspects, the base sequence of an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% identical or complementary to TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17). In some aspects, the base sequence of an oligonucleotide comprises AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19). In some aspects, the base sequence of an oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% identical or complementary to AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19).Lengths

[0126] As appreciated by those skilled in the art, oligonucleotides can be of various lengths to provide desired properties and / or activities for various uses. Many technologies for assessing, selecting and / or optimizing oligonucleotide length are available in the art and can be utilized in accordance with the present disclosure. As demonstrated herein, in many aspects, provided oligonucleotides are of suitable lengths to hybridize with their targets and reduce levels of their targets and / or a product thereof. In some aspects, an oligonucleotide is long enough to recognize a target nucleic acid (e.g., a CHI3L1 mRNA). In some aspects, anoligonucleotide is sufficiently long to distinguish between a target nucleic acid and other nucleic acids (e.g., a nucleic acid having a base sequence which is not a CHI3L1 sequence) to reduce off-target effects. In some aspects, an oligonucleotide is sufficiently short to reduce complexity of manufacture or production and to reduce cost of products.

[0127] In certain aspects, oligonucleotides targeted to a CHI3L1 nucleic acid can be shortened or truncated. For example, a single subunit can be deleted from the 5’ end (5’ truncation), or alternatively from the 3’ end (3’ truncation). A shortened or truncated antisense oligonucleotide targeted to a CHI3L1 nucleic acid can have two subunits deleted from the 5’ end, or alternatively can have two subunits deleted from the 3’ end, of the antisense oligonucleotide.

[0128] Alternatively, the deleted nucleosides can be dispersed throughout the antisense oligonucleotide, for example, in an antisense oligonucleotide having one nucleoside deleted from the 5’ end and one nucleoside deleted from the 3’ end.

[0129] When a single additional subunit is present in a lengthened antisense oligonucleotide, the additional subunit can be located at the 5’ or 3’ end of the antisense oligonucleotide. When two or more additional subunits are present, the added subunits can be adjacent to each other, for example, in an antisense oligonucleotide having two subunits added to the 5’ end (5’ addition), or alternatively to the 3’ end (3’ addition), of the antisense oligonucleotide. Alternatively, the added subunits can be dispersed throughout the antisense oligonucleotide, for example, in an antisense oligonucleotide having one subunit added to the 5’ end and one subunit added to the 3’ end.

[0130] It is possible to increase or decrease the length of an antisense oligonucleotide, such as a modified oligonucleotide, and / or introduce mismatch bases without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model. Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target mRNA, albeit to a lesser extent than oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.

[0131] Gautschi et al (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo.

[0132] Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358,1988) tested a series of tandem 14-nucleobase oligonucleotides, and 28- and 42-nucleobase oligonucleotides comprised of the sequence of two or three of the tandem oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14-nucleobase oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28- or 42-nucleobase oligonucleotides.

[0133] Oligonucleotides of the present disclosure can be of various lengths. In various related aspects, oligonucleotides, single-stranded, double-stranded, or triple-stranded, can range in length from about 4 to about 10 nucleosides, from about 10 to about 50 nucleosides, from about 20 to about 50 nucleosides, from about 15 to about 30 nucleosides, from about 20 to about 30 nucleosides in length. In some aspects, an oligonucleotide is at least 15 nucleosides in length. In some aspects, an oligonucleotide is at least 15 nucleosides in length. In some aspects, an oligonucleotide is at least 16 nucleosides in length. In some aspects, an oligonucleotide is at least 17 nucleosides in length. In some aspects, an oligonucleotide is at least 18 nucleosides in length. In some aspects, an oligonucleotide is at least 19 nucleosides in length. In some aspects, an oligonucleotide is at least 20 nucleosides in length. In some aspects, an oligonucleotide is at least 25 nucleosides in length.

[0134] In some aspects, a base sequence is about 15-25 nucleobases in length. In some aspects, a base sequence is about 15-22 nucleobases in length. In some aspects, a base sequence is about 18-22 nucleobases in length. In some aspects, a base sequence is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases in length. In some aspects, a base sequence is at least about 15 nucleobases in length. In some aspects, a base sequence is at least about 16 nucleobases in length. In some aspects, a base sequence is at least about 17 nucleobases in length. In some aspects, a base sequence is at least about 18 nucleobases in length. In some aspects, a base sequence is at least about 19 nucleobases in length. In some aspects, a base sequence is at least about 20 nucleobases in length. In some aspects, a base sequence is at least about 21 nucleobases in length. In some aspects, a base sequence is at least about 22 nucleobases in length. In some aspects, a base sequence is at least about 23 nucleobases in length. In some aspects, a base sequence is at least about 24 nucleobases in length. In some aspects, a base sequence is at least about 25 nucleobases in length. In some aspects, a base sequence is about 15 nucleobases in length. In some aspects, a base sequence is about 16nucleobases in length. In some aspects, a base sequence is about 17 nucleobases in length. In some aspects, a base sequence is about 18 nucleobases in length. In some aspects, a base sequence is about 19 nucleobases in length. In some aspects, a base sequence is about 20 nucleobases in length. In some aspects, a base sequence is about 21 nucleobases in length. In some aspects, a base sequence is about 22 nucleobases in length. In some aspects, a base sequence is about 23 nucleobases in length. In some aspects, a base sequence is about 24 nucleobases in length. In some aspects, a base sequence is about 25 nucleobases in length. In some other aspects, a base sequence is about at least about 30 nucleobases in length.Nucleobases

[0135] Nucleobases can be utilized in provided oligonucleotides in accordance with the present disclosure. In some aspects, a nucleobase is a natural nucleobase, the most commonly occurring ones being A, T, C, G and U. In some aspects, a nucleobase is a modified nucleobase in that it is not A, T, C, G or U. In some aspects, a nucleobase is optionally substituted A, T, C, G or U, or a substituted tautomer of A T, C, G or U. In some aspects, a nucleobase is optionally substituted A, T, C, G or U, e.g., 5mC, 5 -hydroxymethyl C, etc. In some aspects, a nucleobase is alkyl-substituted A, T, C, G or U. In some aspects, a nucleobase is A. In some aspects, a nucleobase is T. In some aspects, a nucleobase is C. In some aspects, a nucleobase is G. In some aspects, a nucleobase is U. In some aspects, a nucleobase is 5mC. In some aspects, a nucleobase is substituted A, T, C, G or U. In some aspects, a nucleobase is a substituted tautomer of A, T, C, G or U. In some aspects, substitution protects certain functional groups in nucleobases to minimize undesired reactions during oligonucleotide synthesis. Suitable technologies for nucleobase protection in oligonucleotide synthesis are widely known in the art and can be utilized in accordance with the present disclosure. In some aspects, modified nucleobases improves properties and / or activities of oligonucleotides. For example, in many cases, 5mC can be utilized in place of C to modulate certain undesired biological effects, e.g., immune responses. In some aspects, when determining sequence identity, a substituted nucleobase having the same hydrogen-bonding pattern is treated as the same as the unsubstituted nucleobase, e.g., 5mC can be treated the same as C [e.g., an oligonucleotide having 5mC in place of C (e.g., AT5mCG) is considered to have the same base sequence as an oligonucleotide having C at the corresponding location(s) (e.g., ATCG)].

[0136] In some aspects, an oligonucleotide comprises one or more A, T, C, G or U. In some aspects, an oligonucleotide comprises one or more optionally substituted A, T, C, G or U. In some aspects, an oligonucleotide comprises one or more 5-methylcytosine (5mC), 5-hydroxymethylcytosine, 5-formylcytosine, or 5 -carboxylcytosine. In some aspects, an oligonucleotide comprises one or more 5mC. In some aspects, each nucleobase in an oligonucleotide is independently selected from optionally substituted A, T, C, G and U, and optionally substituted tautomers of A, T, C, G and U. In some aspects, each nucleobase in an oligonucleotide is independently optionally protected A, T, C, 5mC, G and U. In some aspects, each nucleobase in an oligonucleotide is optionally substituted A, T, C, G or U. In some aspects, each nucleobase in an oligonucleotide is selected from the group consisting of A, T, C, G, U, and 5mC.

[0137] In some aspects, a nucleobase is optionally substituted 2AP or DAP. In some aspects, a nucleobase is optionally substituted 2AP. In some aspects, a nucleobase is optionally substituted DAP. In some aspects, a nucleobase is 2AP. In some aspects, a nucleobase is DAP.

[0138] In some aspects, a nucleobase is a natural nucleobase or a modified nucleobase derived from a natural nucleobase. Examples include uracil, thymine, adenine, cytosine, and guanine optionally having their respective amino groups protected by acyl protecting groups, 2-fluorouracil, 2-fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pyrimidine analogs such as pseudoisocytosine and pseudouracil and other modified nucleobases such as 8-substituted purines, xanthine, or hypoxanthine (the latter two being the natural degradation products). Certain examples of modified nucleobases are disclosed in Chiu and Rana, RNA, 2003, 9, 1034-1048, Limbach et al. Nucleic Acids Research, 1994, 22, 2183- 2196 and Revankar and Rao, Comprehensive Natural Products Chemistry, vol. 7, 313.

[0139] In some aspects, a provided oligonucleotide comprises one or more 5- methylcytosine. In some aspects, the present disclosure provides an oligonucleotide whose base sequence is disclosed herein, e.g., in Table 1, wherein each T can be independently replaced with U and vice versa, and each cytosine is optionally and independently replaced with 5- methylcytosine or vice versa. As appreciated by those skilled in the art, in some aspects, 5mC can be treated as C with respect to base sequence of an oligonucleotide - such oligonucleotide comprises a nucleobase modification at the C position (e.g., see oligonucleotides in Table 1). In description of oligonucleotides, unless otherwise noted, nucleobases, sugars and internucleotidic linkages are non-modified.

[0140] In some aspects, a modified nucleobase is a modified nucleobase known in the art, e.g., WO2017 / 210647. In some aspects, modified nucleobases are expanded-size nucleobases in which one or more aryl and / or heteroaryl rings, such as phenyl rings, have been added.

[0141] Nucleobases can be protected during oligonucleotide synthesis. Various protection technologies are available and can be utilized in accordance with the present disclosure.

[0142] In some aspects, a modified nucleobase is 5-substituted pyrimidines, 6- azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, or N-2, N- 6 and 0-6 substituted purines. In certain aspects, a modified nucleobase is selected form 2- aminopropyladenine, 5 -hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6- N-methylguanine, 6-N- methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2- thiocytosine, 5-propynyl (-OC-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4- thiouracil, 8-halo, 8-amino, 8-thiol, 8- thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5- trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F- adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3 -deazaguanine, 3 -deazaadenine, 6-N- benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5- methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. In some aspects, a modified nucleobases is a tricyclic pyrimidine, such as l,3-diazaphenoxazine-2-one, 1,3- diazaphenothiazine-2-one or 9-(2-aminoethoxy)-l,3-diazaphenoxazine-2- one (G-clamp). In some aspects, a modified nucleobases is one in which a purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine or 2- pyridone.

[0143] In some aspects, a modified nucleobase is substituted. In some aspects, a modified nucleobase is substituted such that it contains, e.g., heteroatoms, alkyl groups, or linking moieties connected to fluorescent moieties, biotin or avidin moieties, or other protein or peptides. In some aspects, a modified nucleobase is a “universal base” that is not a nucleobase in the most classical sense, but that functions similarly to a nucleobase. One example of a universal base is 3 -nitropyrrole.

[0144] In some aspects, nucleosides that can be utilized in provided technologies comprise modified nucleobases and / or modified sugars, e.g., 4-acetylcytidine; 5- (carboxyhydroxylmethyl)uridine; 2’ -O-methylcytidine; 5-carboxymethylaminomethyl-2- thiouridine; 5-carboxymethylaminomethyluridine; dihydrouridine; 2’-O-methylpseudouridine; beta,D-galactosylqueosine; 2’-O-methylguanosine; N6-isopentenyladenosine; 1- methyladenosine; 1 -methylpseudouridine; 1 -methylguanosine; 1-m ethylinosine; 2,2- dimethylguanosine; 2-methyladenosine; 2-methylguanosine; N7-methylguanosine; 3 -methylcytidine; 5-methylcytidine; 5-hydroxymethylcytidine; 5-formylcytosine; 5-carboxylcytosine; N6-methyladenosine; 7-methylguanosine; 5-methylaminoethyluridine; 5- methoxyaminomethyl-2-thiouridine; beta,D-mannosylqueosine; 5-methoxy carbonylmethyluridine; 5-methoxyuridine; 2-methylthio-N6-isopentenyladenosine; N-((9-beta,D-ribofuranosyl-2-methylthiopurine-6-yl)carbamoyl)threonine; N-((9-beta,D- ribofuranosylpurine-6-yl)-N-methylcarbamoyl)threonine; uridine-5-oxyacetic acid methylester; uridine-5-oxyacetic acid (v); pseudouridine; queosine; 2-thiocytidine; 5-methyl- 2-thiouridine; 2-thiouridine; 4-thiouridine; 5-methyluridine; 2’-O-methyl-5-methyluridine; and / or 2’-O-methyluridine.

[0145] In some aspects, a nucleobase, e.g., a modified nucleobase comprises one or more biomolecule binding moieties such as e.g., antibodies, antibody fragments, biotin, avidin, streptavidin, receptor ligands, or chelating moieties. In other aspects, a nucleobase is 5- bromouracil, 5-iodouracil, or 2,6-diaminopurine. In some aspects, a nucleobase comprises substitution with a fluorescent or biomolecule binding moiety. In some aspects, a substituent is a fluorescent moiety. In some aspects, a substituent is biotin or avidin.

[0146] In some aspects, a nucleobase is one described in US 9394333, US 9744183, US 9605019, US 9598458, US 9982257, US 10160969, US 10479995, US 2020 / 0056173, US 2018 / 0216107, US 2019 / 0127733, US 10450568, US 2019 / 0077817, US 2019 / 0249173, US 2019 / 0375774, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, and / or WO 2019 / 032612, the nucleobase of each of which is incorporated herein by reference. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442- 443.Sugars

[0147] Various sugars, including modified sugars, can be utilized in accordance with the present disclosure. In some aspects, the present disclosure provides sugar modifications and patterns thereof optionally in combination with other structural elements (e.g., nucleobase modifications and patterns thereof, intemucleotidic linkage modifications and patterns thereof, etc.) that when incorporated into oligonucleotides can provide improved properties and / or activities.

[0148] The most common naturally occurring nucleosides comprise ribose sugars (e.g., in RNA) or deoxyribose sugars (e.g., in DNA) linked to the nucleobases adenosine (A), cytosine (C), guanine (G), thymine (T) or uracil (U). In some aspects, a sugar, e.g., various sugars in many oligonucleotides in Table 1 (unless otherwise noted), is a natural DNA sugar (in DNA nucleic acids or oligonucleotides, having the structure of, wherein a nucleobase is attached to the 1’ position, and the 3’ and 5’ positions are connected to intemucleotidic linkages (as appreciated by those skilled in the art, if at the 5 ’-end of an oligonucleotide, the 5’ position can be connected to a 5’-end group (e.g., -OH), and if at the 3’-end of an oligonucleotide, the 3’ position can be connected to a 3 ’-end group (e.g., -OH). In some aspects, a sugar is a natural RNA sugar (in RNA nucleic acids or oligonucleotides, having the structurewherein a nucleobase is attached to the 1’ position, and the 3’ and 5’ positions are connected to intemucleotidic linkages (as appreciated by those skilled in the art, if at the 5 ’-end of an oligonucleotide, the 5’ position can be connected to a 5 ’-end group (e.g., -OH), and if at the 3 ’-end of an oligonucleotide, the 3’ position can be connected to a 3’- end group (e.g., -OH). In some aspects, a sugar is a modified sugar in that it is not a natural DNA sugar or a natural RNA sugar. Among other things, modified sugars can provide improved stability and / or affinity. In some aspects, modified sugars can be utilized to alter and / or optimize one or more hybridization characteristics. In some aspects, modified sugars can be utilized to alter and / or optimize target recognition. In some aspects, modified sugars can be utilized to optimize Tm. In some aspects, modified sugars can be utilized to improve oligonucleotide activities.

[0149] Sugars can be bonded to intemucleotidic linkages at various positions. As nonlimiting examples, intemucleotidic linkages can be bonded to the 2’, 3’, 4’ or 5’ positions of sugars. As most commonly in natural nucleic acids, an intemucleotidic linkage typically connects with one sugar at the 5’ position and another sugar at the 3’ position unless otherwise indicated.

[0150] In some aspects, a sugar is an optionally substituted natural DNA or RNA sugar.In some aspects, a sugar is optionally substituted. In some aspects, the 2’ positionis optionally substituted. In some aspects, a sugar is. In some aspects, a sugar has the structure, wherein each of Rls, R2s, R3s, R4s, and R5sis independently -H, a suitable substituent or suitable sugar modification (e.g., those described in US 9394333, US 9744183, US 9605019, US 9982257, US 20170037399, US 20180216108, US 20180216107, US 9598458, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO2017 / 192679, WO 2017 / 210647, WO 2018 / 098264, WO 2018 / 022473, WO 2018 / 223056,WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO2019 / 032612,WO 2019 / 055951, and / or WO 2019 / 075357, the substituents, sugar modifications, descriptions of Rls, R2S, R3S, R4S, and R5s, and modified sugars of each of which are independently incorporated herein by reference). In some aspects, each of Rls, R2s, R3s, R4s, and R5sis independently -F, -Cl, -Br, -I, -CN, -N3, -NO, -NO2, -Ls-R’, -LS-OR’, -LS-SR’, - Ls- N(R’)2, — O— Ls— OR’, - O- Ls- SR’, or -O-LS-N(R’)2, wherein each R’ is independently -H or an optionally substituted group selected from C1-10 aliphatic, Ce-14 aryl, C1-10 heteroaliphatic having 1-5 heteroatoms, 5-10 membered heteroaryl having 1-5 heteroatoms and 3-10 membered heterocyclyl having 1-4 heteroatoms, or two or more R’ groups are taken together with their intervening atoms to from an optionally substituted 3-10 membered ring having 0-5 heteroatoms in addition to the intervening atoms, independently as described herein, and Lsis a covalent bond or optionally substituted bivalent Ci-6 aliphatic or heteroaliphatic having 1-4 heteroatoms. In some aspects, a sugar has the structureaspects, R4Sis -H. In some aspects, a sugar has the structure, wherein R2sis -H, halogen, or -OR, wherein R is optionally substituted Ci-6 aliphatic. In some aspects, R2sis -H. In some aspects, R2sis -F. In some aspects, R2sis -OMe. In some aspects, R2sis-OCH2CH2OMe.

[0151] In some aspects, a sugar has the structurewherein R2sand R4sare taken together to form -Ls-, wherein Lsis a covalent bond or optionally substituted bivalentCi-6 aliphatic or heteroaliphatic having 1-4 heteroatoms. In some aspects, each heteroatom is independently selected from nitrogen, oxygen or sulfur). In some aspects, Lsis optionally substituted C2-O-CH2-C4. In some aspects, Lsis C2-O-CH2-C4. In some aspects, Lsis C2-O-(7?)-CH(CH2CH3)-C4. In some aspects, Lsis C2-O-(S)-CH(CH2CH3)-C4.

[0152] In some aspects, a modified sugar contains one or more substituents at the 2’ position ( (typically one substituent, and often at the axial position or R2s) independently selected from -F; -CF3, -CN, -N3, -NO, -NO2, -OR’, -SR’, or -N(R’)2, wherein each R’ is independently described in the present disclosure, and in some aspects, optionally substituted Ci-10 aliphatic; -0-(Ci-Cio alkyl), -S-(Ci-Cio alkyl), -NH-(Ci-Cio alkyl), or -N(Ci-Cio alkyl)2; -0-(C2-Cio alkenyl), -S-(C2-Cio alkenyl), -NH-(C2-CIO alkenyl), or -N(C2-CIO alkenyl)2; -0-(C2-Cio alkynyl), -S-(C2-Cio alkynyl), -NH-(C2-CIO alkynyl), or -N(C2-CIO alkynyl)2; or -O — (C1-C10 alkylene)-0 — (C1-C10 alkyl), -0-(Ci-Cio alkylene)-NH-(Ci-Cio alkyl) or -0-(Ci-Cio alkylene)-NH(Ci-Cio alkyl)2, -NH-(Ci-Cio alkylene)-0-(Ci-Cio alkyl), or -N(Ci-Cio alkyl)-(Ci-Cio alkylene)-0-(Ci-Cio alkyl), wherein each of the alkyl, alkylene, alkenyl and alkynyl is independently and optionally substituted. In some aspects, a substituent is -O(CH2)nOCH3, -O(CH2)nNH2, MOE, DMAOE, or DMAEOE, wherein n is from 1 to about 10.

[0153] In some aspects, a modified sugar is a natural RNA sugar whose 2’ -OH is replaced with a group selected from-F, -CF3, -CN, -N3, -NO, -NO2, -OR’, -SR’, or -N(R’)2, wherein each R’ is independently described in the present disclosure; -0-(Ci-Cio alkyl), -S-(Ci-Cio alkyl), -NH-(Ci-Cio alkyl), or-N(Ci-Cio alkyl)2; -0-(C2-Cio alkenyl), -S-(C2-Cio alkenyl), -NH-(C2-CIO alkenyl), or -N(C2-Cio alkenyl)2; -0-(C2-Cio alkynyl), -S-(C2-Cio alkynyl), - NH-(C2-CIO alkynyl), or -N(C2-Cio alkynyl)2; or -0 — (C1-C10 alkylene)-0 — (C1-C10 alkyl), -0-(Ci-Cio alkylene)-NH-(Ci-Cio alkyl) or -0-(Ci-Cio alkylene)-NH(Ci-Cio alkyl)2, - NH-(Ci-Cio alkylene)-0-(Ci-Cio alkyl), or -N(Ci-Cio alkyl)-(Ci-Cio alkylene)-0-(Ci-Cio alkyl), wherein each of the alkyl, alkylene, alkenyl and alkynyl is independently and optionally substituted. In some aspects, the 2’-OH is replaced with -H (deoxyribose). In some aspects, the 2’-OH is replaced with -F. In some aspects, the 2’-OH is replaced with -OR’. In someaspects, the 2’-OH is replaced with -OMe. In some aspects, the 2’-OH is replaced with - OCH2CH2OMe.

[0154] In some aspects, a sugar modification is a 2’ -modification. In some aspects, a 2’- modification is a 2’-ORsmodification. In some aspects, Rsis optionally substituted Ci-4 aliphatic. In some aspects, Rsis optionally substituted Ci-6 alkyl. In some aspects, a modification is 2’-OMe. In some aspects, a modification is 2’-M0E. In some aspects, a 2’- modifi cation is S-cEt. In some aspects, a modified sugar is an LNA sugar. In some aspects, a 2’ -modification is -F.

[0155] In some aspects, a sugar modification replaces a sugar moiety with another cyclic or acyclic moiety. Examples of such moieties are widely known in the art, e.g., those in morpholino, glycol nucleic acids, PNA, etc., and can be utilized in accordance with the present disclosure.

[0156] In some aspects, one or more sugars of an oligonucleotide are independently modified. In some aspects, each sugar of an oligonucleotide or a portion thereof (e.g., a wing) is independently modified. In some aspects, a modified sugar comprises a 2’-modification. In some aspects, each modified sugar independently comprises a 2’ -modification. In some aspects, a 2’-modification is 2’-ORs, wherein Rsis optionally substituted Ci-6 aliphatic. In some aspects, a 2’ -modification is a 2’-OMe modification. In some aspects, a 2’ -modification is a 2’ -MOE modification. In some aspects, a 2’ -modification is an LNA sugar modification. In some aspects, a 2’ -modification is 2’-F. In some aspects, each sugar modification is independently a 2’-modification. In some aspects, each sugar modification is independently a 2’-ORsmodification. In some aspects, each sugar modification is independently 2’-ORs, wherein Rsis optionally substituted Ci-6 alkyl. In some aspects, each sugar modification is 2’- OMe. In some aspects, each sugar modification is 2’ -MOE. In some aspects, each sugar modification is independently 2’-OMe or 2’-M0E. In some aspects, each sugar modification is independently 2’-OMe, 2 ’-MOE, or a LNA sugar.

[0157] As those skilled in the art will appreciate, modifications of sugars, nucleobases, internucleotidic linkages, etc. can and are often utilized in combination in oligonucleotides, e.g., see various oligonucleotides in Table 1.

[0158] In some aspects, a sugar is one described in US 9394333, US 9744183, US 9605019, US 9598458, US 9982257, US 10160969, US 10479995, US 2020 / 0056173, US 2018 / 0216107, US 2019 / 0127733, US 10450568, US 2019 / 0077817, US 2019 / 0249173, US 2019 / 0375774, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO2019 / 217784, and / or WO 2019 / 032612, the sugars of each of which is incorporated herein by reference.

[0159] Various additional sugars useful for preparing oligonucleotides or analogs thereof are known in the art and can be utilized in accordance with the present disclosure.Internucleotidic Linkages

[0160] In some aspects, oligonucleotides (e.g., antisense oligonucleotides) comprise base modifications, sugar modifications, and / or internucleotidic linkage modifications. Various internucleotidic linkages can be utilized in accordance with the present disclosure to link units comprising nucleobases, e.g., nucleosides. In some aspects, oligonucleotides (e.g., antisense oligonucleotides) comprise both one or more modified internucleotidic linkages and one or more natural phosphate linkages. As widely known by those skilled in the art, natural phosphate linkages are widely found in natural DNA and RNA molecules; they have the structure of -OP(O)(OH)O-, connect sugars in the nucleosides in DNA and RNA, and can be in various salt forms, for example, at physiological pH (about 7.4), natural phosphate linkages are predominantly exist in salt forms with the anion being -OP(O)(O )O- A modified internucleotidic linkage, or a non-natural phosphate linkage, is an internucleotidic linkage that is not natural phosphate linkage or a salt form thereof. Modified internucleotidic linkages, depending on their structures, can also be in their salt forms. For example, as appreciated by those skilled in the art, phosphorothioate internucleotidic linkages which have the structure of -OP(O)(SH)O- can be in various salt forms, e.g., at physiological pH (about 7.4) with the anion being -OP(O)(S )O-

[0161] As used herein, the phrase “internucleotidic linkage” refers generally to a linkage linking nucleoside units of an oligonucleotide or a nucleic acid. In some aspects, an internucleotidic linkage is a phosphodiester linkage, as extensively found in naturally occurring DNA and RNA molecules (natural phosphate linkage (-OP(=O)(OH)O-), which as appreciated by those skilled in the art can exist as a salt form). In some aspects, an internucleotidic linkage is a modified internucleotidic linkage (not a natural phosphate linkage). In some aspects, an internucleotidic linkage is a “modified internucleotidic linkage” wherein at least one oxygen atom or -OH of a phosphodiester linkage is replaced by a different organic or inorganic moiety. In some aspects, such an organic or inorganic moiety is selected from =S, =Se, =NR’, -SR’, -SeR’, -N R’)2, B(R’X -S-, -Se-, and -N(R’)-, wherein each R’ is independently -H or an optionally substituted group selected from Ci-io aliphatic, Ce-14 aryl, Ci-io heteroaliphatic having 1-5 heteroatoms, 5-10membered heteroaryl having 1-5heteroatoms and 3-10 membered heterocyclyl having 1-4 heteroatoms, or two or more R’ groups are taken together with their intervening atoms to from an optionally substituted 3-10 membered ring having 0-5 heteroatoms in addition to the intervening atoms. In some aspects, a modified internucleotidic linkage is a phosphorothioate linkage. In some aspects, an internucleotidic linkage is one of, e.g., PNA (peptide nucleic acid) or PMO (phosphorodiamidate Morpholino oligomer) linkage. It is understood by a person of ordinary skill in the art that an internucleotidic linkage can exist as an anion or cation at a given pH due to the existence of acid or base moieties in the linkage.

[0162] In some aspects, an oligonucleotide (e.g., antisense oligonucleotides) comprises an internucleotidic linkage which is a modified internucleotidic linkage, e.g., phosphorothioate, phosphorodithioate, methylphosphonate, phosphoroamidate, thiophosphate, 3 ’-thiophosphate, or 5 ’-thiophosphate.

[0163] In some aspects, an internucleotidic linkage is described in US 9394333, US 9744183, US 9605019, US 9598458, US 9982257, US 10160969, US 10479995, US 2020 / 0056173, US 2018 / 0216107, US 2019 / 0127733, US 10450568, US 2019 / 0077817, US 2019 / 0249173, US 2019 / 0375774, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, and / or WO 2019 / 032612, the internucleotidic linkages of each of which is incorporated herein by reference. In some aspects, an internucleotidic linkage is described in U.S. Pat. Nos. 3687808, 4469863, 4476301, 5177195, 5023243, 5034506, 5166315, 5185444, 5188897, 5214134, 5216141, 5235033, 5264423, 5264564, 5276019,5278302, 5286717, 5321131, 5399676, 5405938, 5405939, 5434257, 5453496, 5455233,5466677, 5466677, 5470967, 5476925, 5489677, 5519126, 5536821, 5541307, 5541316,5550111, 5561225, 5563253, 5571799, 5587361, 5596086, 5602240, 5608046, 5610289,5618704, 5623070, 5625050, 5633360, 564562, 5663312, 5677437, 5677439, 6160109,6239265, 6028188, 6124445, 6169170, 6172209, 6277603, 6326199, 6346614, 6444423,6531590, 6534639, 6608035, 6683167, 6858715, 6867294, 6878805, 7015315, 7041816,7273933, 7321029, or RE39464, the internucleotidic linkages of each of which is incorporated herein by reference.

[0164] In some aspects, an oligonucleotide comprises one or more modified internucleotidic linkages. In some aspects, each modified internucleotidic linkage is independently a phosphorothioate internucleotidic linkage. In some aspects, one or more, e.g., about 1-20, 1-15, 1-10, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or moreof all intemucleotidic linkages in an oligonucleotide, are independently phosphorothioate internucleotidic linkage intemucleotidic linkage. In some aspects, about 10% or more of all intemucleotidic linkages are independently phosphorothioate internucleotidic linkages. In some aspects, about 25% or more of all intemucleotidic linkages are independently phosphorothioate intemucleotidic linkages. In some aspects, about 50% or more of all internucleotidic linkages are independently phosphorothioate internucleotidic linkages. In some aspects, about 60% or more of all intemucleotidic linkages are independently phosphorothioate intemucleotidic linkages. In some aspects, about 70% or more of all internucleotidic linkages are independently phosphorothioate internucleotidic linkages. In some aspects, about 75% or more of all intemucleotidic linkages are independently phosphorothioate intemucleotidic linkages. In some aspects, about 80% or more of all internucleotidic linkages are independently phosphorothioate internucleotidic linkages. In some aspects, about 85% or more of all intemucleotidic linkages are independently phosphorothioate intemucleotidic linkages. In some aspects, about 90% or more of all internucleotidic linkages are independently phosphorothioate internucleotidic linkages. In some aspects, about 95% or more of all intemucleotidic linkages are independently phosphorothioate internucleotidic linkages. In some aspects, each internucleotidic linkage bonded to a natural DNA sugar is independently a phosphorothioate internucleotidic linkage. In some aspects, each intemucleotidic linkage in an oligonucleotide is independently a phosphorothioate intemucleotidic linkage.

[0165] In some aspects, an oligonucleotide (e.g., antisense oligonucleotides) comprises one or more natural phosphate linkages. In some aspects, each natural phosphate linkage independently bonds to at least one modified sugar. In some aspects, each sugar bonded to a natural phosphate linkage is independently a modified sugar. In some aspects, each sugar bonded to a natural phosphate linkage is independently a 2’-ORsmodified sugar or a bicyclic sugar (e.g., a LNA sugar). In some aspects, each sugar bonded to a natural phosphate linkage is independently a 2’-ORsmodified sugar. In some aspects, each sugar bonded to a natural phosphate linkage is independently a 2’ -MOE modified sugar.Wings and Gaps

[0166] In certain aspects, modified oligonucleotides (e.g., antisense oligonucleotides) have a gapmer motif, which is defined by two external regions or “wings” and a central or internal region or “gap.” The three regions of a gapmer motif (the 5’-wing, the gap, and the 3’-wing)form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3 ’-most nucleoside of the 5 ’-wing and the 5 ’-most nucleoside of the 3 ’-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing / gap junction). In certain aspects, the sugar moieties within the gap are the same as one another. In certain aspects, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain aspects, the sugar motifs of the two wings are the same as one another (symmetric gapmer).

[0167] In certain aspects, the sugar motif of the 5 ’-wing differs from the sugar motif of the 3 ’-wing (asymmetric gapmer). In certain aspects, the wings of a gapmer comprise 1-6 nucleosides. In certain aspects, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain aspects, at least one nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain aspects, at least two nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain aspects, at least three nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain aspects, at least four nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain aspects, at least five nucleosides of each wing of a gapmer comprises a modified sugar moiety.

[0168] In certain aspects, the gap of a gapmer comprises 7-12 nucleosides. In certain aspects, each nucleoside of the gap of a gapmer comprises a 2’-deoxy ribosyl sugar moiety. In certain aspects, at least six nucleosides of the gap of a gapmer comprise a 2’-P-D-deoxyribosyl sugar moiety. In certain aspects, each nucleoside of the gap of a gapmer comprises a 2’-|3-D- deoxyribosyl sugar moiety. In certain aspects, at least one nucleoside of the gap of a gapmer comprises a modified sugar moiety. In certain aspects, at least one nucleoside of the gap of a gapmer comprises a 2’-0Me sugar moiety.

[0169] In certain aspects, the gapmer is a deoxy gapmer. In certain aspects, the nucleosides on the gap side of each wing / gap junction comprise 2’ -deoxyribosyl sugar moieties and the nucleosides on the wing sides of each wing / gap junction comprise modified sugar moieties. In certain aspects, at least six nucleosides of the gap of a gapmer comprise a 2’-P-D-deoxyribosyl sugar moiety. In certain aspects, each nucleoside of the gap of a gapmer comprises a 2’- deoxyribosyl sugar moiety. In certain aspects, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain aspects, one nucleoside of the gap comprises amodified sugar moiety and each remaining nucleoside of the gap comprises a 2’-deoxyribosyl sugar moiety. In certain aspects, modified oligonucleotides comprise or consist of a portion having a fully modified sugar motif. In such aspects, each nucleoside of the fully modified portion of the modified oligonucleotide comprises a modified sugar moiety.

[0170] In certain aspects, each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety. In certain aspects, modified oligonucleotides comprise or consist of a portion having a fully modified sugar motif, wherein each nucleoside within the fully modified portion comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain aspects, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain aspects, each nucleoside of a uniformly modified oligonucleotide comprises the same 2’-modification.

[0171] Herein, the lengths (number of nucleosides) of the three regions of a gapmer can be provided using the notation [# of nucleosides in the 5 ’-wing] - [# of nucleosides in the gap] - [# of nucleosides in the 3’-wing], Thus, a 5-10-5 gapmer consists of 5 linked nucleosides in each wing and 10 linked nucleosides in the gap. Where such nomenclature is followed by a specific modification, that modification is the modification in each sugar moiety of each wing and the gap nucleosides comprises a 2’-P-deoxyribosyl sugar moiety. Thus, a 5-10-5 MOE gapmer consists of 5 linked 2’-M0E nucleosides in the 5’-wing, 10 linked 2’-|3- deoxynucleosides in the gap, and 5 linked 2’-M0E nucleosides in the 3’-wing.

[0172] In certain aspects, modified oligonucleotides (e.g., antisense oligonucleotides) are 5-10-5 MOE gapmers. In certain aspects, modified oligonucleotides are 4-10-6 MOE gapmers. In certain aspects, modified oligonucleotides are 6-10-4 MOE gapmers. In certain aspects, modified oligonucleotides (e.g., antisense oligonucleotides) are 4-8-6 MOE gapmers. In certain aspects, modified oligonucleotides are 6-8-4 MOE gapmers. In certain aspects, modified oligonucleotides (e.g., antisense oligonucleotides) are 5-8-5 MOE gapmers. In certain aspects, modified oligonucleotides (e.g., antisense oligonucleotides) are X-Y-Z MOE gapmers, wherein X and Z are independently selected from 1, 2, 3, 4, 5, 6, or 7 linked 2’-M0E nucleosides and Y is selected from 7, 8, 9, 10, or 11 linked deoxynucleosides. In certain aspects, gapmers provided herein include, for example 20-mers having a motif of 5-10-5. In certain aspects, gapmers provided herein include, for example 19-mers having a motif of 5-9-5.

[0173] In certain aspects, modified oligonucleotides have the following sugar motif (5’ to3’): eeeeedyddddddddeeeee, eeeeeddddddddddeeeee, eeeeeeddddddddddeeee,eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee, wherein ‘d’ represents a 2’ -deoxyribosyl sugar moiety, ‘e’ represents a 2’-M0E sugar moiety, and ‘y’ represents a 2’-0Me sugar moiety.

[0174] Wings and gaps can independently be of various suitable lengths. In some aspects, there are about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more nucleobases independently in a wing or gap. In some aspects, each nucleobase independently comprises an optionally substituted monocyclic, bicyclic or polycyclic ring, which ring has at least one nitrogen ring atom; in some aspects, each nucleobase is independently optionally substituted A, T, C, G or U, or a substituted tautomer of A, T, C, G or U. In some aspects, the number of nucleobases in a wing is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some aspects, the number is 5 for a wing. In some aspects, in a wing of a wing-gap-wing structure, the two wings are of the same length. In some aspects, the two wings are of different length. In some aspects, the number is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more for a gap. In some aspects, the number is about 5-15, e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, for a gap. In some aspects, the number is 10 for a gap.

[0175] In some aspects, a wing comprises one or more sugar modifications. In some aspects, each sugar in a wing is independently modified. In some aspects, each wing sugar in an oligonucleotide is independently modified. In some aspects, each modified sugar independently comprises a 2’-modification (e.g., a 2’-ORsmodified sugar, an LNA sugar, etc.). In some aspects, each wing sugar is independently a 2’-ORsmodified sugar. In some aspects, each sugar modification in a wing is the same. In some aspects, a wing comprises different sugar modifications, e.g., different 2’-ORsmodifications. In some aspects, 2’-ORsis 2’-OMe. In some aspects, 2’-ORsis 2’-M0E. In some aspects, each sugar in a wing is a 2’-M0E modified sugar. In some aspects, each sugar in a wing is a 2’-OMe modified sugar. In some aspects, a wing comprises one or more 2’-OMe modified sugars and one or more 2’ -MOE modified sugars.

[0176] In some aspects, the two wings of a wing-gap-wing structure comprise different sugar modifications or patterns thereof.

[0177] In some aspects, certain sugar modifications, e.g., 2’-M0E, provide more stability under certain conditions than other sugar modifications, e.g., 2’-OMe or natural DNA or RNA sugars.

[0178] In some aspects, a wing comprises a bicyclic sugar. In some aspects, a bicyclic sugar is a LNA, a cEt or a BNA sugar.

[0179] In some aspects, one or more intemucleotidic linkages bonded to a 5 ’-wing sugar are each independently a modified intemucleotidic linkage. In some aspects, they are each independently a phosphorothioate intemucleotidic linkage. In some aspects, each intemucleotidic linkage bonded to a 5 ’-wing sugar is independently a modified intemucleotidic linkage. In some aspects, each such intemucleotidic linkage is independently a phosphorothioate intemucleotidic linkage.

[0180] In some aspects, one or more intemucleotidic linkages bonded to a 3 ’-wing sugar are each independently a modified intemucleotidic linkage. In some aspects, they are each independently a phosphorothioate intemucleotidic linkage. In some aspects, each intemucleotidic linkage bonded to a 3 ’-wing sugar is independently a modified intemucleotidic linkage. In some aspects, each such intemucleotidic linkage is independently a phosphorothioate intemucleotidic linkage.

[0181] In some aspects, a gap comprises one or more, e.g., about 1-20, 5-20, 6-20, 7-20, 8- 20, 9-20, 10-20, or 5-15, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 natural DNA sugars. In some aspects, such DNA sugars are consecutive. In some aspects, each sugar in a gap is independently a natural DNA sugar.

[0182] In some aspects, one or more intemucleotidic linkages bonded to a gap sugar are each independently a modified intemucleotidic linkage. In some aspects, they are each independently a phosphorothioate intemucleotidic linkage. In some aspects, each intemucleotidic linkage bonded to a gap sugar is independently a modified intemucleotidic linkage. In some aspects, each such intemucleotidic linkage is independently a phosphorothioate intemucleotidic linkage.

[0183] In some aspects, a gap is able to hybridize to a target mRNA, forming a duplex structure recognizable by RNase H, such that RNase H is able to cleave the mRNA.Oligonucleotides

[0184] Among other things, the present disclosure provides various oligonucleotides (e.g., antisense oligonucleotides). As described herein, oligonucleotides (e.g., antisense oligonucleotides) can contain various nucleobase modifications, sugar modifications, intemucleotidic linkages and patterns thereof. In some aspects, the present disclosure provides the oligonucleotides described in Table 1 as exemplary oligonucleotides (e.g., antisense oligonucleotides) or portions thereof.

[0185] Table 1. Exemplary oligonucleotides and ASOs

[0186] As appreciated by those skilled in the art, intemucleotidic linkages connect 5’ and 3’ positions of sugars. Unless otherwise noted (e.g., by which is for a phosphorothioate intemucleotidic linkage), an intemucleotidic linkage is a natural phosphate linkage. Unless otherwise noted, each of A, T, C and G is independently deoxyadenosine, deoxythymidine, deoxycytidine, and deoxyguanosine, respectively (e.g., as typically found in natural DNA). “2M0Er” indicates a 2’-M0E modification to a sugar; “5” indicates a nucleoside has a 5’-OH group (e.g., when at the 5’-end of an oligonucleotide); “3” indicates a nucleoside has a 3’-OH group (e.g., when at the 3 ’-end of an oligonucleotide); “i” indicates an nucleoside is in the middle of an oligonucleotide and its 5’- and 3’- positions are bonded to intemucleotidic linkages as indicated; and “Me-dC” indicates a 5-methyl-2’ -deoxy cytidine nucleoside. As those skilled in the art appreciates, oligonucleotides can exist in various forms including various salt forms.* is -O-P(O)(SH)-O-;

[0187] As shown in Table 2, “Start site” indicates the 5’-most nucleoside to which the modified oligonucleotide is complementary in the target nucleic acid sequence. “Stop site” indicates the 3 ’-most nucleoside to which the modified oligonucleotide is complementary in the target nucleic acid sequence.

[0188] Table 2. 67 / / .? / . / -Targeting ASO Target Positions and Sequences

[0189] In some aspects, provided oligonucleotides are capable of hybridizing to a CHI3L1 transcript (e.g., a human CHI3L1 transcript). In some aspects, the human CHI3L1 transcript is complementary to the nucleic acid sequence of SEQ ID NO: 29 (NCBI RefSeq: NC_000001.11 :c203186704-203178931).GAGGCCCTGTCTAGGTAGCTGGCACCAGGAGCCGTGGGCAAGGGAAGAGGCCACACCCTGCCCTGCTCTG CTGCAGCCAGAATGGGTGTGAAGGCGTCTCAAACAGGTATCTGGGCTAGCCAAGGTTAATCCATCAGAGT TGTGGGTTTTCAGGCCCAGACAGCCCGCAGAGCCATCTGCCTGCTGGGTGAGGGACTAAGGGAGTGGGCA GAGGGGGAGGAGAAGCAGAGCCAGGGGAGGGACTGAGGCTGCAACCAGGAGGTGGGGGTGGGGGAGGTGG GTCTCAGTTGCTTGGGGGAGGGAGCAGGGCGGAAGGGCAGGATGCACTTGCAGGGGTCTCATCCTGGATT TCTCTTCAGGCTTTGTGGTCCTGGTGCTGCTCCAGTGCTGTGAGTAATCCCTCCACCTCCACTTTTAAGT CCAGAGGCGTGGCGAGGGCACAGGGCAGGTGTGGAGGAGGTCTTAGCTCCAAGGGAACACTTTGCCAGGT TCTTCTGTGCTTCCAATGACTTCGAAATAGTCACGTTTGCTAAACTGGAGTGAGGAGTATATGGATGTTT ATTTTGCTATACTCTTTGGTATATGTGAAAATTCTCAAAATAAGAAACTTTAAAAGGTCCTGGTTCAGTG AAGGCTTTGACTAACAGCCCCTGGGAGCCGCTAGTACAGTTGCCCAGTAGCTGCTTGGATGAGTGATGCC CACATTGTTTGCAGCAGGAGAAACAGAATTAGAGGCGAGGAAGGATTTCCTGGTCCATTGTGATATTGTG CCCCAGCCTGGGGGACATGCCGAGGGAGCACAGGACTGCCATTCCGGGTGGGTTACAAGTTAGAGGCACT CTCACCAGGAGGCAGAGAAAGGTGGGCCAGAGTCCCTCATGGATGAAGGACCTCACTGCAGGTCACTAAA GGTGCCAGCCTGAAAGCCAGGGCCATCTGTGACACAGGCTATCTTGGGCCTTCCCCTCCCACAAAGCCAC TGCTTCCAGGAAGCCTGCTGTGCTGGCACCAAGTCCCATTTCATCCTTATTCCCCAGCTCCTACCCTTCC CCCACACAGTGCCTGTAGCGTATTCATCCCCTGCATTGGATCTTTTCTAAGCATTTTCAGAATAGGCCTT ATTTTCACCAGTCAGGGAACTCCCCAGAGGCAGGGGGACCTGAACCAGCTCCTTTCATTTAAGAATTCTG ACTTTGCTCACAATCTGCACCCCACTCCTCCCTACCCAACCCCACACCCCATTGGTGCTCAGCTCTGGGC TCAGCCTGAGGTCTCTTGCCGAATCCTGGCCCGGGCCCCATCCCAGACTTCTCCTTCAGGCTCTGCATAC AAACTGGTCTGCTACTACACCAGCTGGTCCCAGTACCGGGAAGGCGATGGGAGCTGCTTCCCAGATGCCC TTGACCGCTTCCTCTGTACCCACATCATCTACAGCTTTGCCAATATAAGCAACGATCACATCGACACCTG GGAGTGGAATGATGTGACGCTCTACGGCATGCTCAACACACTCAAGAACAGGTTGGGCCAGGGCTGGCCA GGAGAGGAGGGACCAGCTGGGCTGGTCCCAGGGCAGGGCAACCCCACCCAGGAGGAAGGGCGAGGCCCCA CCCTGCTCACCTATGTTTGGAGAGTTAGAGGGGCTTGGCTTAAATGGGTGGAGGGGATGACTGTAGGTGC TGGGCAATATTTGGGGTGATGAGAGACTGTAGACGGAAGCGCAGCTGAGCCCCTCTGGGAGAGGGGAACC CTCTCCTGCCCCTAACGTGCTCTCCAGGGAGCATGGAAAATGAGCAAGACTCTACTTTGCCATACTCTGT CTTCTCCACTGGGGAAAACAAAAATGGGCAGCAGACCTCAGAGTAACTCCCATGAAGCCTGTGACCCCTC AGAGATCCACCACTATGAATCTCTATGGGATTCCCATGATGTCCTATGGGAGGACATCAGCGGCCTAACC CAGCCTCTCACCCAAAGCAGGAAACCTTCTATGGCCTCTCAGACATGGGGCCACCCAGTGTCATGACAAT GTCATTCCACTCCTGCCCTCCCCACCTCCCTGTGCTCCACAGGAACCCCAACCTGAAGACTCTCTTGTCT GTCGGAGGATGGAACTTTGGGTCTCAAAGGTAGGAGCCTCTCCCCAGGGGCAGGACGGCAGAGGATGATG GCATAGGAGTGAGGAGCTTGGGTCTCCCGCATCCACTGTATGGATGTTCCAGGGGCTCCAGACTAGATAG GTACAAGGCCTACCTGTTTGTCAAGGGCCTGCCTGATGTGTAGCAAAGAAAGCAGAGCCCAGAGAGAGAG CAGGACTTGCCAAGAGTCACACAGCAAGTTAACAGTGGATCTCCCAATTCCCTGCCAATGCTCTATTTAC TACCTCACAGGCCCGAAAATATGGGACTTCTGGGGCTACCACCATTAGGGCTGGAAAGAGAGAGATGGAA ACCAATGGGGACATTGAGAAGTGGGGAGACCCTGGGAGGAGTCTTTGGATTAGGTGGGGTTGGAGCAGGG CTTGAAATGGGGGTGGTTATGGCCATCGTTGGCACCCATGTGCTGGGTACTCTTTCTGTGTCCAGCACCC TGTCTCCCCATGATCCCATGTTGTCCTCACAACAGCAAGGTGAGCTGTTATATTTGTCCCCATTTTACAGATGATGAAACTGAGACTCAGGTTATAACCTTTCACAGTGGCTGGCTAGTAAGTGATAGAGCCAGACTTGG AAACCTGGAATGCCTGGCTCTAAGGCACATGCATGCCTGGAGGCGACCCCTGTCCCAATCATGCCCTCCC AGAGCTGTGTGGCCTCAGGATCCCAGCTCTGCAGGTCCTGGAAACCCCACCAGAGGCCCAAGGCACCTAG CATATCAGTGCTGAGCATGCTACAGGGCTGATTTTGGTCCTAGATTTTCCAAGATAGCCTCCAACACCCA GAGTCGCCGGACTTTCATCAAGTCAGTACCGCCATTTCTGCGCACCCATGGCTTTGATGGGCTGGACCTT GCCTGGCTCTACCCTGGACGGAGAGACAAACAGCATTTTACCACCCTAATCAAGGTGCTGGTCAGGTCAG GGACAGGGAGGGAGGTGGGCAGGCATGAGGGAATGGGGTGGGCTAGAAGCCGGCGTCAGCTGCTGTCCTC CTGAGGACAGGTAAAGAGGGACTTCAGCCTCAGGGCAGTGTCCTGGGACCCTGTGCCCTGAAGATCTCAC ATAGCAAGGAAGGCTTCTTGTGACCATGGTGGGAGGTGGGAATGGGGTTCTAAGAGGTGGAAGGTTGTGA CTGAGCAGAGCACCCACTTATAACTACCCACTTAGTGCATTGCCCATTGCCCACCCTTCAATCCCATACT GATGCCACCCATACCCAGCATGCACTGTGTCCAGCAGCTCTCAGCTCTGCCTGGGGGCAGCCTAAGTATC TCCAGTTACCAGGGGCAGAAGGAGAGTCTAAACAAATTGTTCACAATACCAGCAGCAATCACTTTAACTT TGGGATTTCATGCACCAGCTAGAACAAAGCACAGACCGAAAGGCAAATGTCTCCCAAAGTCATCTGTGGG CCAATAGGGGTCACCCACTGTCCGATGCTCCCTCCAGGACAGGGAGTAATTGAGTGCTGATGGGTGTGCA TGGGTTTGGGGAGAAGATTAGTCAGTTTTTTAGGAAAAGGATGGGTGACTTGAGGATGGGACCACTGATG AGCCACTTTATCACTTCCACTAGGCCCCAGGCAGGTTGGGGAGTACAGCAAATGGGTTGCGCAGAGACCTAGTCCGCCCTCGATGAGTCTACCTCTCATGCCACTTGGGACCCTTTCTCTCACCTGCCTGTCTCCCATCT AGGAAATGAAGGCCGAATTTATAAAGGAAGCCCAGCCAGGGAAAAAGCAGCTCCTGCTCAGCGCAGCACT GTCTGCGGGGAAGGTCACCATTGACAGCAGCTATGACATTGCCAAGATATCCCAGTGAGTCTCCTGCCCC AGGCAGCCTCCCCAGAACCTCTGCCAACACTCCTGTTTCCCCGCCACCCCCAGCCCTAGCACTCCATGTA GACTGAGGACACTGGGCTTCCAGTCCCAGTTCTTCCAAAGCCTTGATGTGTGACCTTGAGCAAGTCACTT CCCTGCCCTGTGCCTCAGTTTCCCCATCTGTCAAATGAGGCATAACAATCCTTGCCTTTCCTTTTTCACC TGGGCTGTTGGCTGAGCAGTTGAGAGAGCTGCTATGAAAGTATTTTGGAAAGGGAAGTGGAAAAAGCTAT TCAAACCCTCCAGCTATTGCAGAGTATTTTCTCCACACCAGGCAGAGCAGAGTGCTGGGCCCTGGAGAGG CCACACAGCAGCCTCTTTCTAGAGTGCTGGGGAGTCCTCAAGGCTCTCTCATACACACAGGCCTCCCCCT TTCCTGTTGGCCCCACGCCTCATCCTCACCCCACCCCTCATGCCTGTGAGGAACAAGGAACAGCCAAGCA GCCTCATCTCTCCTGAGAGCAGAGCCATGGGTCTCGGGAAACCCAGGAGTAAGGAACAAAGACTCTTCAA AATGACTTCAGAGCTTTCTTTAGGATCCCAGGGAGGTGTAAACTCAGTGCTTAATTAAATGGATTCTTTA GAGGGTGGGAAACAGGTGGATGTCAACCATTTGCCCCACATACCCGTATTCATGCAATCCACCCCCAGTG GGCTCACCGGTGCGGGTGTGCAAAACCTCCTCCCACCCCAGTCATCTTAGGTTCAGGTCATCCTTTGGTC CTGCTCTTTCCCCGCCAGGCTGTCTGTTGATGCTACTTTTAATCTGCTTTCACTAAGATAAGCCTGGCAG AAGTGGTGGGGGTAAGGTGGGCTGTAGGCCAGCTCCCAAATGTGTGCTGGGCATAACAGAAGACCCATTC TTGACTGAAGTGCCCTTGTGGGACCCTGAGCCCGTGCCCTGGAGTGGCACAGGGAGGTGTGCCAGCAATG GGGACCGAGGTCACTGGGGACTGCTGGGGTTCGGGCTAGTGGCCTGTCTGGCTGCTGTCTGCTTCCCTCG TTCACATCCTGCTGGAGCCTTAAATAGGAGCCCAAAAGCTTTTCTTTCTTACTTTTTTTTGAGACAAAAT CTCACTCTGTTGCCCAGGCCGGAGTGCAGTGGCACAACCTCTGCCGCCTGGGTTCAAGCGATTCTCCTGC CTCAGCCTCCCGAGTAGCTGGGATTACAGGTGCCTGCCACCATGCCTGGCTAATTTTCGTAGTTAGAGTA GAGACGGGGTTTCACCATCTTGGCCAGGCTGGTCTTGAACTCCTCACCTCATGATCCACCTGCCTCGGCC TCCCAAAGTGCTGGGATTCCAGGTATGAGCCACCACGCCCGGCCTAAAGCTTTTCTATTAATAATTTCCT GCCTCACCCTCCATCCCCTTCCTCCTCAGACACCTGGATTTCATTAGCATCATGACCTACGATTTTCATG GAGCCTGGCGTGGGACCACAGGCCATCACAGTCCCCTGTTCCGAGGTCAGGAGGATGCAAGTCCTGACAG ATTCAGCAACACTGTGAGTTCCCAGAAGGAGGGAGGGCCAGGAGGGGGCCGCAAGACCTGCCATCTGCCA GTGCTCACACACCAATCTCTCTAGCCCTCAGTACAGTCCTGCAAGAGGGGGGTCATGAGGCCCATTCCAC AGATAAGGAAACTGAGGCCCAAAGTCTGGGCATGCTGCGTTGCTCTGGGAAGGTGATCTGCAGGGTAAAT GGAGTGAGGGCAGGGGGCCGAATGGGGAGAGGCTGGGAGCCGAGGAGGTAGGAGTCATTGTGCCCTCAGA GCCAACCACCTGATTTCTGCATCTGTCAAATAGTAATAGCCCCTTCCTATGCCTCAAAGGATTTTTTTCA AGAATGAAACTGTAAAATTCACTTTAAAGTGACATGATCCGTTCCCGGAGGGACAGGGGAATCCCCAGTG CACCATACACCAATAACCCCTGCTAAGGCAGCAGTATTAATTGCTCAACCTTCCGCACCTGTGCACTAAC TGCTCACGTTGTTCCCACCCTACCCCACCCAGGACTATGCTGTGGGGTACATGTTGAGGCTGGGGGCTCC TGCCAGTAAGCTGGTGATGGGCATCCCCACCTTCGGGAGGAGCTTCACTCTGGCTTCTTCTGAGACTGGT GTTGGAGCCCCAATCTCAGGACCGGGAATTCCAGGCCGGTTCACCAAGGAGGCAGGGACCCTTGCCTACT ATGAGGTAATGGAGTTGGGGAGAAGGTAGGATTCCCCCACACCACCAGCAGCCCTGGGGAAGGTGATTCC CCACCACGTTCTTGCTTTTTCTCCTTTGGGAATAAAGAAAATGTCCGGTTGCCCCAGCATGCCTGAGGAA GTGGAAGGGAGAGGTTAGGACATTTGTTGCTGAAAATCTCCAGCAGGTACAGGCACATGGGCCTGCACCA CTAGGCACCTGGGATAGCCCTCTGGCTATGGGGCTGAGGTCTTCCTTCCAGCCCAGGAAAGAGCAGAGGT CAAGAGGCAGATTTTTTGTTTCACTCTAGCCTCTGCTACTCTGTGTGGCCTTGGGCCTGTCCTCAGTGTC AACCAGCAGGCCTCACATCTCTGTTTAAATGGAAGAAGCTAAGCAGGGCCAAGGCAGCCACCATCTCTGG GTCATTTGCCTCTGGTTTGTATAAACTTGTGTGATGCATGCAGCCTGCAGACCCTGCAGAGAGTGAGGCT GCAGGATGGAGCAGGAGCTAAAAGAGATTTGGAGAGTGGCGTCTCCTGGTGACCTGCAAGGTCTCGGCAC GACTCCCCACACTGCCTTTTCCCTGTTATCTGCTCAGATCTGTGACTTCCTCCGCGGAGCCACAGTCCAT AGAATCCTCGGCCAGCAGGTCCCCTATGCCACCAAGGGCAACCAGTGGGTAGGATACGACGACCAGGAAAGCGTCAAAAGCAAGGTAGGTTTCCCCAAGGCCACACCTCAGGACAAAGAGAAAGAAGGAGGCCCCGCTCC CAGCAGCCAGATTCCTGTCCCTTGCACTGAGGTCTGGGCTGGGCTCACAGAGCACATGTGCCCTGTACAC ACTCTGGGTCAGGGAACCCAGCCCTGCTCCTCTGGGCCTCCCCTGCCAGGTGCAGTACCTGAAGGACAGG CAGCTGGCGGGCGCCATGGTATGGGCCCTGGACCTGGATGACTTCCAGGGCTCCTTCTGTGGCCAGGATC TGCGCTTCCCTCTCACCAATGCCATCAAGGATGCACTCGCTGCAACGTAGCCCTCTGTTCTGCACACAGC ACGGGGGCCAAGGATGCCCCGTCCCCCTCTGGCTCCAGCTGGCCGGGAGCCTGATCACCTGCCCTGCTGA GTCCCAGGCTGAGCCTCAGTCTCCCTCCCTTGGGGCCTATGCAGAGGTCCACAACACACAGATTTGAGCT CAGCCCTGGTGGGCAGAGAGGTAGGGATGGGGCTGTGGGGATAGTGAGGCATCGCAATGTAAGACTCGGG ATTAGTACACACTTGTTGATTAATGGAAATGTTTACAGATCCCCAAGCCTGGCAAGGGAATTTCTTCAAC TCCCTGCCCCCCAGCCCTCCTTATCAAAGGACACCATTTTGGCAAGCTCTATCACCAAGGAGCCAAACAT CCTACAAGACACAGTGACCATACTAATTATACCCCCTGCAAAGCCCAGCTTGAAACCTTCACTTAGGAAC GTAATCGTGTCCCCTATCCTACTTCCCCTTCCTAATTCCACAGCTGCTCAATAAAGTACAAGAGCTTAAC AGTG ( SEQ ID NO : 29 )

[0190] In some aspects, provided oligonucleotides can reduce levels of CHI3L1 transcripts or products thereof. In some aspects, provided oligonucleotide can reduce levels of CHI3L1 mRNA. In some aspects, provided oligonucleotide can reduce levels of YKL-40 protein. In some aspects, provided oligonucleotide can reduce activity levels of YKL-40 protein observed in a system (e.g., a sample, a subject, etc.). In some aspects, an oligonucleotide (e.g., antisense oligonucleotide) comprises or is selected from an oligonucleotide or ASO disclosed in Table 1. In some aspects, an oligonucleotide is a pharmaceutically acceptable salt of an oligonucleotide or ASO disclosed in Table 1.

[0191] The oligonucleotides (e.g., antisense oligonucleotides) provided herein can also have a defined percent identity to a particular nucleotide sequence, SEQ ID NO, or portion thereof. As used herein, an oligonucleotide is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, an RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the oligonucleotides described herein as well as compounds having non-identical bases relative to the oligonucleotides provided herein also are contemplated. The non-identical bases can be adjacent to each other or dispersed throughout the oligonucleotide. Percent identity of an oligonucleotide is calculated according to the number of bases that have identical base pairing relative to the sequence to which it is being compared.

[0192] In certain aspects, the oligonucleotides, or portions thereof, are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the antisense oligonucleotides or SEQ ID NOs, or a portion thereof, disclosed herein. In certain aspects, a portion of the oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain aspects, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid. In certainaspects, a portion of the oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain aspects, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

[0193] In certain aspects, the antisense oligonucleotide is characterized as a 5-10-5 MOE gapmer, having a sequence of (from 5’ to 3’) of any one of SEQ ID NOs: 11, 13, 15, 17, or 19 (as shown in Table 1), which is complementary to a portion of nucleobases in SEQ ID NO: 29, and wherein each of nucleosides 1-5 and 16-20 are 2’-O-methoxyethylribose modified nucleosides, and each of nucleosides 6-15 are 2’ -deoxynucleosides, wherein the internucleoside linkages between nucleosides 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 17 to 18, 18 to 19, and 19 to 20 are phosphorothioate linkages, and wherein each cytosine is a 5’- methylcytosine.

[0194] In some aspects, the present disclosure provides oligonucleotides that are particularly effective in reducing levels of CHI3L1 transcripts, YKL-40 polypeptides, and / or YKL-40 activity.

[0195] In some aspects, an oligonucleotide comprises or has the structure of / 52MOErC / * / i2MOErC / * / i2MOErC / * / i2MOErA / * / i2MOErT / *dG*dT*dG*iMe-dC*iMe- dC*dT*dG*dT*dA*iMe-dC* / i2MOErC / * / i2MOErT / * / i2MOErG / * / i2MOErC / * / 32MOErT / or a salt thereof.

[0196] In some aspects, an oligonucleotide comprises or has the structure of / 52MOErT / * / i2MOErT / * / i2MOErG / * / i2MOErG / * / i2MOErC / *iMe-dC*iMe- dc * dT * dG* iMe-dC * dT * dT * d A* dG* iMe- dC* / i2MOErT / * / i2MOErT / * / i2MOErC / * / i2MOErT / * / 32MOErT / (SEQ ID NO: 43) or a salt thereof.

[0197] In some aspects, an oligonucleotide comprises or has the structure of / 52MOErA / * / i2MOErT / * / i2MOErA / * / i2MOErA / * / i2MOErT / *dT*dA*dG*dT*dA*dT*dG* dG*dT*iMe-dC* / i2MOErA / * / i2MOErC / * / i2MOErT / * / i2MOErG / * / 32MOErT / (SEQ ID NO: 52) or a salt thereof.

[0198] In some aspects, an oligonucleotide comprises or has the structure of / 52MOErT / * / i2MOErT / * / i2MOErG / * / i2MOErT / * / i2MOErA / *iMe- dC*dT*dT*dT*dA*dT*dT*dG*dA*dG* / i2MOErC / * / i2MOErA / * / i2MOErG / * / i2MOErC / * / 32MOErT / (SEQ ID NO: 53) or a salt thereof.

[0199] In some aspects, an oligonucleotide comprises or has the structure of / 52MOErA / * / i2MOErA / * / i2MOErG / * / i2MOErC / * / i2MOErT / *iMe- dc * dT * dT * dG* dT * d A* iMe- dC*dT*dT*dT* / i2MOErA / * / i2MOErT / * / i2MOErT / * / i2MOErG / * / 32MOErA / (SEQ ID NO: 54) or a salt thereof.

[0200] In some aspects, the present disclosure provides compositions comprising an oligonucleotide (e.g., an antisense oligonucleotide) disclosed herein. In some aspects, an oligonucleotide composition comprises a disclosed oligonucleotide (e.g., an antisense oligonucleotide) or a salt thereof, and / or various diastereomers or salt thereof. In some aspects, an oligonucleotide composition comprises a disclosed oligonucleotide (e.g., an antisense oligonucleotide) or a salt thereof, and / or various diastereomers with respect to chiral linkage phosphorus and salt thereof. In some aspects, oligonucleotides (e.g., antisense oligonucleotide) can exist in one or more forms. In some aspects, oligonucleotides (e.g., antisense oligonucleotides) in a composition exist in a salt form. In some aspects, oligonucleotides (e.g., antisense oligonucleotides) in a composition exist in one or more salt forms. In some aspects, a salt form is a pharmaceutically acceptable salt form. In some aspects, a salt form is a metal salt. In some aspects, a salt form is a alkali metal salt. In some aspects, a salt form is a sodium salt. In some aspects, a salt form is a potassium salt. In some aspects, a salt form is a calcium salt. In some aspects, a salt form is an ammonium salt form (e.g., of N(R’)s wherein R’ is as described herein; in some aspects, each R’ is independently -H or optionally substituted Ci-6 alkyl). In some aspects, an oligonucleotide composition is a liquid composition, wherein an oligonucleotide is dissolved in a solution. In some aspects, a solution is a buffer. In some aspects, a solution is a buffered saline. In some aspects, in a composition acidic internucleotidic linkages, e.g., natural phosphate linkages, phosphorothioate internucleotidic linkages, e.g., independently exist as anionic forms, and the composition comprises one or more types of cations, e.g., Na+, K+, etc.Additional Chemical Moieties

[0201] In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) comprises one or more additional chemical moieties. Various additional chemical moieties, e.g., targeting moieties, carbohydrate moieties, lipid moieties, etc. are known in the art and can be utilized in accordance with the present disclosure to modulate properties and / or activities of oligonucleotides, e.g., stability, half life, activities, delivery, pharmacodynamics properties, pharmacokinetic properties, etc. In some aspects, certain additional chemical moieties facilitatedelivery of oligonucleotides to desired cells, tissues and / or organs, including but not limited the cells of the central nervous system. In some aspects, certain additional chemical moieties facilitate internalization of oligonucleotides. In some aspects, certain additional chemical moieties increase oligonucleotide stability. In some aspects, the present disclosure provides technologies for incorporating various additional chemical moieties into oligonucleotides.

[0202] Certain additional chemical moieties groups and chemical moieties have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N. Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., NucL Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et A., EMBO J., 1991, 10, 1111-1118; Kabanov et a\ , EEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49- 54), a phospholipid, e.g., di-hexadecyl-rac-glycerol ortriethyl-ammonium 1,2-di-O-hexadecyl- rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et \., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid a palmityl moiety (Mishra et a\., Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937), a tocopherol group (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220; and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a GalNAc cluster (e.g., WO2014 / 179620).

[0203] Certain useful additional chemical moieties are described in US 9394333, US 9744183, US 9605019, US 9598458, US 9982257, US 10160969, US 10479995, US 2020 / 0056173, US 2018 / 0216107, US 2019 / 0127733, US 10450568, US 2019 / 0077817, US 2019 / 0249173, US 2019 / 0375774, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, and / or WO 2019 / 032612, the additional chemical moieties of each of which are incorporated herein by reference.Manufacturing

[0204] Various technologies are available in the art to manufacture the disclosed oligonucleotides (e.g., antisense oligonucleotides) and can be utilized in accordance with the present disclosure. For example, in some aspects, oligonucleotides (e.g., antisenseoligonucleotides) are manufactured on solid support using phosphoramidites. In some aspects, oligonucleotides (e.g., antisense oligonucleotides) are manufactured in solution. In some aspects, manufacturing of oligonucleotides (e.g., antisense oligonucleotides) comprise multiple cycles, in each of which one or more nucleoside units, typically one, are added. In some aspects, a cycle comprises coupling of a phosphoramidite, blocking unreacted 5 ’-OH groups, modification (e.g., sulfurization), and / or de-blocking protected 5’-OH groups in newly coupled nucleosides. In some aspects, modification can be performed at the end of cycles when certain lengths of oligonucleotides (e.g., antisense oligonucleotides) are achieved.

[0205] Certain technologies for manufacturing oligonucleotides (e.g., antisense oligonucleotides) are described in US 3687808, US 4469863, US 4476301, US 5177195, US 5023243, US 5034506, US 5166315, US 5185444, US 5188897, US 5214134, US 5216141, US 5235033, US 5264423, US 5264564, US 5276019, US 5278302, US 5286717, US 5321131, US 5399676, US 5405938, US 5405939, US 5434257, US 5453496, US 5455233, US 5466677, US 5466677, US 5470967, US 5476925, US 5489677, US 5519126, US 5536821, US 5541307, US 5541316, US 5550111, US 5561225, US 5563253, US 5571799, US 5587361, US 5596086, US 5602240, US 5608046, US 5610289, US 5618704, US 5623070, US 5625050, US 5633360, US 564562, US 5663312, US 5677437, US 5677439, US 6160109, US 6239265, US 6028188, US 6124445, US 6169170, US 6172209, US 6277603, US 6326199, US 6346614, US 6444423, US 6531590, US 6534639, US 6608035, US 6683167, US 6858715, US 6867294, US 6878805, US 7015315, US 7041816, US 7273933, US 7321029, US RE39464, US 9394333, US 9744183, US 9605019, US 9598458, US 9982257, US 10160969, US 10479995, US 2020 / 0056173, US 2018 / 0216107, US 2019 / 0127733, US 10450568, US 2019 / 0077817, US 2019 / 0249173, US 2019 / 0375774, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, or WO 2019 / 032612.

[0206] In some aspects, oligonucleotides (e.g., antisense oligonucleotides) and / or compositions are provided as stereorandom compositions with respect to chiral linkage phosphorus. For example, when using traditional phosphoramidites comprising N, N- diisopropylamino and 2-cyanoethyloxy groups for oligonucleotide synthesis, chiral linkages can be formed with no or low stereoselectivity. In some aspects, oligonucleotides are provided as a mixture of various diastereomers and / or salts thereof. In some aspects, a composition comprises an oligonucleotide (e.g., an antisense oligonucleotide), and / or one or more or all of its diastereomers with respect to chiral linkage phosphorus. In some aspects, an oligonucleotide(e.g., an antisense oligonucleotide) and / or its diastereomers are independently in one or more forms. In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) and / or its diastereomers are independently in one or more salt forms, e.g., one or more pharmaceutically acceptable salt forms. In some aspects, for each chiral linkage phosphorus, both the Rp and the 5p configurations are present in the composition. In some aspects, for each chiral linkage phosphorus, both the Rp and the A'p configurations have a percentage of at least about 10%, 15%, 20%, 25%, 30% 35%, 40%, or 45%. In some aspects, for a chiral internucleotidic linkage both the Rp and the 5p configurations have a percentage of about 50%. In some aspects, for each chiral internucleotidic linkage both the Rp and the A'p configurations have a percentage of about 50%. In some aspects, for each chiral internucleotidic linkage both the Rp and the 5p configurations have a percentage of about 20-80%. In some aspects, for each chiral internucleotidic linkage both the Rp and the A'p configurations have a percentage of about 30- 70%. In some aspects, for each chiral internucleotidic linkage both the Rp and the 5p configurations have a percentage of about 40-60%. In some aspects, for each chiral internucleotidic linkage both the Rp and the A'p configurations have a percentage of about 45- 55%. In some aspects, for each linkage phosphorus the Rp configuration independently has a percentage of about 20-80%, 30-70%, 40-60%, or 45-55%, or about 20%, 30%, 40%, 50%, 60%, 70% or 80%.

[0207] Amount, concentration, etc., of provided oligonucleotides (e.g., antisense oligonucleotides) can be assessed utilizing various technologies in accordance with the present disclosure, e.g., by UV (e.g., at 260 nm), weight, etc. In some aspects, amount, concentration, etc., of all oligonucleotides (e.g., antisense oligonucleotides) present in a composition is assessed. In some aspects, amount, concentration, etc., include all oligonucleotides share the same constitution (e.g., diastereomers with respect to chiral linkage phosphorus) including all their forms including pharmaceutically acceptable salt forms.Oligonucleotide (ASO) Target - Chitinase 3 like protein 1 (CHI3L1), also known as CHI3L1

[0208] Chitinase 3 -like protein 1 (CHI3L1) — also commonly known as YKL-40 or human cartilage glycoprotein 39 (HC-gp39) — is a chitin-binding lectin that belongs to the glycosyl hydrolase family. The name “YKL-40 was created to reflect both the structure and molecular weight of the protein: YKL-40 has three N-terminal amino acids-tyrosine (Y), lysine (K), and leucine (L) — and a molecular mass of 40 kDa. The terms CHI3L1, YKL-40 and CHI3L1 / YKL- 40, as used herein, refer to the same gene / protein.

[0209] Human CHISLl nco s a single polypeptide chain that is 383 amino acids in length, which is folded to produce a protein having two globular domains. The first globular domain is a large domain composed of a (p / a)8 structure that includes a triose-phosphate isomerase (TIM) barrel fold, and the second globular domain is a small a / p domain that consists of five antiparallel P-strands and one a-helix that is positioned in the loop between strand P7 and helix a7 of the TIM barrel. The folded YKL-40 has a complex grooved-shaped construction. The amino acid sequence for human YKL-40(UniProt: P36222) is shown below:

[0210] MGVKASQTGFVVLVLLQCCSAYKLVCYYTSWSQYREGDGSCFPDALDRF LCTHIIYSFANISNDHIDTWEWNDVTLYGMLNTLKNRNPNLKTLLSVGGWNFGSQRF SKIASNTQSRRTFIKSVPPFLRTHGFDGLDLAWLYPGRRDKQHFTTLIKEMKAEFIKE AQPGKKQLLLSAALSAGKVTIDSSYDIAKISQHLDFISIMTYDFHGAWRGTTGHHSPL FRGQED ASPDRF SNTD YAVGYMLRLGAP ASKLVMGIPTFGRSFTL AS SETGVGAPISG PGIPGRFTKEAGTLAYYEICDFLRGATVHRILGQQVPYATKGNQWVGYDDQESVKS KVQYLKDRQLAGAMVWALDLDDFQGSFCGQDLRFPLTNAIKDALAAT (SEQ ID NO: 39)

[0211] CHI3L1 is expressed in astrocytes in the brain and macrophages in the periphery. The expression of CHI3L1 mRNA in vitro is highly expressed in the course of human macrophage differentiation. Additionally, in vivo studies have shown that expression of CHI3L1 mRNA and protein is present in a various inflammation infiltrates and is involved in remodeling of extracellular matrix (ECM). YKL-40 protein is expressed by several types of cells including macrophages, chondrocytes, neutrophils and synovial fibroblasts.

[0212] In some aspects, CHI3L1 can refer to a gene or a gene product thereof (e.g., a nucleic acid (e.g., DNA, RNA, etc.), a transcript (e.g., a CHI3L1 mRNA), and / or a protein encoded thereby (e.g., a YKL-40 polypeptide), etc.) from a species. Various CHI3L1 sequences including variants thereof are readily available to those of skill in the art. Various technologies, e.g., assays, cells, animal models, etc., have also been reported and can be utilized for characterization and / or assessment of provided technologies (e.g., oligonucleotides, compositions, methods, etc.) in accordance with the present disclosure.

[0213] The present disclosure provides oligonucleotide compositions and methods that decrease levels of RNA transcripts of a CHI3L1 gene. The CHI3L1 gene can be within a cell, e.g., a cell within a subject, such as a human. The present disclosure also provides methods of using the oligonucleotide compositions of the disclosure for inhibiting the expression of a CHI3L1 gene and / or for treating a subject having a disorder that would benefit from inhibitingor reducing the expression of a CHI3L1 gene, e.g., a C / 7 / 3 / . / -associated disease (e.g., glioblastoma).CHI 3L1 -Associated Conditions, Disorders or Diseases

[0214] Certain conditions, disorders or diseases associated with CHI3L1 (e.g., glioblastoma) can be prevented or treated with present disclosure. Generally, a disease, disorder, or condition is associated with CHI3L1 if the presence, level, activity, and / or form of CHI3L1 and / or products (e.g., transcripts, encoded proteins, etc.) thereof correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some aspects, a condition, disorder or disease associated with CHI3L1 can be treated and / or prevented by reducing expression, level and / or activity of CHI3L1 transcripts and / or proteins.

[0215] To date, approved pharmacologic treatments for (77 / 3 / . / -associated diseases or disorders are directed to treatment of symptoms, not to prevention or cure, and such treatments are of limited efficacy, particularly as C / / / 3 / . / -associated diseases or disorders advance in an affected individual. Therefore, there is a need for therapies for subjects suffering from CHI3L1- associated diseases and disorders (e.g., brain cancer, such as glioblastoma).

[0216] Among other things, the present disclosure provides technologies for preventing and / or treating certain conditions, disorders or diseases. In some aspects, the cancer is brain cancer. In some aspects, the brain cancer is a glioblastoma.Characterization and Assessment

[0217] In some aspects, properties and / or activities of provided oligonucleotides (e.g., antisense oligonucleotides) and compositions thereof can be characterized and / or assessed using technologies available to those skilled in the art, e.g., biochemical assays (e.g., RNase H assays), cell based assays, animal models, clinical trials, etc. Certain useful technologies are described in the Examples and / or Tables disclosed herein. Those skilled in the art reading the present disclosure will readily appreciate that other technologies, e.g., in vitro models (e.g., cell lines) for various conditions, disorders or diseases, animal models for various conditions, disorders or diseases, clinical trials, etc. can be designed and / or utilized to assess provided technologies (e.g., oligonucleotides (e.g., antisense oligonucleotides), compositions, methods, etc.) in accordance with the present disclosure.Biological Applications

[0218] In some aspects, the present disclosure provides a method for reducing level of CHI3L1 mRNA in a system (e.g., a cell, a tissue, an organ, an organism, or a subject), comprising administering or delivering to the system an effective amount of an oligonucleotide (e.g., antisense oligonucleotides) or an oligonucleotide composition disclosed herein. In some aspects, the present disclosure provides a method for reducing level of a YKL-40 polypeptide in a system, comprising administering or delivering to the system an effective amount of an oligonucleotide (e.g., antisense oligonucleotides) or an oligonucleotide composition. In some aspects, the present disclosure provides a method for reducing level of YKL-40activity in a system, comprising administering or delivering to the system an effective amount of an oligonucleotide (e.g., an antisense oligonucleotide) or an oligonucleotide composition. In some aspects, reduction of CHI3L1 mRNA and / or YKL-40 polypeptide levels increases mRNA and / or polypeptide levels of a CHI3L1 YKL-40 target. YKL-40 has been reported to interact with various partners, e.g., CD44 and IL-13Ra2. In some aspects, the present disclosure provide technologies for modulating interaction between YKL-40 and a partner. In some aspects, the present disclosure provides technologies for modulating YKL-40 interaction with a partner in a system, comprising administering or delivering to the system an effective amount of an oligonucleotide (e.g., an antisense oligonucleotide) or an oligonucleotide composition that targets CHI3L1.

[0219] In some aspects, a system comprises CHI3L1 mRNA. In some aspects, a system expresses CHI3L1 mRNA. In some aspects, a system expresses YKL-40 polypeptides.

[0220] In some aspects, a system is an in vitro system. In some aspects, a system is an in vivo system.

[0221] In some aspects, a system is a neuronal cell. In some aspects, the neuronal cell is an astrocyte. In some aspects, a cell is a cell in the neuronal system. In some aspects, a cell is a cell in the central nervous system (CNS). In some aspects, a cell possesses one or more characteristics, properties and / or activities of a neuronal cell.

[0222] In some aspects, a system is a tissue. In some aspects, a system comprises a tissue. In some aspects, a system is an organ. In some aspects, a system comprises an organ. In some aspects, a system is a brain or a portion thereof. In some aspects, a system comprises a brain or a portion thereof. In some aspects, a system is an organism. In some aspects, a system comprises an organism. In some aspects, a system is a subject. In some aspects, a system is a mammal, e.g., a mouse, rat, monkey, etc. In some aspects, a system is a human.

[0223] In some aspects, a level is reduced by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% compared to absence of a disclosed oligonucleotide (e.g., an antisense oligonucleotides) or composition and / or presence of a reference oligonucleotide (e.g., antisense oligonucleotide) or composition thereof. In some aspects, such a reduction is achieved at certain oligonucleotide (e.g., antisense oligonucleotide) concentrations (e.g., 10 uM) or doses. In some aspects, such a reduction is achieved in a system, e.g., as determined by suitable assays (e.g., in vitro cell-based assays, assays described in the Examples, etc.). In some aspects, a reference composition comprises no oligonucleotides (e.g., antisense oligonucleotides) targeting CHI3L1. In some aspects, a reference oligonucleotide (e.g., antisense oligonucleotides) targets a different nucleic acid than CHI3L1. In some aspects, a level is of mRNA, e.g., CHI3L1 mRNA levels. In some aspects, a level is of a polypeptide, e.g., YKL-40 protein levels. In some aspects, a level is reduced by at least about 10%. In some aspects, a level is reduced by at least about 20%. In some aspects, a level is reduced by at least about 30%. In some aspects, a level is reduced by at least about 40%. In some aspects, a level is reduced by at least about 50%. In some aspects, a level is reduced by at least about 60%. In some aspects, a level is reduced by at least about 70%. In some aspects, a level is reduced by at least about 75%. In some aspects, a level is reduced by at least about 80%. In some aspects, a level is reduced by at least about 85%. In some aspects, a level is reduced by at least about 90%. In some aspects, a level is reduced by at least about 95%. In some aspects, level of CHI3L1 mRNA is reduced about or at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% at about 10 uM oligonucleotides when assessed, e.g., using an assay in the Examples. In some aspects, a reduction is about or at least about 50%. In some aspects, a reduction is about or at least about 55%. In some aspects, a reduction is about or at least about 60%. In some aspects, a reduction is about or at least about 65%. In some aspects, a reduction is about or at least about 70%. In some aspects, a reduction is about or at least about 75%. In some aspects, a reduction is about or at least about 80%. In some aspects, a reduction is about or at least about 85%. In some aspects, a reduction is about or at least about 90%. In some aspects, a reduction is assessed at or after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 days, or about 1, 2, 3 or 4 weeks following administering or delivering a provided oligonucleotide or composition. In some aspects, a reduction is assessed at or after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 days, or about 1, 2, 3 or 4 weeks following removal or washout of a provided oligonucleotide or composition. In some aspects, a reduction is assessed at day 0. In some aspects, a reduction is assessed at about day 3. In some aspects, a reduction is assessedat about day 10. In some aspects, a reduction is assessed at about day 14. In some aspects, a reduction is assessed at about day 21. In some aspects, reductions of at one or more assessments, e.g., of CHI3L1 mRNA levels, are independently about or at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%; in some aspects, reductions are independently about or at least about 75%; in some aspects, reductions are about or at least about 80%. In some aspects, reductions of one or more assessments, e.g., of YKL- 40 protein or activity, are independently about or at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80%; in some aspects, reductions are about or at least about 20%; in some aspects, reductions are about or at least about 25%; in some aspects, reductions are about or at least about 30%; in some aspects, reductions are about or at least about 35%; in some aspects, reductions are about or at least about 40%; in some aspects, reductions are about or at least about 45%; in some aspects, reductions are about or at least about 50%; in some aspects, reductions are about or at least about 55%; in some aspects, reductions are about or at least about 60%; in some aspects, reductions are about or at least about 70%. In some aspects, reductions are relative to absence of oligonucleotides. In some aspects, reductions are relative to presence of reference oligonucleotides or compositions, e.g., oligonucleotides targeting NEAT1 as described herein. In some aspects, assessments are performed according to those described in the Examples, e.g., in some aspects, using iPSC- derived astrocytes with oligonucleotide concentrations at about 10 pM with gymnotic delivery.Pharmaceutical Compositions

[0224] In some aspects, the present disclosure provides pharmaceutical compositions comprising a provided compound, e.g., an oligonucleotide (e.g., an antisense oligonucleotide), or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. In some aspects, for example, for therapeutic and clinical purposes, oligonucleotides (e.g., antisense oligonucleotides) of the present disclosure are provided as pharmaceutical compositions.

[0225] As appreciated by those skilled in the art, oligonucleotides (e.g., antisense oligonucleotides) can be provided in various forms. In some aspects, oligonucleotides (e.g., antisense oligonucleotides) can be in acid forms, e.g., for natural phosphate linkages, in the form of -OP(O)(OH)O-; for phosphorothioate internucleotidic linkages, in the form of -OP(O)(SH)O-; etc. In some aspects, provided oligonucleotides (e.g., antisense oligonucleotides) can be in salt forms, e.g., for natural phosphate linkages, in the form of -OP(O)(ONa)O- in sodium salts; for phosphorothioate internucleotidic linkages, in the form of -OP(O)(SNa)O- in sodium salts; etc. Unless otherwise noted, oligonucleotides (e.g.,antisense oligonucleotides) of the present disclosure can exist in acid, base and / or salt forms. In some aspects, a composition comprises one or more forms of an oligonucleotide (e.g., an antisense oligonucleotide). In some aspects, a composition comprises one or more salt forms of an oligonucleotide (e.g., an antisense oligonucleotide). In some aspects, a composition comprises one or more pharmaceutically acceptable salt forms of an oligonucleotide (e.g., an antisense oligonucleotide).

[0226] When used as therapeutics, a provided oligonucleotide (e.g., an antisense oligonucleotide) or composition is typically administered as a pharmaceutical composition. In some aspects, a pharmaceutical composition is suitable for administration or delivery of an oligonucleotide (e.g., an antisense oligonucleotide) to an area or portion of a body affected by a condition, disorder or disease. In some aspects, a pharmaceutical composition comprises a therapeutically effective amount of a provided oligonucleotide (e.g., an antisense oligonucleotide) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some aspects, a pharmaceutical composition comprises a therapeutically effective amount of oligonucleotides (e.g., antisense oligonucleotides) which are diastereomers of each other, wherein the oligonucleotides (e.g., antisense oligonucleotides) exist in one or more forms. In some aspects, a pharmaceutical composition comprises a therapeutically effective amount of oligonucleotides (e.g., antisense oligonucleotides) which are diastereomers of each other with respect to chiral linkage phosphorus, wherein the oligonucleotides (e.g., antisense oligonucleotides) exist in one or more forms.

[0227] In some aspects, a pharmaceutically acceptable carrier is a buffer. In some aspects, a pharmaceutically acceptable carrier is a buffered saline. In some aspects, a pharmaceutically acceptable carrier is artificial cerebrospinal fluid. In some aspects, a composition is a liquid composition comprising dissolved oligonucleotides (e.g., antisense oligonucleotides).

[0228] In some aspects, a pharmaceutical composition is formulated for intravenous injection, oral administration, buccal administration, inhalation, nasal administration, topical administration, ophthalmic administration or otic administration. In some aspects, a pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop or an ear drop. In some aspects, a pharmaceutical composition is formulated for intrathecal administration.

[0229] As those skilled in the art will appreciate, oligonucleotides (e.g., antisense oligonucleotides) can exist in various salt forms. In some aspects, a salt is a pharmaceutically acceptable salt. In some aspects, a pharmaceutical composition comprises an oligonucleotide(e.g., an antisense oligonucleotide), optionally in its salt form, and a sodium salt. In some aspects, a pharmaceutical composition comprises an oligonucleotide (e.g., an antisense oligonucleotide), optionally in its salt form, and sodium chloride. In some aspects, each hydrogen ion of an oligonucleotide (e.g., an antisense oligonucleotide) that can be donated to a base (e.g., under conditions of an aqueous solution, a pharmaceutical composition, etc.) is replaced by a non-H+cation. For example, in some aspects, a pharmaceutically acceptable salt of an oligonucleotide (e.g., an antisense oligonucleotide) is an all-metal ion salt, wherein each hydrogen ion (for example, of -OH, -SH, etc.) of each internucleotidic linkage (e.g., a natural phosphate linkage, a phosphorothioate internucleotidic linkage, etc.) is replaced by a metal ion. Various suitable metal salts for pharmaceutical compositions are widely known in the art and can be utilized in accordance with the present disclosure. In some aspects, a pharmaceutically acceptable salt is a sodium salt. In some aspects, a pharmaceutically acceptable salt is magnesium salt. In some aspects, a pharmaceutically acceptable salt is a calcium salt. In some aspects, a pharmaceutically acceptable salt is a potassium salt. In some aspects, a pharmaceutically acceptable salt is an ammonium salt (cation N(R’)4+). In some aspects, a pharmaceutically acceptable salt comprises one and no more than one types of cation. In some aspects, a pharmaceutically acceptable salt comprises two or more types of cation. In some aspects, a cation is Li+, Na+, K+, Mg2+or Ca2+. In some aspects, a pharmaceutically acceptable salt is an all-sodium salt. In some aspects, a pharmaceutically acceptable salt is an all-sodium salt, wherein each internucleotidic linkage which is a natural phosphate linkage (acid form -O-P(O)(OH)-O-), if any, exists as its sodium salt form (-O-P(O)(ONa)-O-), and each internucleotidic linkage which is a phosphorothioate internucleotidic linkage (acid form -O-P(O)(SH)-O-), if any, exists as its sodium salt form (-O-P(O)(SNa)-O-).

[0230] In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) or a composition, e.g., a pharmaceutical composition, is provided as solid. In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) or a composition, e.g., a pharmaceutical composition, is lyophilized.

[0231] In some aspects, an oligonucleotide (e.g., an antisense oligonucleotide) or a composition, e.g., a pharmaceutical composition, is stored at a temperature lower than an ambient temperature, e.g., at about or no more than about -78, -20, 0, 4, or 10 °C.

[0232] In some aspects, oligonucleotides (e.g., antisense oligonucleotides) are administered or delivered via gymnotic uptake.

[0233] In some aspects, oligonucleotides (e.g., antisense oligonucleotides) or compositions are formulated for a variety of modes of administration, including systemic and topical orlocalized administration. In some aspects, the oligonucleotide or composition is administered or delivered intratumorally, intrathecally, intracerebrally, intracerebroventricularly, intranasally, intraocularly, and / or intravenously. Techniques and formulations generally can be found in Remington, The Science and Practice of Pharmacy (20th ed. 2000).EXAMPLES

[0234] Certain examples of provided technologies are presented herein. Those skilled in the art appreciate that many technologies can be utilized to prepare and / or assess properties and / or activities of provided technologies in accordance with the present disclosure.

[0235] As appreciated by those skilled in the art, various technologies can be utilized to prepare oligonucleotides and compositions thereof in accordance with the present disclosure, including solid-phase processes using phosphoramidite chemistry. In some aspects, preparation of oligonucleotides or compositions thereof comprises multiple cycles, each of which may independently comprise several steps. For example, in some aspects, for incorporating a natural phosphate linkage, a cycle comprises detrityl ati on, coupling, capping and oxidation; in some aspects, for incorporating a phosphorothioate linkage, a cycle comprises detrityl ati on, coupling, sulfurization and capping. Certain useful technologies are described in the “Manufacturing” section. See also, e.g., Yang J et al. J. Org. Chem. 2018; 83(19): 11577-11585.Example 1. Various ASOs reduce CHI3L1 expression in induced pluripotent stem cell (iPSC)-derived astrocytes.

[0236] In this Example, ASOs targeting CHI3L1 were tested in vitro to determine their ability to reduce levels of CHI3L1 mRNA.

[0237] Induced pluripotent stem cell (iPSC)-derived astrocytes (FujiFilm) were seeded at 12.8k cells / well in 96-well format, in duplicates. 80 different antisense oligonucleotides (ASOs 1-80) were assessed at a 10 pM concentration. Controls included a medium control (no treatment), a vehicle control (1% TE buffer), an ASO targeting NEAT1 (10 pM; as a positive control to confirm gymnotic uptake), and an ASO targeting Scr-Pl (10 pM; as a negative control).

[0238] A subset of the ASO base sequences that were tested is shown in Table 1. The NEAT1 -human positive control sequence was<T*G*C*A*A*>G*T*C*T*G*A*C*G*C*C*<C*A*T*C*T> (SEQID N0. 40)anc] the Scr- Pl negative control sequence was<A*C*T*C*T*>A*C*C*A*T*A*T*C*C*G*<T*T*G*G*T> (SEQID NQ.41)A11nucleosides were DNA nucleosides except those in <>, which were 2’ -MOE modified, and each * independently represents a phosphorothioate internucleotidic linkage.

[0239] iPSC-derived astrocytes were thawed and seeded on day 0. Medium was subsequently refreshed on days 2 and 4. ASO treatment was performed on Day 7, and after a 72 hr incubation, cells were harvested at Day 10. Cell viability was assessed with a CellTiter- Fluor assay (Promega, Cat.# G6081).

[0240] RNA was isolated using a MagMAX mirVana Total RNA Isolation Kit (Thermo, Cat.# A27828), with automated RNA isolation using the Kingfisher Apex (Thermo). Following RNA isolation, cDNA synthesis was performed using SuperScript IV VILO Master Mix (Thermo, Cat.# 11756500). RT-qPCR was then performed using a TaqMan Fast Advanced Master Mix for qPCR (Thermo, Cat.# 4444557). A CHI3L1 RT-qPCR assay (Hs01072228_ml from ThermoFisher Scientific) was multiplexed with a SFRS9 assay (Hs01596548_gl from ThermoFisher Scientific). A custom assay to assess NEAT1 (positive control) levels was multiplexed with an SFRS9 (reference gene) assay.

[0241] Strong separation of assay signal for positive and negative control ASOs was observed for all plates tested. No effect of control ASOs on reference gene expression was observed. NEAT1 knockdown was observed at 91%, demonstrating successful ASO delivery by gymnosis. Stable SFRS9 expression was observed for all groups, suggesting good reproducibility and cell viability. Variation between replicates within each control group (medium, vehicle, Scr-Pl and NEAT1) was minimal, remaining within 1 Ct value o NEATl and SFRS9.

[0242] Multiple candidate ASOs were identified that markedly reduced CHI3L1 expression compared to medium, vehicle, positive, and negative controls. Of the 80 ASOs tested for the ability to reduce levels of CHI3L1 mRNA in iPSC-derived astrocytes, eleven ASOs were found to reduce CHI3L1 mRNA levels by at least 50% compared to negative control. Five ASOs were found to reduce CHI3L1 mRNA levels by at least 70% compared to negative control, including ASOs 64, 68, 77, 78, and 79 (Sequences in Table 1.) The highest knockdown was observed with ASO 78, with a knockdown of 88% compared to negative control. A summary of the CHI3L1 mRNA knockdown results is shown in Table 3. These results suggest that the level of knockdown achieved by a given ASO sequence was driven in a highly specific manner by the sequence in the target transcript to which the ASO sequence iscomplementary. For example, ASOs 63-70 have similar target start sites (see Table 2), but knockdown of CHI3L1 mRNA by ASO 64 and 68 exceeded knockdown of CHI3L1 mRNA by ASOs 63, 65, 66, 67, 69, and 70. Similarly, ASOs 75-80 have similar target start sites (see Table 2), but knockdown of CHI3L1 mRNA by ASOs 77, 78, and 79 exceeded knockdown of CHI3L1 mRNA by ASOs 75, 76, and 80.

[0243] Table 3. Reduction of CHI3L1 mRNA by oligonucleotide compositions

[0244] Stable expression of the reference gene SFRS9 was observed throughout the experiments described, suggesting successful technical execution and robustness of data. Minimal inter- and intra-group variation in reference gene Ct values was observed across medium, vehicle, positive, and negative control groups. Additionally, treatment of iPSC- derived astrocytes with control and C / 7 / 3 / . / -targeting ASOs did not result in reductions in cell viability, as shown in Table 3.

[0245] This Example thus shows that several ASOs successfully reduced CHI3L1 mRNA expression with no attendant cytotoxicity.Example 2. Two ASOs reduce CHI3L1 mRNA expression in glioblastoma patient-derived cell lines.

[0246] In this Example, two ASOs tested in Example 1, ASO68 and ASO78, were assessed in glioblastoma patient-derived cell lines (PDCLs) of varying characteristics.

[0247] Three distinct glioblastoma PDCLs (PDCL1, PDCL2, and PDCL3) were selected for pilot CHI3L1 mRNA reduction assessment based on relative baseline levels of CHI3L1 mRNA expression. The three glioblastoma PDCLs were thawed and expanded in NS A growth media and plated as 2D adherent cells on laminin-coated plates. The glioblastoma PDCLs were seeded at 250,000 cells / well in a 6-well plate and incubated for 24 hours. ASOs were applied at a 10 pM concentration. Each plate included a vehicle control (equal volume TE buffer). The glioblastoma PDCLs were then incubated for 72 hours followed by cell lystate collection. The cell lysates were used for nucleic acid isolation followed by RT-qPCR of the target gene CHI3L1 (Hs01072228_ml from ThermoFisher Scientific) and housekeeping gene SRSF9 (Hs01596548_gl from ThermoFisher Scientific). The data were analyzed using the delta-delta CT method of relative expression compared to the housekeeping gene SRSF9. The results showed that ASO68 resulted in a 0.33 to 0.81 fold change in CHI3L1 mRNA expression, while ASO78 resulted in a 0.04 to 0.13 fold change in CHI3L1 mRNA expression (FIG. 1). These results supported further analysis of glioblastoma PDCLs.

[0248] Thirteen additional glioblastoma PDCLs were selected across a variety of characteristics (e.g., MGMT promoter methylation status, primary recurrent tumor, treatment naive or previous treatment, age, race, and ethnicity) along with PDCL1, PDCL2, and PDCL3. These sixteen glioblastoma PDCLs were used for assessment of ASO-mediated CHI3L1 mRNA reduction via gymnotic uptake as described above. Fold change after incubation with ASO68 and ASO78 in CHI3L1 expression for each cell line (PDCL1-16) is shown in FIG. 2. As shown in FIG. 2, mRNA expression analysis did not reveal preferential ASO knockdown as a function of any of the cell line characteristics studied.

[0249] This Example thus shows that ASO68 and ASO78 successfully reduced CHI3L1 mRNA expression in several glioblastoma PDCLs of varying characteristics.

[0250] Each of the literature and patent publications listed herein is incorporated by reference in its entirety. While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain aspects, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references, GenBank accession numbers, and the like recited in the present application is incorporated herein by reference in its entirety.

[0251] While certain aspects have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described in the present disclosure, and each of such variations and / or modifications is deemed to be included. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be example and that the actual parameters, dimensions, materials, and / or configurations can depend upon the specific application or applications for which the teachings of the present disclosure is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the aspects of the present disclosure. It is, therefore, to be understood that the foregoing aspects are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, claimed technologies can be practiced otherwise than as specifically described and claimed. In addition, any combination of two or more features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present disclosure.

Claims

WHAT IS CLAIMED IS:

1. An oligonucleotide comprising a base sequence, wherein the base sequence comprises 20 or more contiguous nucleobases comprising: CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11), TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13), ATAATTAGTATGGTCACTGT (SEQ ID NO: 15), TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17), or AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19), optionally wherein each T is replaced with U; and wherein the oligonucleotide comprises a modified nucleobase, a modified sugar, a modified internucleotidic linkage, or any combination thereof.

2. The oligonucleotide of claim 1, wherein the base sequence of the oligonucleotide is CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11), TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13), ATAATTAGTATGGTCACTGT (SEQ ID NO: 15), TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17), or AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19).

3. The oligonucleotide of claim 1 or 2, wherein the base sequence of the oligonucleotide is CCCATGTGCCTGTACCTGCT (SEQ ID NO: 11).

4. The oligonucleotide of claim 1 or 2, wherein the base sequence of the oligonucleotide is TTGGCCCTGCTTAGCTTCTT (SEQ ID NO: 13).

5. The oligonucleotide of claim 1 or 2, wherein the base sequence of the oligonucleotide is ATAATTAGTATGGTCACTGT (SEQ ID NO: 15).

6. The oligonucleotide of claim 1 or 2, wherein the base sequence of the oligonucleotide is TTGTACTTTATTGAGCAGCT (SEQ ID NO: 17).

7. The oligonucleotide of claim 1 or 2, wherein the base sequence of the oligonucleotide is AAGCTCTTGTACTTTATTGA (SEQ ID NO: 19).

8. The oligonucleotide of any one of claims 1-7, wherein the oligonucleotide comprises a 5 ’-wing-gap-wing-3’ structure.

9. The oligonucleotide of any one of claims 1-8, wherein there are about 3-10 nucleosides in the 5 ’-wing, optionally wherein there are 5 nucleosides in the 5 ’-wing.

10. The oligonucleotide of any one of claims 1-9, wherein each sugar in the 5’-wing is independently a modified sugar.

11. The oligonucleotide of any one of claims 1-9, wherein a sugar in the 5 ’-wing is a 2’- ORSmodified sugar wherein Rsis Ci-6 aliphatic; wherein a sugar in the 5’-wing is a 2’-M0E modified sugar; wherein a sugar in the 5 ’-wing is a 2’-OMe modified sugar; and / orwherein a sugar in the 5 ’-wing is a bicyclic sugar, optionally wherein the bicyclic sugar is a LNA sugar or cEt sugar.

12. The oligonucleotide of any one of claims 1-11, wherein each sugar in the 5’-wing is independently a 2’-ORsmodified sugar, wherein Rsis Ci-6 aliphatic, or wherein each sugar in the 5’-wing is independently a 2’-M0E modified sugar.

13. The oligonucleotide of any one of claims 1-12, wherein there are about 8-15 nucleosides in the gap, optionally wherein there are 10 nucleosides in the gap.

14. The oligonucleotide of any one of claims 1-13, wherein each sugar in the gap is independently a natural DNA sugar.

15. The oligonucleotide of any one of claims 1-14, wherein the gap contains no cytosine and / or wherein the gap comprises one or more 5-methylcytosine.

16. The oligonucleotide of any one of claims 1-15, wherein there are about 3-10 nucleosides in the 3 ’-wing, optionally wherein there are 5 nucleosides in the 3 ’-wing.

17. The oligonucleotide of any one of claims 1-16, wherein each sugar in the 3’-wing is independently a modified sugar.

18. The oligonucleotide of any one of claims 1-17, wherein a sugar in the 3’-wing is a 2’- ORSmodified sugar, wherein Rsis Ci-6 aliphatic; wherein a sugar in the 3’-wing is a 2’-M0E modified sugar; wherein a sugar in the 3 ’-wing is a 2’-0Me modified sugar; and / or wherein a sugar in the 3 ’-wing is a bicyclic sugar, optionally wherein the bicyclic sugar is a LNA sugar or cEt sugar.

19. The oligonucleotide of any one of claims 1-18, wherein each sugar in the 3’-wing is independently a 2’-ORsmodified sugar, wherein Rsis Ci-6 aliphatic or wherein each sugar in the 3’-wing is independently a 2’-M0E modified sugar.

20. The oligonucleotide of any one of claims 1-19, wherein the oligonucleotide comprises a modified intemucleotidic linkage, optionally wherein the modified internucleotidic linkage is a phosphorothioate internucleotidic linkage.

21. The oligonucleotide of any one of claims 1-20, wherein each intemucleotidic linkage is independently a modified internucleotidic linkage and / or wherein each internucleotidic linkage is independently a phosphorothioate internucleotidic linkage.

22. An oligonucleotide comprising 12 to 30 linked nucleosides, wherein the oligonucleotide comprises a base sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to:a. an equal length portion within nucleobases 6412-6431 of SEQ ID NO: 29; b. an equal length portion within nucleobases 6613-6632 of SEQ ID NO: 29; c. an equal length portion within nucleobases 7641-7660 of SEQ ID NO: 29; d. an equal length portion within nucleobases 7742-7761 of SEQ ID NO: 29; or e. an equal length portion within nucleobases 7748-7767 of SEQ ID NO: 29; wherein the oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified intemucleoside linkage.

23. An oligonucleotide comprising or having the structure of: / 52MOErC / * / i2MOErC / * / i2MOErC / * / i2MOErA / * / i2MOErT / *dG*dT*dG*iMe-dC*iMe- dC*dT*dG*dT*dA*iMe-dC* / i2MOErC / * / i2MOErT / * / i2MOErG / * / i2MOErC / * / 32MOErT / (SEQ ID NO: 43), / 52MOErT / * / i2MOErT / * / i2MOErG / * / i2MOErG / * / i2MOErC / *iMe- dC*iMe-dC*dT*dG*iMe-dC*dT*dT*dA*dG*iMe- dC* / i2MOErT / * / i2MOErT / * / i2MOErC / * / i2MOErT / * / 32MOErT / (SEQ ID NO: 47), / 52MOErA / * / i2MOErT / * / i2MOErA / * / i2MOErA / * / i2MOErT / *dT*dA*dG*dT*dA*dT*dG* dG*dT*iMe-dC* / i2MOErA / * / i2MOErC / * / i2MOErT / * / i2MOErG / * / 32MOErT / (SEQ ID NO: 52), / 52MOErT / * / i2MOErT / * / i2MOErG / * / i2MOErT / * / i2MOErA / *iMe- dC*dT*dT*dT*dA*dT*dT*dG*dA*dG* / i2MOErC / * / i2MOErA / * / i2MOErG / * / i2MOErC / * / 32MOErT / (SEQ ID NO: 53), / 52MOErA / * / i2MOErA / * / i2MOErG / * / i2MOErC / * / i2MOErT / *iMe- dc * dT * dT * dG* dT * d A* iMe- dC*dT*dT*dT* / i2MOErA / * / i2MOErT / * / i2MOErT / * / i2MOErG / * / 32MOErA / (SEQ ID NO: 54), or a salt thereof, wherein:* is -O-P(O)(SH)-O-;26. The oligonucleotide of claim 23, wherein the oligonucleotide is / 52MOErA / * / i2MOErT / * / i2MOErA / * / i2MOErA / * / i2MOErT / *dT*dA*dG*dT*dA*dT*dG* dG*dT*iMe-dC* / i2MOErA / * / i2MOErC / * / i2MOErT / * / i2MOErG / * / 32MOErT / (SEQ IDNO: 52), or a salt thereof, wherein:

28. The oligonucleotide of claim 23, wherein the oligonucleotide is / 52MOErA / * / i2MOErA / * / i2MOErG / * / i2MOErC / * / i2MOErT / *iMe- dc * dT * dT * dG* dT * d A* iMe- dC*dT*dT*dT* / i2MOErA / * / i2MOErT / * / i2MOErT / * / i2MOErG / * / 32MOErA / (SEQ ID NO: 54), or a salt thereof, wherein:

29. The oligonucleotide of any one of claim 1-28, wherein the oligonucleotide is a pharmaceutically acceptable salt, optionally wherein the oligonucleotide is a sodium salt.

30. The oligonucleotide of any one of claims 1-29, wherein the base sequence of the oligonucleotide is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a portion of SEQ ID NO: 29.

31. The oligonucleotide of any one of claims 1 to 30, wherein the oligonucleotide is an antisense oligonucleotide (ASO).

32. A composition comprising an oligonucleotide of any one of claims 1-31 and a pharmaceutically acceptable carrier.

33. The composition of claim 32, wherein the composition comprises one or more pharmaceutically acceptable salts of the oligonucleotide.

34. The composition of claim 32 or 33, wherein the composition is a liquid composition.

35. The composition of any one of claims 32-34, wherein the pharmaceutically acceptable carrier is a buffer, buffered saline, or artificial cerebrospinal fluid.

36. A method for reducing CHI3L1 mRNA levels in a system, comprising administering or delivering to the system an oligonucleotide or composition of any one of the preceding claims.

37. A method for reducing YKL-40 polypeptide levels in a system, comprising administering or delivering to the system an oligonucleotide or composition of any one of the preceding claims.

38. A method for reducing YKL-40 activity in a system, comprising administering or delivering to the system an oligonucleotide or composition of any one of the preceding claims.

39. The method of any one of claims 36-38, wherein the system expresses CHI3L1 mRNA.

40. The method of any one of claims 36-39, wherein the system is or comprises a cell, a tissue, an organ, brain or a portion thereof, an organism, a subject, or a human.

41. The method of any one of claims 37-40, wherein the level of YKL-40polypeptide in the system is reduced by about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% compared to absence of the oligonucleotide or composition.

42. The method of any one of claims 36-41, wherein the reduction is assessed in iPSC- derived astrocytes and / or glioblastoma patient-derived cell lines with oligonucleotide concentration at about 10 pM with gymnotic delivery.

43. A method for preventing or treating a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount of an oligonucleotide or composition of any one of claims 1-35.

44. The method of claim 43, wherein the onset of the condition, disorder or disease is delayed or prevented.

45. A method for treating a condition, disorder or disease, comprising administering or delivering to a subject suffering therefrom an effective amount of an oligonucleotide or composition of any one of claims 1-35.

46. The method of claim 45, wherein the severity of a symptom of the condition, disorder or disease is reduced.

47. The method of claim 45 or 46, wherein the condition, disorder or disease is a brain cancer.

48. The method of claim 47, wherein the cancer is glioblastoma.

49. A method for treating a glioblastoma in a subject in need thereof comprising administering to said subject a therapeutically effective amount of an oligonucleotide or composition of any one of claims 1-35.

50. The method of any one of claims 45-49, wherein one or more clinical assessment results of the subject are independently improved.

51. The method of claim 50, wherein the clinical assessment comprises a reduction in tumor size.

52. The method of any one of claims 43-51, wherein the oligonucleotide or composition is administered or delivered intratum orally, intrathecally, intracerebrally, intracerebroventricularly, intranasally, intraocularly, intravenously and / or intraci sternally.

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