MODULATORS OF HSD17B13 EXPRESSION

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0350WOSEQ_ST25.txt created Dec. 13, 2019, which is 640 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

The present embodiments provide methods, compounds, and compositions useful for inhibiting hydroxysteroid 17-beta dehydrogenase 13 (LOC345275; 17-beta hydroxysteroid dehydrogenase; HSD17B13; HSD17013) expression, and in certain instances, reducing the amount of HSD17B13 protein in a cell or animal, which can be useful for treating, preventing, or ameliorating a disease associated with HSD17B13.

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is defined as fat accumulation in the liver exceeding 5% by weight, in the absence of significant alcohol consumption, steatogenic medication, or hereditary disorders (Kotronen et al, Arterioscler Thromb. Vasc. Biol. 2008, 28: 27-38).

Non-alcoholic steatohepatitis (NASH) is NAFLD with signs of inflammation and hepatic injury. NASH is defined histologically by macrovesicular steatosis, hepatocellular ballooning, and lobular inflammatory infiltrates (Sanyal, Hepatol. Res. 2011. 41: 670-4). NASH is estimated to affect 2-3% of the general population. In the presence of other pathologies, such as obesity or diabetes, the estimated prevalence increases to 7% and 62% respectively (Hashimoto et al, J. Gastroenterol. 2011. 46(1): 63-69).

SUMMARY

Certain embodiments provided herein are compounds and methods for reducing the amount or activity of HSD17B13 mRNA, and in certain embodiments, reducing the amount or activity of HSD17B13 protein in a cell or animal. In certain embodiments, the animal has a liver disease. In certain embodiments, the disease is NASH. In certain embodiments, the disease is alcoholic steatohepatitis (ASH). In certain embodiments, the disease is NAFLD. In certain embodiments, the disease is hepatic steatosis. In certain embodiments, the disease is cirrhosis. In certain embodiments, the disease is hepatocellular carcinoma. In certain embodiments, the disease is alcoholic liver disease. In certain embodiments, the disease is HCV hepatitis. In certain embodiments, the disease is chronic hepatitis. In certain embodiments, the disease is hereditary hemochromatosis. In certain embodiments, the disease is primary sclerosing cholangitis. Certain compounds provided herein are directed to compounds and compositions that reduce liver damage, steatosis, liver fibrosis, liver inflammation, liver scarring or cirrhosis, liver failure, liver enlargement, elevated transaminases, or hepatic fat accumulation in an animal.

Certain embodiments provided herein are directed to potent and tolerable compounds and compositions useful for inhibiting HSD17B13 expression, which can be useful for treating, preventing, ameliorating, or slowing progression of liver diseases. Certain embodiments provided herein are directed to compounds and compositions that are more potent or have greater therapeutic value than compounds publicly disclosed.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting.

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

It is understood that the sequence set forth in each SEQ ID NO in the examples contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Compounds described by ION number indicate a combination of nucleobase sequence, chemical modification, and motif.

Definitions

Unless otherwise indicated, the following terms have the following meanings:

“2′-deoxyfuranosyl sugar moiety” or “2′-deoxyfuranosyl sugar” means a furanosyl sugar moiety having two hydrogens at the 2′-position. 2′-deoxyfuranosyl sugar moieties may be unmodified or modified and may be substituted at positions other than the 2′-position or unsubstituted. A β-D-2′-deoxyribosyl sugar moiety in the context of an oligonucleotide is an unsubstituted, unmodified 2′-deoxyfuranosyl and is found in naturally occurring deoxyribonucleic acids (DNA).

“2′-deoxynucleoside” means a nucleoside comprising 2′-H(H) furanosyl sugar moiety, as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

“2′-O-methoxyethyl” (also 2′-MOE) refers to a 2′-O(CH₂)₂—OCH₃) in the place of the 2′-OH group of a ribosyl ring. A 2′-O-methoxyethyl modified sugar is a modified sugar.

“2′-MOE nucleoside” (also 2′-O-methoxyethyl nucleoside) means a nucleoside comprising a 2′-MOE modified sugar moiety.

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

“3′ target site” refers to the nucleotide of a target nucleic acid which is complementary to the 3′-most nucleotide of a particular compound.

“5′ target site” refers to the nucleotide of a target nucleic acid which is complementary to the 5′-most nucleotide of a particular compound.

“5-methylcytosine” means a cytosine with a methyl group attached to the 5 position.

“About” means within 10% of a value. For example, if it is stated, “the compounds affected about 70% inhibition of HSD17B13”, it is implied that HSD17B13 levels are inhibited within a range of 60/c and 80%.

“Administration” or “administering” refers to routes of introducing a compound or composition provided herein to an individual to perform its intended function. An example of a route of administration that can be used includes, but is not limited to parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion.

“Administered concomitantly” or “co-administration” means administration of two or more compounds in any manner in which the pharmacological effects of both are manifest in the patient. Concomitant administration does not require that both compounds be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of both compounds need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive. Concomitant administration or co-administration encompasses administration in parallel or sequentially.

“Amelioration” refers to an improvement or lessening of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. In certain embodiments, amelioration includes a delay or slowing in the progression or severity of one or more indicators of a condition or disease. The progression or severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art.

“Animal” refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees.

“Antisense activity” means any detectable and/or measurable activity attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound to the target.

“Antisense compound” means a compound comprising an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. Examples of antisense compounds include single-stranded and double-stranded compounds, such as, oligonucleotides, ribozymes, siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.

“Antisense inhibition” means reduction of target nucleic acid levels in the presence of an antisense compound complementary to a target nucleic acid compared to target nucleic acid levels in the absence of the antisense compound.

“Antisense mechanisms” are all those mechanisms involving hybridization of a compound with target nucleic acid, wherein the outcome or effect of the hybridization is either target degradation or target occupancy with concomitant stalling of the cellular machinery involving, for example, transcription or splicing.

“Antisense oligonucleotide” means an oligonucleotide having a nucleobase sequence that is complementary to a target nucleic acid or region or segment thereof. In certain embodiments, an antisense oligonucleotide is specifically hybridizable to a target nucleic acid or region or segment thereof.

“Bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety. “Bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

“Branching group” means a group of atoms having at least 3 positions that are capable of forming covalent linkages to at least 3 groups. In certain embodiments, a branching group provides a plurality of reactive sites for connecting tethered ligands to an oligonucleotide via a conjugate linker and/or a cleavable moiety.

“Cell-targeting moiety” means a conjugate group or portion of a conjugate group that is capable of binding to a particular cell type or particular cell types.

“cEt” or “constrained ethyl” means a ribosyl bicyclic sugar moiety wherein the second ring of the bicyclic sugar is formed via a bridge connecting the 4′-carbon and the 2′-carbon, wherein the bridge has the formula: 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge is in the S configuration.

“cEt nucleoside” means a nucleoside comprising a cEt modified sugar moiety.

“Chemical modification” in a compound describes the substitutions or changes through chemical reaction, of any of the units in the compound relative to the original state of such unit. “Modified nucleoside” means a nucleoside having, independently, a modified sugar moiety and/or modified nucleobase. “Modified oligonucleotide” means an oligonucleotide comprising at least one modified internucleoside linkage, a modified sugar, and/or a modified nucleobase.

“Chemically distinct region” refers to a region of a compound that is in some way chemically different than another region of the same compound. For example, a region having 2′-O-methoxyethyl nucleotides is chemically distinct from a region having nucleotides without 2′-O-methoxyethyl modifications.

“Chimeric antisense compounds” means antisense compounds that have at least 2 chemically distinct regions, each position having a plurality of subunits.

“Cleavable bond” means any chemical bond capable of being split. In certain embodiments, a cleavable bond is selected from among: an amide, a polyamide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, a di-sulfide, or a peptide.

“Cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.

“Complementary” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposing directions. Nucleobase matches or complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), and 5-methyl cytosine (^mC) and guanine (G) unless otherwise specified. Complementary oligonuclotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside and may include one or more nucleobase mismatches. By contrast, “fully complementary” or “100% complementary” in reference to oligonucleotides means that such oligonucleotides have nucleobase matches at each nucleoside without any nucleobase mismatches.

“Conjugate group” means a group of atoms that is attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.

“Conjugate linker” means a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

“Conjugate moiety” means a group of atoms that is attached to an oligonucleotide via a conjugate linker.

“Contiguous” in the context of an oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or internucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.

“Designing” or “Designed to” refer to the process of designing a compound that specifically hybridizes with a selected nucleic acid molecule.

“Diluent” means an ingredient in a composition that lacks pharmacological activity, but is pharmaceutically necessary or desirable. For example, the diluent in an injected composition can be a liquid, e.g. saline solution.

“Differently modified” means chemical modifications or chemical substituents that are different from one another, including absence of modifications. Thus, for example, a MOE nucleoside and an unmodified DNA nucleoside are “differently modified,” even though the DNA nucleoside is unmodified. Likewise, DNA and RNA are “differently modified,” even though both are naturally-occurring unmodified nucleosides.

Nucleosides that are the same but for comprising different nucleobases are not differently modified. For example, a nucleoside comprising a 2′-OMe modified sugar and an unmodified adenine nucleobase and a nucleoside comprising a 2′-OMe modified sugar and an unmodified thymine nucleobase are not differently modified.

“Dose” means a specified quantity of a compound or pharmaceutical agent provided in a single administration, or in a specified time period. In certain embodiments, a dose may be administered in two or more boluses, tablets, or injections. For example, in certain embodiments, where subcutaneous administration is desired, the desired dose may require a volume not easily accommodated by a single injection. In such embodiments, two or more injections may be used to achieve the desired dose. In certain embodiments, a dose may be administered in two or more injections to minimize injection site reaction in an individual. In other embodiments, the compound or pharmaceutical agent is administered by infusion over an extended period of time or continuously. Doses may be stated as the amount of pharmaceutical agent per hour, day, week or month.

“Dosing regimen” is a combination of doses designed to achieve one or more desired effects.

“Double-stranded antisense compound” means an antisense compound comprising two oligomeric compounds that are complementary to each other and form a duplex, and wherein one of the two said oligomeric compounds comprises an oligonucleotide.

“Effective amount” means the amount of compound sufficient to effectuate a desired physiological outcome in an individual in need of the compound. The effective amount may vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual's medical condition, and other relevant factors.

“Efficacy” means the ability to produce a desired effect.

“Expression” includes all the functions by which a gene's coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to, the products of transcription and translation.

“Gapmer” means an oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage 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 may be referred to as the “gap” and the external regions may be referred to as the “wings.”

“HSD17B13” means any nucleic acid or protein of HSD17B13. “HSD17B13 nucleic acid” means any nucleic acid encoding HSD17B13. For example, in certain embodiments, a HSD17B13 nucleic acid includes a DNA sequence encoding HSD17B13, an RNA sequence transcribed from DNA encoding HSD17B13 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding HSD17B13. “HSD17B13 mRNA” means an mRNA encoding a HSD17B13 protein. The target may be referred to in either upper or lower case.

“HSD17B13 specific inhibitor” refers to any agent capable of specifically inhibiting HSD17B13 RNA and/or HSD17B13 protein expression or activity at the molecular level. For example, HSD17B13 specific inhibitors include nucleic acids (including antisense compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of HSD17B13 RNA and/or HSD17B13 protein.

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

“Immediately adjacent” means there are no intervening elements between the immediately adjacent elements of the same kind (e.g. no intervening nucleobases between the immediately adjacent nucleobases).

“Individual” means a human or non-human animal selected for treatment or therapy.

“Inhibiting the expression or activity” refers to a reduction or blockade of the expression or activity relative to the expression of activity in an untreated or control sample and does not necessarily indicate a total elimination of expression or activity.

“Internucleoside linkage” means a group or bond that forms a covalent linkage between adjacent nucleosides in an oligonucleotide. “Modified internucleoside linkage” means any internucleoside linkage other than a naturally occurring, phosphate internucleoside linkage. Non-phosphate linkages are referred to herein as modified internucleoside linkages.

“Lengthened oligonucleotides” are those that have one or more additional nucleosides relative to an oligonucleotide disclosed herein, e.g. a parent oligonucleotide.

“Linked nucleosides” means adjacent nucleosides linked together by an internucleoside linkage.

“Linker-nucleoside” means a nucleoside that links an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of a compound. Linker-nucleosides are not considered part of the oligonucleotide portion of a compound even if they are contiguous with the oligonucleotide.

“Mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary to the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotides are aligned. For example, nucleobases including but not limited to a universal nucleobase, inosine, and hypoxanthine, are capable of hybridizing with at least one nucleobase but are still mismatched or non-complementary with respect to nucleobase to which it hybridized. As another example, a nucleobase of a first oligonucleotide that is not capable of hybridizing to the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotides are aligned is a mismatch or non-complementary nucleobase.

“Modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism. For example, modulating HSD17B13 RNA can mean to increase or decrease the level of HSD17B13 RNA and/or HSD17B13 protein in a cell, tissue, organ or organism. A “modulator” effects the change in the cell, tissue, organ or organism. For example, a HSD17B13 compound can be a modulator that decreases the amount of HSD17B13 RNA and/or HSD17B13 protein in a cell, tissue, organ or organism.

“MOE” means methoxyethyl.

“Monomer” refers to a single unit of an oligomer. Monomers include, but are not limited to, nucleosides and nucleotides.

“Motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

“Natural” or “naturally occurring” means found in nature.

“Non-bicyclic modified sugar” or “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

“Nucleic acid” refers to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

“Nucleobase” means a heterocyclic moiety capable of pairing with a base of another nucleic acid. As used herein a “naturally occurring nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). A “modified nucleobase” is a naturally occurring nucleobase that is chemically modified. A “universal base” or “universal nucleobase” is a nucleobase other than a naturally occurring nucleobase and modified nucleobase, and is capable of pairing with any nucleobase.

“Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage.

“Nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

“Oligomeric compound” means a compound comprising a single oligonucleotide and, optionally, one or more additional features, such as a conjugate group or terminal group.

“Oligonucleotide” means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another. Unless otherwise indicated, oligonucleotides consist of 8-80 linked nucleosides. “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, nucleobase, or internucleoside linkage is modified. “Unmodified oligonucleotide” means an oligonucleotide that does not comprise any sugar, nucleobase, or internucleoside modification.

“Parent oligonucleotide” means an oligonucleotide whose sequence is used as the basis of design for more oligonucleotides of similar sequence but with different lengths, motifs, and/or chemistries. The newly designed oligonucleotides may have the same or overlapping sequence as the parent oligonucleotide.

“Parenteral administration” means administration through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

“Pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an individual. For example, a pharmaceutically acceptable carrier can be a sterile aqueous solution, such as PBS or water-for-injection.

“Pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds or oligonucleotides, i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

“Pharmaceutical agent” means a compound that provides a therapeutic benefit when administered to an individual.

“Pharmaceutical composition” means a mixture of substances suitable for administering to an individual. For example, a pharmaceutical composition may comprise one or more compounds or salt thereof and a sterile aqueous solution.

“Phosphorothioate linkage” means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom. A phosphorothioate internucleoside linkage is a modified internucleoside linkage.

“Phosphorus moiety” means a group of atoms comprising a phosphorus atom. In certain embodiments, a phosphorus moiety comprises a mono-, di-, or tri-phosphate, or phosphorothioate.

“Portion” means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an oligomeric compound.

“Prevent” refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time from minutes to indefinitely.

“Prodrug” means a compound in a form outside the body which, when administered to an individual, is metabolized to another form within the body or cells thereof. In certain embodiments, the metabolized form is the active, or more active, form of the compound (e.g., drug). Typically conversion of a prodrug within the body is facilitated by the action of an enzyme(s) (e.g., endogenous or viral enzyme) or chemical(s) present in cells or tissues, and/or by physiologic conditions.

“Reduce” means to bring down to a smaller extent, size, amount, or number.

“RefSeq No.” is a unique combination of letters and numbers assigned to a sequence to indicate the sequence is for a particular target transcript (e.g., target gene). Such sequence and information about the target gene (collectively, the gene record) can be found in a genetic sequence database. Genetic sequence-databases include the NCBI Reference Sequence database, GenBank, the European Nucleotide Archive, and the DNA Data Bank of Japan (the latter three forming the International Nucleotide Sequence Database Collaboration or INSDC).

“Region” is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic.

“RNAi compound” means an antisense compound that acts, at least in part, through RISC or Ago2, but not through RNase H, to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics.

“Segments” are defined as smaller or sub-portions of regions within a nucleic acid.

“Side effects” means physiological disease and/or conditions attributable to a treatment other than the desired effects. In certain embodiments, side effects include injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, myopathies, and malaise. For example, increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality.

“Single-stranded” in reference to a compound means the compound has only one oligonucleotide.

“Self-complementary” means an oligonucleotide that at least partially hybridizes to itself. A compound consisting of one oligonucleotide, wherein the oligonucleotide of the compound is self-complementary, is a single-stranded compound. A single-stranded compound may be capable of binding to a complementary compound to form a duplex.

“Sites” are defined as unique nucleobase positions within a target nucleic acid.

“Specifically hybridizable” refers to an oligonucleotide having a sufficient degree of complementarity between the oligonucleotide and a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids. In certain embodiments, specific hybridization occurs under physiological conditions.

“Specifically inhibit” with reference to a target nucleic acid means to reduce or block expression of the target nucleic acid while exhibiting fewer, minimal, or no effects on non-target nucleic acids. Reduction does not necessarily indicate a total elimination of the target nucleic acid's expression.

“Standard cell assay” means assay(s) described in the Examples and reasonable variations thereof.

“Standard in vivo experiment” means the procedure(s) described in the Example(s) and reasonable variations thereof.

“Stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

“Sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a p-D-ribosyl moiety, as found in naturally occurring RNA, or a β-D-2′-deoxyribosyl sugar moiety as found in naturally occurring DNA. As used herein, “modified sugar moiety” or “modified sugar” means a sugar surrogate or a furanosyl sugar moiety other than a β-D-ribosyl or a β-D-2′-deoxyribosyl. Modified furanosyl sugar moieties may be modified or substituted at a certain position(s) of the sugar moiety, substituted, or unsubstituted, and they may or may not have a stereoconfiguration other than β-D-ribosyl. Modified furanosyl sugar moieties include bicyclic sugars and non-bicyclic sugars.

“Sugar surrogate” means a modified sugar moiety that docs not comprise a furanosyl or tetrahydrofuranyl ring (is not a “furanosyl sugar moiety”) and that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or nucleic acids.

“Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

“Target gene” refers to a gene encoding a target.

“Targeting” means the specific hybridization of a compound to a target nucleic acid in order to induce a desired effect.

“Target nucleic acid,” “target RNA,” “target RNA transcript” and “nucleic acid target” all mean a nucleic acid capable of being targeted by compounds described herein.

“Target region” means a portion of a target nucleic acid to which one or more compounds is targeted.

“Target segment” means the sequence of nucleotides of a target nucleic acid to which a compound is targeted. “5′ target site” refers to the 5′-most nucleotide of a target segment. “3′ target site” refers to the 3′-most nucleotide of a target segment.

“Terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

“Therapeutically effective amount” means an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to an individual.

“Treat” refers to administering a compound or pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal.

Certain Embodiments

Certain embodiments provide methods, compounds and compositions for inhibiting HSD17B13 expression.

Certain embodiments provide compounds targeted to a HSD17B13 nucleic acid. In certain embodiments, the HSD17B13 nucleic acid has the sequence set forth in RefSeq or GENBANK Accession No. NM_178135.4 (incorporated by reference, disclosed herein as SEQ ID NO: 1), the complement of GENBANK Accession No. NC_000004.12 truncated from nucleotides 87301001 to 87326000 (incorporated by reference, disclosed herein as SEQ ID NO: 2), the sequence listed as SEQ ID NO: 3, or GENBANK Accession No. NM_001136230.2 (incorporated by reference, disclosed herein as SEQ ID NO: 4). In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of 8-2896. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 9 to 80 linked nucleosides and having a nucleobase sequence comprising at least 9 contiguous nucleobases of any of the nucleobase sequences of 8-2896. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 80 linked nucleosides and having a nucleobase sequence comprising at least 10 contiguous nucleobases of any of the nucleobase sequences of 8-2896. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 11 to 80 linked nucleosides and having a nucleobase sequence comprising at least 11 contiguous nucleobases of any of the nucleobase sequences of 8-2896. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 11 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 12 to 80 linked nucleosides and having a nucleobase sequence comprising at least 12 contiguous nucleobases of any of the nucleobase sequences of 8-2896. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 12 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of 8-2896. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of 8-2896. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded.

In certain embodiments, the compound is double-stranded.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion within nucleobases 3095-3369, 3371-7564, 7565-7672, 7673-8777, 8778-8909, 8910-10401, 10402-10508, 10509-12040, 12041-12178, 12179-15641, 15642-15758, 15759-20692, or 20693-22212 of SEQ ID NO: 2, wherein said modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 2. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion within nucleobases 1-46, 58-142, 1-142, 74-89, 154-197, 154-234, 200-232, 218-234, 240-345, 254-269, 354-746, 354-830, 519-534, 565-580, 603-628, 693-716, 734-750, 734-830, 749-828, 835-862, 835-957, 966-1044, 1017-1043, 1054-1106, 1055-1070, 1075-1169, 1074-1132, 1136-1169, 1175-1218, 1180-1217, 1250-1292, 1251-1279, 1296-1146, 1296-1448, 1308-1448, 1461-1481, 1461-1519, 1461-1647, 1461-1646, 1483-1535, 1538-1646, 1544-1561, 1597-1645, 1654-1685, 1654-1817, 1702-1817, 1705-1741, 1748-2211, 2174-2219, 2240-2272, 2244-2272, 2349-2370, 2350-2371, or 2378-2394 of an HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 1.

In certain embodiments, compounds target within nucleobases 3095-3454, 3095-3140, 3152-3236, 3168-3183, 3248-3328, 3312-3328, 3334-3390, 3348-3390, 3401-3420, 3429-3451, 3429-3454, 3474-3719, 3474-3644, 3478-3494, 3505-3531, 3544-3559, 3568-3634, 3671-3736, 3676-3717, 3721-3799, 3741-3771, 3750-3770, 3782-3799, 3834-3849, 3834-4154, 3877-3897, 3902-3917, 3933-3967, 3933-3979, 3988-4005, 3988-4017, 4068-4091, 4103-4118, 4123-4155, 4133-4155, 4220-4240, 4220-4264, 4249-4264, 4222-4240, 4296-4311, 4360-4378, 4389-4427, 4389-4431, 4405-4449, 4476-4496, 4517-4588, 4517-4552, 4537-4552, 4572-4588, 4640-4678, 4640-4879, 4641-4667, 4862-4879, 4991-5006, 4991-5305, 5029-5098, 5046-5098, 5104-5120, 5121-5141, 5125-5141, 5156-5256, 5158-5217, 5223-5242, 5267-5319, 5268-5319, 5395-5950, 5646-5695, 5655-5858, 5712-5752, 5712-5777, 5758-5777, 5782-5797, 5782-5862, 5804-5862, 5870-5910, 5871-6005, 5870-5910, 5870-5911, 5916-6007, 5935-5950, 5974-6007, 6029-6048, 6029-6055, 6035-6164, 6084-6099, 6084-6104, 6134-6164, 6170-6248, 6170-6275, 6170-6277, 6191-6218, 6221-6243, 6246-6275, 6284-6350, 6284-6352, 6298-6372, 6357-6372, 6388-6406, 6422-6493, 6422-6497, 6426-6621, 6567-6758, 6567-6582, 6597-6653, 6626-6653, 6710-6779, 6784-6811, 6785-6800, 6795-6811, 6913-6930, 6914-6929, 6914-6930, 6915-6930, 7101-7138, 7101-7441, 7125-7145, 7426-7441, 7473-7494, 7473-7498, 7481-7498, 7526-7543, 7550-7565, 7550-7634, 7563-7699, 7643-7676, 7680-7698, 7680-7699, 7708-7723, 7751-7819, 7768-7796, 7828-7866, 7834-7969, 7938-7968, 7938-7969, 7973-7994, 8017-8032, 8039-8186, 8039-8065, 8040-8065, 8121-8156, 8125-8151, 8164-8185, 8164-8186, 8205-8297, 8205-8220, 8236-8252, 8236-8271, 8256-8294, 8279-8297, 8487-8502, 8487-8627, 8529-8579, 8587-8628, 8636-8732, 8643-8910, 8744-8762, 8786-8910, 8939-9027, 8939-8996, 9000-9027, 9057-9096, 9080-9230, 9110-9173, 9188-9240, 9256-9275, 9312-9365, 9372-9401, 9373-9394, 9410-9446, 9410-9491, 9476-9555, 9497-9555, 9588-9678, 9588-9681, 9712-9737, 9712-9742, 9751-9811, 9751-10040, 9887-9902, 9908-10017, 10025-10040, 10058-10079, 10112-10160, 10124-10160, 10138-10160, 10180-10227, 10180-10233, 10258-10279, 10292-10310, 10293-10310, 10335-10375, 10335-10538, 10380-10538, 10554-10569, 10584-10599, 10728-10745, 10831-10870, 10930-10946, 10931-10946, 10970-10993, 10971-11015, 1100-11015, 11030-11045, 11073-11094, 11074-11094, 11115-11132, 11117-11132, 11155-11171, 11210-11228, 11210-11276, 11235-11276, 11290-11323, 11308-11323, 11384-11407, 11385-11443, 11428-11443, 11468-11529, 11542-11605, 11621-11636, 11621-11638, 11621-11668, 11652-11668, 11742-11808, 11742-11811, 11853-11881, 11853-11909, 11892-11912, 11924-11940, 11925-12226, 11953-12027, 12038-12226, 12238-12270, 12337-12531, 12337-12368, 12410-12448, 12465-12531, 12598-12642, 12598-12742, 12647-12742, 12758-12832, 12761-12832, 12862-12904, 13548-13627, 13551-13654, 13638-13674, 13688-13798, 13704-13798, 13813-13932, 13949-14064, 13951-13969, 13975-14064, 14077-14107, 14089-14107, 14126-14147, 14165-14221, 14166-14221, 14243-14298, 14243-14299, 14315-14336, 14316-14336, 14362-14414, 14432-14454, 14461-14514, 14465-14514, 14541-14815, 14541-14636, 14724-14746, 1400-14815, 14905-14951, 14916-14951, 15019-15039, 15022-15039, 15170-15185, 15200-15232, 15211-15268, 15244-15268, 15279-15295, 15279-15399, 15312-15343, 15350-15399, 15405-15460, 15492-15526, 15570-15586, 15633-15808, 15641-15657, 15643-15711, 15716-15765, 15771-15802, 16116-16144, 16116-16149, 16189-16206, 16189-16342, 16218-16240, 16254-16310, 16327-16352, 16377-16397, 16377-16400, 16407-16439, 16407-16440, 16461-16476, 16533-16548, 16755-16770, 16895-16920, 16905-16920, 16956-16984, 16956-17092, 17014-17034, 17135-17159, 17041-17062, 17077-17092, 17135-17159, 17227-17254, 17672-17795, 17675-17872, 17802-17817, 17857-17872, 17909-17945, 17909-17971, 17953-17971, 17954-17971, 17984-18061, 17985-18048, 18075-18117, 18087-18115, 18138-18160, 18176-18193, 18505-18555, 18506-18536, 18585-18600, 18658-18712, 18662-18762, 18720-18763, 18798-18864, 18871-18888, 18901-18940, 18925-18940, 18958-18983, 18958-19013, 19388-19460, 19467-19513, 19474-19505, 19531-19626, 19533-19626, 19649-19717, 19649-19726, 19731-19801, 19731-19842, 19815-19875, 19860-19951, 19887-19951, 19970-19985, 19970-20054, 19999-20024, 20037-20061, 20087-20102, 20109-20153, 20087-20207, 20172-20212, 20356-20438, 20248-20437, 20248-20264, 20470-20508, 20481-20507, 20571-20623, 20571-20644, 20685-20700, 20706-21032, 20706-20772, 20781-20859, 20869-20984, 20990-21033, 21065-21102, 21065-21263, 21092-21632, 21276-21500, 21517-21632, 21989-22034, 22059-22087, or 22164-22209 of an HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 2.

In certain embodiments, compounds have at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion within nucleobases 3095-3454, 3095-3140, 3152-3236, 3168-3183, 3248-3328, 3312-3328, 3334-3390, 3348-3390, 3401-3420, 3429-3451, 3429-3454, 3474-3719, 3474-3644, 3478-3494, 3505-3531, 3544-3559, 3568-3634, 3671-3736, 3676-3717, 3721-3799, 3741-3771, 3750-3770, 3782-3799, 3834-3849, 3834-4154, 3877-3897, 3902-3917, 3933-3967, 3933-3979, 3988-4005, 3988-4017, 4068-4091, 4103-4118, 4123-4155, 4133-4155, 4220-4240, 4220-4264, 4249-4264, 4222-4240, 4296-4311, 4360-4378, 4389-4427, 4389-4431, 4405-4449, 4476-4496, 4517-4588, 4517-4552, 4537-4552, 4572-4588, 4640-4678, 4640-4879, 4641-4667, 4862-4879, 4991-5006, 4991-5305, 5029-5098, 5046-5098, 5104-5120, 5121-5141, 5125-5141, 5156-5256, 5158-5217, 5223-5242, 5267-5319, 5268-5319, 5395-5950, 5646-5695, 5655-5858, 5712-5752, 5712-5777, 5758-5777, 5782-5797, 5782-5862, 5804-5862, 5870-5910, 5871-6005, 5870-5910, 5870-5911, 5916-6007, 5935-5950, 5974-6007, 6029-6048, 6029-6055, 6035-6164, 6084-6099, 6084-6104, 6134-6164, 6170-6248, 6170-6275, 6170-6277, 6191-6218, 6221-6243, 6246-6275, 6284-6350, 6284-6352, 6298-6372, 6357-6372, 6388-6406, 6422-6493, 6422-6497, 6426-6621, 6567-6758, 6567-6582, 6597-6653, 6626-6653, 6710-6779, 6784-6811, 6785-6800, 6795-6811, 6913-6930, 6914-6929, 6914-6930, 6915-6930, 7101-7138, 7101-7441, 7125-7145, 7426-7441, 7473-7494, 7473-7498, 7481-7498, 7526-7543, 7550-7565, 7550-7634, 7563-7699, 7643-7676, 7680-7698, 7680-7699, 7708-7723, 7751-7819, 7768-7796, 7828-7866, 7834-7969, 7938-7968, 7938-7969, 7973-7994, 8017-8032, 8039-8186, 8039-8065, 8040-8065, 8121-8156, 8125-8151, 8164-8185, 8164-8186, 8205-8297, 8205-8220, 8236-8252, 8236-8271, 8256-8294, 8279-8297, 8487-8502, 8487-8627, 8529-8579, 8587-8628, 8636-8732, 8643-8910, 8744-8762, 8786-8910, 8939-9027, 8939-8996, 9000-9027, 9057-9096, 9080-9230, 9110-9173, 9188-9240, 9256-9275, 9312-9365, 9372-9401, 9373-9394, 9410-9446, 9410-9491, 9476-9555, 9497-9555, 9588-9678, 9588-9681, 9712-9737, 9712-9742, 9751-9811, 9751-10040, 9887-9902, 9908-10017, 10025-10040, 10058-10079, 10112-10160, 10124-10160, 10138-10160, 10180-10227, 10180-10233, 10258-10279, 10292-10310, 10293-10310, 10335-10375, 10335-10538, 10380-10538, 10554-10569, 10584-10599, 10728-10745, 10831-10870, 10930-10946, 10931-10946, 10970-10993, 10971-11015, 1100-11015, 11030-11045, 11073-11094, 11074-11094, 11115-11132, 11117-11132, 11155-11171, 11210-11228, 11210-11276, 11235-11276, 11290-11323, 11308-11323, 11384-11407, 11385-11443, 11428-11443, 11468-11529, 11542-11605, 11621-11636, 11621-11638, 11621-11668, 11652-11668, 11742-11808, 11742-11811, 11853-11881, 11853-11909, 11892-11912, 11924-11940, 11925-12226, 11953-12027, 12038-12226, 12238-12270, 12337-12531, 12337-12368, 12410-12448, 12465-12531, 12598-12642, 12598-12742, 12647-12742, 12758-12832, 12761-12832, 12862-12904, 13548-13627, 13551-13654, 13638-13674, 13688-13798, 13704-13798, 13813-13932, 13949-14064, 13951-13969, 13975-14064, 14077-14107, 14089-14107, 14126-14147, 14165-14221, 14166-14221, 14243-14298, 14243-14299, 14315-14336, 14316-14336, 14362-14414, 14432-14454, 14461-14514, 14465-14514, 14541-14815, 14541-14636, 14724-14746, 1400-14815, 14905-14951, 14916-14951, 15019-15039, 15022-15039, 15170-15185, 15200-15232, 15211-15268, 15244-15268, 15279-15295, 15279-15399, 15312-15343, 15350-15399, 15405-15460, 15492-15526, 15570-15586, 15633-15808, 15641-15657, 15643-15711, 15716-15765, 15771-15802, 16116-16144, 16116-16149, 16189-16206, 16189-16342, 16218-16240, 16254-16310, 16327-16352, 16377-16397, 16377-16400, 16407-16439, 16407-16440, 16461-16476, 16533-16548, 16755-16770, 16895-16920, 16905-16920, 16956-16984, 16956-17092, 17014-17034, 17135-17159, 17041-17062, 17077-17092, 17135-17159, 17227-17254, 17672-17795, 17675-17872, 17802-17817, 17857-17872, 17909-17945, 17909-17971, 17953-17971, 17954-17971, 17984-18061, 17985-18048, 18075-18117, 18087-18115, 18138-18160, 18176-18193, 18505-18555, 18506-18536, 18585-18600, 18658-18712, 18662-18762, 18720-18763, 18798-18864, 18871-18888, 18901-18940, 18925-18940, 18958-18983, 18958-19013, 19388-19460, 19467-19513, 19474-19505, 19531-19626, 19533-19626, 19649-19717, 19649-19726, 19731-19801, 19731-19842, 19815-19875, 19860-19951, 19887-19951, 19970-19985, 19970-20054, 19999-20024, 20037-20061, 20087-20102, 20109-20153, 20087-20207, 20172-20212, 20356-20438, 20248-20437, 20248-20264, 20470-20508, 20481-20507, 20571-20623, 20571-20644, 20685-20700, 20706-21032, 20706-20772, 20781-20859, 20869-20984, 20990-21033, 21065-21102, 21065-21263, 21092-21632, 21276-21500, 21517-21632, 21989-22034, 22059-22087, or 22164-22209 of an HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 2. In certain embodiments, these compounds are antisense compounds, oligomeric compounds, or oligonucleotides. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, compounds have a nucleobase sequence complementary to nucleobases 1323-1338, 1600-1615, 1627-1642, or 1782-1797 of an HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 1.

In certain embodiments, compounds have a nucleobase sequence comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobases complementary within an equal length portion of nucleobases 1323-1338, 1600-1615, 1627-1642, or 1782-1797 of an HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 1. In certain embodiments, these compounds are antisense compounds, oligomeric compounds, or oligonucleotides. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, compounds have a nucleobase sequence complementary to nucleobases 3439-3454, 3552-3567, 3754-3769, 3963-3978, 4406-4421, 4123-4138, 4139-4154, 4991-5006, 5045-5060, 5662-5677, 6476-6491, 6478-6493, 17992-18007, 21138-21153, 21415-21430, 21442-21457, or 21597-21612 of an HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 2.

In certain embodiments, compounds have a nucleobase sequence comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobases complementary within an equal length portion of nucleobases 3439-3454, 3552-3567, 3754-3769, 3963-3978, 4406-4421, 4123-4138, 4139-4154, 4991-5006, 5045-5060, 5662-5677, 6476-6491, 6478-6493, 17992-18007, 21138-21153, 21415-21430, 21442-21457, or 21597-21612 of an HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 2. In certain embodiments, these compounds are antisense compounds, oligomeric compounds, or oligonucleotides. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, any of the foregoing modified oligonucleotides has at least one modified internucleoside linkage, at least one modified sugar, and/or at least one modified nucleobase.

In certain embodiments, at least one nucleoside of any of the foregoing modified oligonucleotides comprises a modified sugar. In certain embodiments, the modified sugar comprises a 2′-O-methoxyethyl group. In certain embodiments, the modified sugar is a bicyclic sugar, such as a 4′-CH(CH3)-O-2′ group, a 4′-CH2-O-2′ group, or a 4′-(CH2)₂—O-2′ group.

In certain embodiments, at least one internucleoside linkage of the modified oligonucleotide comprises a modified internucleoside linkage, such as a phosphorothioate internucleoside linkage.

In certain embodiments, at least one nucleobase of any of the foregoing modified oligonucleotides comprises a modified nucleobase, such as 5-methylcytosine.

In certain embodiments, any of the foregoing modified oligonucleotides has:

- a gap segment consisting of linked deoxynucleosides;
- a 5′ wing segment consisting of linked nucleosides; and
- a 3′ wing segment consisting of linked nucleosides;
  
  wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide consists of 12 to 30 linked nucleosides and has a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 8-2896. In certain embodiments, the modified oligonucleotide is 16 to 30 linked nucleosides in length having a nucleobase sequence comprising the nucleobase sequence recited in any one of SEQ ID NOs: 8-2896. In certain embodiments, the modified oligonucleotide is 16 linked nucleosides in length having a nucleobase sequence consisting of the sequence recited in any one of SEQ ID NOs: 8-2896.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the nucleobase sequence recited in any one of 8-2896, wherein the modified oligonucleotide has:

- a gap segment consisting of linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of linked nucleosides; and
- a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides

In certain embodiments, a compound comprises or consists of a modified oligonucleotide 12-30 linked nucleobases in length having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 286, 817, 983, 1215, 747, 43, 355, 1602, 201, 734, 1249, 208, 513, 1449, 1448, and 1595, wherein the modified oligonucleotide has:

- a gap segment consisting of ten linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of three linked nucleosides; and
- a 3′ wing segment consisting of three linked nucleosides;
  
  wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

- a gap segment consisting of nine linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of three linked nucleosides; and
- a 3′ wing segment consisting of four linked nucleosides;
  
  wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of the 5′ wing segment comprises a cEt sugar; wherein the sugar residues of the nucleosides of the 3′ wing segment are 5′-cEt-cEt-cEt-MOE-3′; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

- a gap segment consisting of ten linked nucleosides;
- a 5′ wing segment consisting of three linked nucleosides; and
- a 3′ wing segment consisting of four linked nucleosides;
  
  wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein the gap segment consists of 5′-one deoxy, one 2′-O-methyl nucleoside, and eight deoxynucleosides-3′, wherein each nucleoside of each of the wing segments comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16-30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In any of the foregoing embodiments, the compound or oligonucleotide can be at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% complementary to a nucleic acid encoding HSD17B13.

In any of the foregoing embodiments, the compound can be single-stranded. In certain embodiments, the compound comprises deoxyribonucleotides. In certain embodiments, the compound is double-stranded. In certain embodiments, the compound is double-stranded and comprises ribonucleotides. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

In any of the foregoing embodiments, the compound can consist of 8 to 80, 10 to 30, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked nucleosides. In certain embodiments, the compound comprises or consists of an oligonucleotide.

In certain embodiments, a compound comprises a modified oligonucleotide described herein and a conjugate group. In certain embodiments, the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. In certain embodiments, the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide. In certain embodiments, the conjugate group comprises at least one N-Acetylgalactosamine (GalNAc), at least two N-Acetylgalactosamines (GalNAcs), or at least three N-Acetylgalactosamines (GalNAcs).

In certain embodiments, compounds or compositions provided herein comprise a pharmaceutically acceptable salt of the modified oligonucleotide. In certain embodiments, the salt is a sodium salt. In certain embodiments, the salt is a potassium salt.