WO2022098748A1

WO2022098748A1 - Uses for hsd17b13 inhibitors

Info

Publication number: WO2022098748A1
Application number: PCT/US2021/057883
Authority: WO
Inventors: Heather Kay Webb HSU; Michael Carleton; Brian K. FARMER
Original assignee: Inipharm, Inc.
Priority date: 2020-11-06
Filing date: 2021-11-03
Publication date: 2022-05-12

Abstract

Described herein are HSD17B13 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of liver disease, metabolic disease, or cardiovascular disease. Specifically the compounds are useful in the treatment or prevention of a cholestatic disease, liver injury due to protein accumulation, a viral infection-induced liver injury, severity of inflammation or acute immune response in a subject with a viral infection, hepatic malignancy, hemochromatosis, lysosomal acid lipase deficiency (LAL-D), or to improve autophagy in a subject.

Description

USES FOR HSD17B13 INHIBITORS

CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63/110,774 filed November 6, 2020 which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 17p-Hydroxy steroid dehydrogenases (HSD17Bs) comprise a large family of 15 members some of which involved in sex hormone metabolism. Some HSD17Bs enzymes also play key roles in cholesterol and fatty acid metabolism. A recent study showed that hydroxysteroid 17p-dehydrogenase 13 (HSD17B13), an enzyme with unknown biological function, is a novel liver-specific lipid droplet (LD)-associated protein in mouse and humans. HSD17B13 expression is markedly upregulated in patients and mice with non-alcoholic fatty liver disease (NAFLD). Hepatic overexpression of HSD17B13 promotes lipid accumulation in the liver.

[0003] Inactive HSD17B13 polymorphisms have been shown to protect against non-alcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD). Inactive HSD17B13 has also been shown to protect against fulminant disease in the context of Wilson’s disease and rapidly progressing fibrosis in the context of HCV infection. The primary histological and gene expression changes associated with inactive HSD17B13 are decreases in pathways that are associated with inflammation and fibrosis. Inflammation and fibrosis are among the pathological features of other liver diseases but they are caused by other disfunctions. Finally, inactive HSD17B13 has been shown to have higher levels of phophatidylcholine in the liver and plasma as well has high expression in the gallbladder supporting the use of HSD17B13 inhibitors in diseases that involve cholestasis and biliary and gallbladder injury.

SUMMARY OF THE INVENTION

[0004] Provided herein are methods for reducing expression or activity of HSD17B13 in a subj ect in need thereof.

[0005] Disclosed herein is a method of treating or preventing a cholestatic disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

[0006] In some embodiments, the cholestatic disease is primary sclerosis cholangitis (PSC), primary biliary cholangitis (PBC), Alagille Syndrome, biliary atresia, liver injury in a cystic fibrosis patient, progressive familial intrahepatic cholestasis (PFIC), intrahepatic cholestasis of pregnancy; drug-induced cholestasis, AIDS cholangiopathy, IG4-associated cholangitis, biliary stricture, or low phospholipid- associated cholestasis.

[0007] In some embodiments, the cholestatic disease is primary sclerosis cholangitis (PSC). In some embodiments, the PSC is accompanied by inflammatory bowel disease (IBD). In some embodiments, the PSC is accompanied by elevated levels of lipopolysaccharide (LPS) (endotoxemia). In some embodiments, the elevated levels of LPS is in the blood. In some embodiments, the elevated levels of LPS is in the liver. In some embodiments, the elevated levels of LPS is in the biliary tree. In some embodiments, the cholestatic disease is primary biliary cholangitis (PBC). In some embodiments, the cholestatic disease is Alagille Syndrome In some embodiments, the cholestatic disease is biliary atresia. In some embodiments, the cholestatic disease is liver injury in a cystic fibrosis patient. In some embodiments, the cholestatic disease is progressive familial intrahepatic cholestasis (PFIC). In some embodiments, the PFIC is PFIC-3 type. In some embodiments, the cholestatic disease is treated or prevented by improving bile flow in the subject in need thereof. In some embodiments, the cholestatic disease is treated or prevented by improving cholesterol secretion out of the liver in the subject in need thereof. In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some

comprises an estradiol mimetic, an anti-HSD17B13 antibody or antibody fragment, an oligonucleotide directed against an HSD17B13 encoding oligonucleotide, an antisense oligonucleotide, an RNAi, or an siRNA. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0008] Also disclosed herein is a method of treating or preventing liver injury due to protein accumulation in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the protein accumulation is cleared via autophagy. In some embodiments, the protein is a misfolded protein. In some embodiments, the liver injury is due to alpha 1-antitrypsin deficiency. In some embodiments, the liver disease associated with alpha 1- antitrypsin deficiency include inflammation. In some embodiments, the liver disease associated with alpha 1-antitrypsin deficiency include decreases in platelets. In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor i

some embodiments, the HSD17B13 inhibitor comprises an estradiol mimetic, an anti-

HSD17B13 antibody or antibody fragment, an oligonucleotide directed against an HSD17B13 encoding oligonucleotide, an antisense oligonucleotide, an RNAi, or an siRNA. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0009] Also disclosed herein is a method of improving autophagy in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17- beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the autophagy eliminates accumulated protein in the liver. In some embodiments, the protein is a misfolded protein. In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor

. In some embodiments, the

HSD17B13 inhibitor comprises an estradiol mimetic, an anti-HSD17B13 antibody or antibody fragment, an oligonucleotide directed against an HSD17B13 encoding oligonucleotide, an antisense oligonucleotide, an RNAi, or an siRNA. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0010] Also disclosed herein is a method of treating or preventing a viral infection-induced liver injury in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the viral infection is SARS-Cov-2. In some embodiments, the viral infection is hepatitis A. In some embodiments, the viral infection is hepatitis B. In some embodiments, the viral infection is hepatitis C. In some embodiments, the viral infection is associated with a dysregulated liver inflammatory response. In some embodiments, the administration results in lowering the levels of immune response activation genes. In some embodiments, the administration results in decreased inflammation. In some embodiments, the subject in need thereof has elevated levels of alanine aminotransferase (ALT). In some embodiments, the subject in need thereof has elevated levels of aspartate aminotransferase

(AST). In some embodiments, the subject in need thereof has decreased levels of albumin. In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor i

In some embodiments, the HSD17B13 inhibitor comprises an estradiol mimetic, an anti-HSD17B13 antibody or antibody fragment, an oligonucleotide directed against an HSD17B13 encoding oligonucleotide, an antisense oligonucleotide, an RNAi, or an siRNA. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0011] Also disclosed herein is a method of decreasing the severity of inflammation in a subject with a viral infection, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the viral infection is SARS-Cov-2. In some embodiments, the viral infection is hepatitis A. In some embodiments, the viral infection is hepatitis B. In some embodiments, the viral infection is hepatitis C. In some embodiments, the viral infection is associated with a dysregulated liver inflammatory response. In some embodiments, the administration results in lowering the levels of immune response activation genes. In some embodiments, the administration results in decreased inflammation. The method of any one of claims 37-45, wherein the subject in need thereof has elevated levels of alanine aminotransferase (ALT). In some embodiments, the subject in need thereof has elevated levels of aspartate aminotransferase (AST). In some embodiments, the subject in need thereof has decreased levels of albumin. In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor i

[0012] Also disclosed herein is a method of decreasing the severity of acute immune response in a subject with a viral infection, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the viral infection is SARS-Cov-2. In some embodiments, the viral infection is hepatitis A. In some embodiments, the viral infection is hepatitis B. In some embodiments, the viral infection is hepatitis C. In some embodiments, the viral infection is associated with a dysregulated liver inflammatory response. In some embodiments, the administration results in lowering the levels of immune response activation genes. In some embodiments, the administration results in decreased inflammation. The method of any one of claims 37-45, wherein the subject in need thereof has elevated levels of alanine aminotransferase (ALT). In some embodiments, the subject in need thereof has elevated levels of aspartate aminotransferase (AST). In some embodiments, the subject in need thereof has decreased levels of albumin. In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor i

. In some embodiments, the HSD17B13 inhibitor comprises an estradiol mimetic, an anti-HSD17B13 antibody or antibody fragment, an oligonucleotide directed against an HSD17B13 encoding oligonucleotide, an antisense oligonucleotide, an RNAi, or an siRNA. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0013] Also disclosed herein is a method of treating or preventing a malignancy selected from hepatocellular carcinoma (HCC), cholangioadenoma, cholangiocarcinoma, gallbladder adenocarcinoma, and malignancy of bile duct, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the malignancy is hepatocellular carcinoma (HCC). In some embodiments, the malignancy is cholangioadenoma. In some embodiments, the malignancy is cholangiocarcinoma. In some embodiments, the malignancy is gallbladder adenocarcinoma. In some embodiments, the HSD17B13 receptor is expressed in the peritumoral space. In some embodiments, the

HSD17B13 inhibitor i

. In some embodiments, the HSD17B13 inhibitor comprises an estradiol mimetic, an anti-HSD17B13 antibody or antibody fragment, an oligonucleotide directed against an HSD17B13 encoding oligonucleotide, an antisense oligonucleotide, an RNAi, or an siRNA. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. [0014] Also disclosed herein is a method of treating or preventing hemochromatosis in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the hemochromatosis is primary hemochromatosis. In some embodiments, the hemochromatosis is secondary hemochromatosis. In some embodiments, the hemochromatosis is caused by a liver disease. In some embodiments, the hemochromatosis is drug-induced hemochromatosis. In some embodiments, the HSD17B13 inhibitor i

. In some embodiments, the

[0015] Also disclosed herein is a method of treating or preventing lysosomal acid lipase deficiency (LAL-D) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSDI7B13) inhibitor to the subject. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) causes Wolman disease. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) causes Cholesteryl ester storage disease. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) causes a buildup of fatty substances in the body's cells and tissues. In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B 13 inhibitor

. In some embodiments, the

INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0018] FIG. 1A. depicts the Western Blots of autophagy substrate, p62, and autophagy marker, LC3B, and cleaved caspase 3 in HepG2 clonal cells lines expressing the active full length protein (KO-TA-A6) after 48 hours in culture under different stress conditions. Lane 7 - control, Lane 8 + fructose, Lane 9 + LPS, Lane 10 + ethanol, Lane 11 + fructose & palmitate, Lane 12 + acetaminophen.

[0019] FIG. IB. depicts the Western Blots of autophagy substrate, p62, and autophagy marker, LC3B, and cleaved caspase 3 in HepG2 clonal cells lines expressing the knock out (KO- EV-D5) after 48 hours in culture under different stress conditions. Lane 7 - control, Lane 8 + fructose, Lane 9 + LPS, Lane 10 + ethanol, Lane 11 + fructose & palmitate, Lane 12 + acetaminophen.

[0020] FIG. 1C. depicts the Western Blots of autophagy substrate, p62, and autophagy marker, LC3B, and cleaved caspase 3 in HepG2 clonal cells lines expressing the inactive splice variant (KO-TD-A3) after 48 hours in culture under different stress conditions. Lane 7 - control, Lane 8 + fructose, Lane 9 + LPS, Lane 10 + ethanol, Lane 11 + fructose & palmitate, Lane 12 + acetaminophen. [0021] FIG. 2 depicts the improved markers of autophagy with HSD17B13 polymorphisms. The change was in the autophagy substrate, p62, and autophagy marker, LC3B, in normal media and in response to 200 pM ethanol supplemented media. The change was measures between days 3 and 4 for primary hepatocytes in culture.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0022] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0023] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

[0024] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0025] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0026] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0027] As used herein, the term ‘about’ a number refers to that number plus or minus 10% of that number. The term ‘about’ a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0028] “HSD17B13” means hydroxysteroid 17-beta dehydrogenase 13 and refers to any nucleic acid of HSD17B13. For example, in some embodiments, HSD17B13 includes a DNA sequence encoding HSD17B13, an RNA sequence transcribed from DNA encoding HSD17B13 (including genomic DNA comprising introns and exons). HSD17B13 can also refer to any amino acid sequence of HSD17B13 (may include secondary or tertiary structures of the protein molecule), encoded by a DNA sequence and/or RNA sequence. The target may be referred to in either upper or lower case.

[0029] The term “fragment” or “derivative” when referring to a protein (e.g., HSD17B13) generally means proteins or polypeptides which retain essentially the same biological function or activity in at least one assay as the native protein(s). For example, the fragments or derivatives of the referenced protein maintains at least about 50% of the activity of the native proteins, at least 75%, at least about 95% of the activity of the native proteins.

[0030] The term “modulate,” or “modify” as used interchangeably herein, generally means to interact with a target protein (e.g., HSD17B 13) either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target.

[0031] As used herein, the term “modulator” generally refers to a compound that alters an activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor (e.g., HSD17B13 inhibitor), which decreases the magnitude of one or more activities of a target (e.g., a HSD17B13 protein). In certain embodiments, an inhibitor completely prevents one or more activities of a target. In certain embodiments, a modulator changes the cellular distribution of the target (e g., a HSD17B13 protein).

[0032] As used herein, the term “target activity” generally refers to a biological activity capable of being modulated by a modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, and amelioration of one or more symptoms associated with a liver disease or condition.

[0033] The terms “kit” and “article of manufacture” are used as synonyms.

[0034] The term “subject,” “patient,” or “individual” generally encompasses mammals, nonmammals, and a biological entity containing expressed genetic materials. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human. The subject may be diagnosed or suspected of being at high risk for a liver condition or disease. In some cases, the subject may be diagnosed or suspected of being at risk for a condition or disease that needs to receive a particular therapy, which could cause or exacerbate a liver condition or disease. In some cases, the subject is not necessarily diagnosed or suspected of being at risk for the liver disease or condition.

[0035] The terms “treat,” “treating” or “treatment,” as used herein in reference to a pharmaceutical or other intervention regimen, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[0036] As used herein, amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, prevention of sequelae, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0037] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. [0038] The term “pharmaceutically acceptable,” as used herein, generally refers a material, such as a carrier, diluent, or formulation, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0039] The term “pharmaceutical composition” generally refers to a mixture of a compound (e.g., a HSD17B13 inhibitor), described herein with other chemical components, such as carriers, stabilizers, diluents, surfactants, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, subcutaneous, intramuscular, pulmonary and topical administration.

[0040] The term “biliary tree,” “biliary tract,” or “biliary system” refers to the liver, gall bladder and bile ducts, and how they work together to make, store and secrete bile. Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated bilirubin. Some components are synthesized by hepatocytes (liver cells), the rest are extracted from the blood by the liver.

[0041] The terms “effective amount” or “therapeutically effective amount,” as used herein, generally refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition, required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

[0042] In prophylactic applications, compositions described herein are administered to a subject susceptible to or otherwise at risk of a particular disease, disorder or condition, such as a liver disease or condition to prevent the subject from developing the liver disease or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the subject's state of health, weight, and the like. When used in a subject, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician. HSD17B13 inhibitors

[0043] In certain embodiments, HSD17B13 inhibitors comprise a nucleic acid molecule that is configured to cause genetic perturbation of HSD17B13 gene resulting in reduced RNA and/or protein expression of HSD17B13. The nucleic acid molecule may comprise genomic DNA, mRNA, or cDNA.

[0044] In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In

[0045] In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor is ARO-HSD.

[0046] In some embodiments, the HSD17B13 inhibitor comprises an estradiol mimetic, an anti-HSD17B13 antibody or antibody fragment, an oligonucleotide directed against an HSD17B13 encoding oligonucleotide, an antisense oligonucleotide, an RNAi, or an siRNA. [0047] In some embodiments, the HSD17B13 inhibitor is disclosed in WO2019183329 which is hereby incorporated by reference for such disclosures. In some embodiments, the HSD17B13 inhibitor is disclosed in CN103520724B which is hereby incorporated by reference for such disclosures. In some embodiments, the HSD17B13 inhibitor is disclosed in W02018190970 which is hereby incorporated by reference for such disclosures. In some embodiments, the HSD17B13 inhibitor is disclosed in WO2019183164 which is hereby incorporated by reference for such disclosures. In some embodiments, the HSD17B13 inhibitor is disclosed in W02019075181 which is hereby incorporated by reference for such disclosures.

Further Forms of Compounds Disclosed Herein

Isomer s/Stereoisomers

[0048] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.

Labeled compounds

[0049] In some embodiments, the compounds described herein exist in their isotopically- labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., ²H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

[0050] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0051] In some embodiments, the labeled compounds described herein are used for measuring in vitro and in vivo binding of unlabeled HSD17B13 inhibitors.

Pharmaceutically acceptable salts

[0052] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0053] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0054] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6- dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxy ethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate. [0055] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l - carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0056] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(CI-4 alkyl)4, and the like.

[0057] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

Solvates

[0058] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [0059] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Tautomers

[0060] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.

Method of Treatment

[0061] Provided herein are methods of inhibiting HSD17B13 expression or activity, which can be useful for treating, preventing, or ameliorating a disease associated with HSD17B13 in a subject in need thereof, by administration of a compound that targets HSD17B13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0062] In some embodiments, inactive HSD17B13 has improved autophagy under stress conditions which provides additional uses for inhibition of HSD17B13 beyond NASH and ALD that involve both cell autonomous effects such as processing misfolded proteins in hepatocytes or cell-cell communication such as regulating cytotoxic killer T cells in the tumor microenvironment.

Cholestatic Diseases

[0063] Provided herein is a method of treating or preventing a cholestatic disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. Provided herein is a method of treating a cholestatic disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxy steroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

[0064] In some embodiments, inhibiting HSD17B13 improves bile flow. In some embodiments, inhibition of HSD17B13 is used to treat a cholestatic disease. Cholestatic diseases include primary sclerosis cholangitis (PSC), primary biliary cholangitis (PBC), Alagille Syndrome, biliary atresia, liver injury in cystic fibrosis patients and progressive familial intrahepatic cholestasis (PFIC).

[0065] HSD17B13 protein is very highly expressed in liver and gallbladder. The gallbladder is developmentally downstream of hepatocytes through the biliary tree. Inactive HSD17B13 has been associated with increases in liver and plasma phosphatidylcholine. Phosphatidylcholine is essential for bile flow. Hepatic phosphatidylcholine is secreted into the bile at a rate equivalent to the total liver levels of phosphatidylcholine being secreted within a day along with bile acids (BAs) and cholesterol. In some embodiments, inactive HSD17B13 is associated with increased plasma levels of VLDL-cholesterol. Meaning that there is a greater secretion of cholesterol out of the liver and not catabolized to bile acids for secretion in bile. In some embodiments, inhibition ofHSD17B13 improves bile flow through increased phosphatidylcholine. In some embodiments, HSD17B13 is protecting the biliary tree by preventing inflammation. In some embodiments, HSD17B13 is protecting the biliary tree by preventing the cytotoxic bile acids from injuring the biliary tree.

[0066] In some embodiments, the cholestatic disease is primary sclerosis cholangitis (PSC), primary biliary cholangitis (PBC), Alagille Syndrome, biliary atresia, liver injury in a cystic fibrosis patient, progressive familial intrahepatic cholestasis (PFIC), intrahepatic cholestasis of pregnancy; drug-induced cholestasis, AIDS cholangiopathy, IG4-associated cholangitis, biliary stricture, or low phospholipid- associated cholestasis.

[0067] In some embodiments, the cholestatic disease is primary sclerosis cholangitis (PSC), primary biliary cholangitis (PBC), Alagille Syndrome, biliary atresia, liver injury in a cystic fibrosis patient, or progressive familial intrahepatic cholestasis (PFIC).

[0068] In some embodiments, the cholestatic disease is primary sclerosis cholangitis (PSC). [0069] In some embodiments, the PSC is accompanied by inflammatory bowel disease (IBD). In some embodiments, the PSC is accompanied by elevated levels of lipopolysaccharide (LPS) (endotoxemia). In some embodiments, the elevated levels of LPS is in the blood. In some embodiments, the elevated levels of LPS is in the liver. In some embodiments, the elevated levels of LPS is in the biliary tree. In some embodiments, the cholestatic disease is primary biliary cholangitis (PBC). In some embodiments, the cholestatic disease is Alagille Syndrome. In some embodiments, the cholestatic disease is biliary atresia. In some embodiments, the cholestatic disease is liver injury in a cystic fibrosis patient. In some embodiments, the cholestatic disease is progressive familial intrahepatic cholestasis (PFIC). In some embodiments, the PFIC is PFIC-3 type. In some embodiments, the PFIC-3 type is due to a mutation in ABCB4 which requires phosphatidylcholine for bile acid transport.

[0070] In some embodiments, the cholestatic disease is treated or prevented by improving bile flow in the subject in need thereof. In some embodiments, the cholestatic disease is treated or prevented by improving cholesterol secretion out of the liver in the subject in need thereof. [0071] In some embodiments, inactive HSD17B13 is associated to lower cytokines and inflammatory gene expression In some embodiments, there is an improvement in the hepatocyte response to LPS in hepatocytes with inactive HSD17B13. In some embodiments, inactive HSD17B13 is associated with improved autophagy in response to LPS (see FIG. 1A, FIG. IB, and FIG. 1C). In some embodiment, increases in LC3B-11 combined with increases in p62 indicate accumulation of autophagosomes and defective autophagy.

Liver injury due to protein accumulation

[0072] Disclosed herein is a method of treating or preventing liver injury due to protein accumulation in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the protein that accumulates is alpha 1 -antitrypsin.

[0073] Alpha 1 -antitrypsin is encoded by the gene SERPINA1. The normal allele is referred to as M, while common SERPINA1 alleles that have been associated with liver disease have amino acid changes Glu264Val, referred to as S and Glu342Lys, referred to as Z. Individuals that are homozygotes for the Z (designated PiZZ) allele, have pulmonary manifestations of their Al AT deficiency and can be treated by supplementation of the enzyme. However, individuals that are heterozygotes for the Z allele either with the M (designated PiMZ) or with the S allele (designated PiSZ) have liver disease manifestations. The protein resulting from translation of the Z and S alleles is a misfolded protein. This misfolded protein has been found to polymerize and lead to cellular injury due to accumulation of misfolded and polymerized protein. Protection against the injury due to accumulated misfolded protein has been observed by increasing autophagy.

[0074] In some embodiments, HSD17B13 plays a role in autophagy (see FIG. 1A, FIG. IB, FIG. 1C, and FIG. 2). In some embodiments, autophagy is important for eliminating misfolded proteins and has been implicated in liver injury due to alpha 1 -antitrypsin deficiency. In some embodiments, inhibition of HSD17B13 improves autophagy and thus improve clearance of misfolded proteins and thus, improve liver health. In some embodiments, liver disease associated with alpha 1 -antitrypsin deficiency include inflammation and decreases in platelets. In some embodiments, inactive HSD17B13 is associated with lower inflammation, decreased inflammatory genes including NF-kB and TGF-p as well as increases in platelets.

[0075] In some embodiments, the protein accumulation is cleared via autophagy. In some embodiments, the protein is a misfolded protein. In some embodiments, the liver injury is due to alpha 1-antitrypsin deficiency. In some embodiments, the alpha 1-antitrypsin deficiency results in a protein that does not get fully processed and accumulates as a mis-folded protein in the liver. In some embodiments, the liver disease associated with alpha 1-antitrypsin deficiency include inflammation. In some embodiments, the liver disease associated with alpha 1- antitrypsin deficiency include decreases in platelets.

Treatment of viral-induced injuries

[0076] Disclosed herein is a method of treating or preventing a viral infection-induced liver injury in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. Disclosed herein is a method of treating a viral infection-induced liver injury in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 1 -beta dehydrogenase 13 (HSD1 B13) inhibitor to the subject.

[0077] Also disclosed herein is a method of decreasing the severity of inflammation in a subject with a viral infection, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSDI7B13) inhibitor to the subject. [0078] Also disclosed herein is a method of decreasing the severity of acute immune response in a subject with a viral infection, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

[0079] Viral infections are often associated with dysregulated liver inflammatory response. In some embodiments, inactive HSD17B13 is associated with lower levels of genes of activation of immune response including innate immune response, cytokines. Inflammation is a key component of viral-driven injury. In some embodiments, inactive HSD17B13 protects against rapidly progressing fibrosis in HCV patients.

[0080] AAV-driven gene therapies are aided by autophagy for incorporating into liver cells so an HSD17B13 inhibitor that improves autophagy and decreases inflammation can both enhance efficacy and decrease side effects.

[0081] In some embodiments, the viral infection is hepatitis A. In some embodiments, the viral infection is hepatitis B. In some embodiments, the viral infection is hepatitis C.

[0082] In some embodiments, the viral infection is SARS-Cov-2. SARS-Cov-2

[0083] Liver injury and elevations of liver transaminases are a common feature in patients with severe SARS-Cov-2 infection. There is no apparent increased risk of COVID-19 associated with liver disease, therefore, 2-11% of patients with CO VID-19 have underlying liver comorbidities. In contrast, a much larger portion of patients (14-53%) have elevated liver transaminases. Patients suspected of having COVID-19 that test positive for the SARS-CoV-2 RNA had elevations in ALT, AST and decreases in albumin when compared to patients that tested negative for the viral RNA consistent with liver injury. In patients that died from COVID- 19, 58% and 78% of patients had liver transaminase elevations. The liver transaminase elevations have been especially notable in patients in intensive care units at 62% compared to 25% of patients not requiring ICU care. Patients with a CT-scan confirmed diagnosis of COVID-19 in the subclinical stage have a lower incidence of liver transaminase elevations when compared to patients diagnosed after the onset of symptoms. While there may be a role of the virus causing direct liver injury as evidenced by the observation of SARS-CoV-2 RNA in blood and feces and 2-10% of patients that have diarrhea, the liver injury may also arise from secondary inflammatory events or the use of many different drugs during critical care.

[0084] In addition to liver injury in patients with severe COVID-19, there is an increase in cytokines, or incidence of cytokine storm that is a cause of multiple organ failure and death. To prevent or treat the cytokine storm would therefore be important to treating the patients with the most severe disease. Analysis of COVLD-19 patient’s blood has shown in general decreases in CD4 and CD8 cells but an increase in Thl7 cells. Similarly, in a cohort of patients with severe disease there was an increase in IL-6, IL-10, IL-2 and IFNy. On the whole, liver injury is seen in COVID-19 patients who are experiencing a broader and more severe disease where multiple organs, beyond the lungs, have become involved. Among the possible reasons for this could be that through an oral route that is then taken up through a more permeable intestinal barrier in patients with co-morbidities such as diabetes. The liver then is exposed to the virus and as a critical mediator for inflammatory responses, could thus mediate either a resolving inflammatory process or mediate an accelerating inflammatory process that leads to increased cytokine release and further organ damage.

[0085] The genetic evidence for the gene for the enzyme HSD17B 13 association with liver transaminase levels and liver diseases has grown rapidly. At this writing the genetic evidence includes many studies with genetic and disease information from more than 200,000 individuals. The lack of HSD17B13 activity has been shown to be protective against liver disease caused by over nutrition, excess and chronic alcohol intake, toxins such as copper and viruses such as HCV. The highly reproducible association of HSD17B13 with liver disease, liver transaminase elevations and liver injury in multiple forms has inspired efforts to develop inhibitors of this enzyme to protect against and reverse liver damage. The variety of toxicants and injuries against which HSD17B13 loss of function protects is such that it is proposed here to protect against liver injury in severe COVID-19.

[0086] HSD17B13 activity has been shown to be involved in inflammation and inflammatory response. HSD17B13 loss of function has recently been associated with decreased gene expression and protein levels of immune response genes involved in adverse outcomes including IL-6, IL-10 and IL-ip. Enzymatically inactive polymorphs of HSD17B13 are associated with lower severity of histopathological endpoints of inflammation in addition to lower ALT levels in patients with nonalcoholic fatty liver disease.

[0087] In some embodiments, HSD17B13 inhibitors prevent and treat liver injury and decrease the severity of inflammation and acute immune response in patients with COVID-19.

[0088] In some embodiments, the viral infection is associated with a dysregulated liver inflammatory response. In some embodiments, the administration results in lowering the levels of immune response activation genes. In some embodiments, the administration results in decreased inflammation. In some embodiments, the subject in need thereof has elevated levels of alanine aminotransferase (ALT). In some embodiments, the subject in need thereof has elevated levels of aspartate aminotransferase (AST). In some embodiments, the subject in need thereof has decreased levels of albumin.

Malignancies

Disclosed herein is a method of treating or preventing a malignancy selected from hepatocellular carcinoma (HCC), cholangioadenoma, cholangiocarcinoma, gallbladder adenocarcinoma, and malignancy of bile duct, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

[0089] Disclosed herein is a method of treating or preventing a malignancy selected from hepatocellular carcinoma (HCC), cholangioadenoma, cholangiocarcinoma, and gallbladder adenocarcinoma in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

[0090] Inactive HSD17B13 is associated with lower rates of HCC. However, HSD17B13 expression is low in tumor tissue but normal in the peritumoral space. High protein levels in the peritumoral space is associated with improved survival and tumor free survival. This apparent contradiction supports the use of small molecules to inhibit HSD17B13 but keep the protein available to support autophagic activity. Autophagy is important to maintaining a killer T cell response and use the body’s own immune system to fight the tumor. By inhibiting HSD17B13, the surrounding tissue will be capable of killer T cell response due to effective autophagy.

[0091] HSD17B13 is highly expressed in normal gallbladder. Inactive HSD17B13 is associated with increased phospotidylcholine which is essential for sequestering cytotoxic bile acids for excretion and bile flow. For these reasons and the additional improved killer T cell response and decreased inflammation and fibrosis are the mechanism by which an inhibitor of HSD17B13 can be used to treat cholangioadenoma and gallbladder adenocarcinoma.

[0092] In some embodiments, the malignancy is hepatocellular carcinoma (HCC). In some embodiments, the malignancy is cholangioadenoma. In some embodiments, the malignancy is cholangiocarcinoma. In some embodiments, the malignancy is gallbladder adenocarcinoma. In some embodiments, the HSD17B13 receptor is expressed in the peritumoral space.

Hemochromatosis

[0093] A method of treating or preventing hemochromatosis in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the hemochromatosis is primary hemochromatosis. In some embodiments, the hemochromatosis is secondary hemochromatosis. In some embodiments, the hemochromatosis is caused by a liver disease. In some embodiments, the hemochromatosis is drug-induced hemochromatosis.

Lysosomal acid lipase deficiency (LAL-D)

[0094] Disclosed herein is a method of treating or preventing lysosomal acid lipase deficiency (LAL-D) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene. In some embodiments, the lysosomal acid lipase deficiency (LAL- D) causes Wolman disease. In some embodiments, the lysosomal acid lipase deficiency (LAL- D) causes Cholesteryl ester storage disease. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) causes a buildup of fatty substances in the body's cells and tissues.

[0095] In some embodiments, the disease to be treated by inhibition of hydroxy steroid 17-beta dehydrogenase 13 (HSD17B13) is listed in table 1. Table 1

Dosing

[0096] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.

[0097] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition. In one aspect, prophylactic treatments include administering to a mammal having patatin-like phospholipase domaincontaining 3 (PNPLA3) polymorphism, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent liver damages. The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3), a protein is expressed in the liver and is involved in lipid metabolism, has recently been identified as a major determinant of liver fat content. Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis, and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis and primary sclerosing cholangitis. In some embodiments, PNPLA3 polymorphism is used to predict liver disease progression. [0098] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0099] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (z.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[00100] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.

[00101] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[00102] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00103] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner

[00104] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LDw and the ED90. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD10 and ED90. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[00105] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.

[00106] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

[00107] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Routes of Administration

[00108] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. [00109] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

Pharmaceutical Compositions/F ormulat ions

[00110] The compounds described herein are administered to to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of this invention may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[00111] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, lohn E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[00112] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.

[00113] The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, selfemulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00114] Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[00115] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [00116] Pharmaceutical compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols In some embodiments, stabilizers are added.

[00117] Pharmaceutical compositions for parental use are formulated as infusions or injections. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and any combinations thereof thereof. In some embodiments, the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.

Combination

[00118] Disclosed herein are method of treating a liver disease, metabolic disease, or cardiovascular disease using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[00119] In some embodiments, the additional therapeutic agent is used for the treatment of diabetes or diabetes related disorder or conditions.

[00120] In some instances, the additional therapeutic agent comprises a statin, an insulin sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a GLP agonist, a GIP agonist, a THR beta agonist, a PDE inhibitor, a DPP-4 inhibitor (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, anaglptin, teneligliptin, alogliptin, gemiglptin, or dutoglpitin), a catecholamine (such as epinephrine, norepinephrine, or dopamine), peroxisome proliferator- activated receptor (PPAR)-gamma agonist (e.g., a thiazolidinedione (TZD) [such as pioglitazone, rosiglitazone, rivoglitazone, or troglitazone], aleglitazar, farglitazar, muraglitazar, or tesaglitazar), peroxisome proliferator-activated receptor (PPAR)-alpha agonist, peroxisome proliferator-activated receptor (PPAR)-delta agonist, a farnesoid X receptor (FXR) agonist (e.g., obeticholic acid), or a combination thereof. In some cases, the statin is a HMG-CoA reductase inhibitor. In other instances, additional therapeutic agents include fish oil, fibrate, vitamins such as niacin, retinoic acid (e.g., 9 cis-retinoic acid), nicotinamide ribonucleoside or its analogs thereof, or combinations thereof. In other instances, additional therapeutic agents include ACC inhibitors, FGF19 and FGF21 mimics, CCR2/CCR5 antagonists, or combinations thereof. [00121] In some embodiments, the additional therapeutic agent is vivitrol.

[00122] In some embodiments, the additional therapeutic agent is a statin such as a HMG-CoA reductase inhibitor, fish oil, fibrate, niacin or a combination thereof. In other instances, the additional therapeutic agent is a dyslipidemia drug that prevent lipid absorption such as orlistat. [00123] In some embodiments, the additional therapeutic agent is a vitamin such as retinoic acid or tocopheryl acetate for the treatment of diabetes and diabetes related disorder or condition such as lowering elevated body weight and/or lowering elevated blood glucose from food intake. [00124] In some embodiments, the additional therapeutic agent is a glucose-lowering agent. In some embodiments, the additional therapeutic agent is an anti-obesity agent. In some embodiments, the additional therapeutic agent is selected from among a peroxisome proliferator activated receptor (PPAR) agonist (gamma, dual, or pan), a dipeptidyl peptidase (IV) inhibitor, a glucagon-like peptide-1 (GLP-I) analog, insulin or an insulin analog, an insulin secretagogue, a sodium glucose co-transporter 2 (SGLT2) inhibitor, a glucophage, a human amylin analog, a biguanide, an alpha-glucosidase inhibitor, a meglitinide, a thiazolidinedione, and sulfonylurea. In some embodiments, the additional therapeutic agent is metformin, sitagliptin, saxaglitpin, repaglinide, nateglinide, exenatide, liraglutide, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin isophane, and glucagon-like peptide 1, or any combination thereof. In some embodiments, the additional therapeutic agent is a lipid-lowering agent.

[00125] In some embodiments, the additional therapeutic agent is an antioxidant, corticosteroid such as budesonide, anti-tumor necrosis factor (TNF), or a combination thereof.

[00126] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating or preventing a cholestatic disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

2. The method of claim 1, wherein the cholestatic disease is primary sclerosis cholangitis (PSC), primary biliary cholangitis (PBC), Alagille Syndrome, biliary atresia, liver injury in a cystic fibrosis patient, progressive familial intrahepatic cholestasis (PFIC), intrahepatic cholestasis of pregnancy; drug-induced cholestasis, AIDS cholangiopathy, IG4-associated cholangitis, biliary stricture, or low phospholipid- associated cholestasis.

3. The method of claim 1 or 2, wherein the cholestatic disease is primary sclerosis cholangitis (PSC).

4. The method of claim 3, wherein the PSC is accompanied by inflammatory bowel disease (IBD).

5. The method of claim 3, wherein the PSC is accompanied by elevated levels of lipopolysaccharide (LPS) (endotoxemia).

6. The method of claim 5, wherein the elevated levels of LPS is in the blood.

7. The method of claim 5, wherein the elevated levels of LPS is in the liver.

8. The method of claim 5, wherein the elevated levels of LPS is in the biliary tree.

9. The method of claim 1 or 2, wherein the cholestatic disease is primary biliary cholangitis

(PBC).

10. The method of claim 1 or 2, wherein the cholestatic disease is Alagille Syndrome.

11. The method of claim 1 or 2, wherein the cholestatic disease is biliary atresia.

12. The method of claim 1 or 2, wherein the cholestatic disease is liver injury in a cystic fibrosis patient.

13. The method of claim 1 or 2, wherein the cholestatic disease is progressive familial intrahepatic cholestasis (PFIC)

14. The method of claim 13, wherein the PFIC is PFIC-3 type.

15. The method of any one of claims 1-14, wherein the cholestatic disease is treated or prevented by improving bile flow in the subject in need thereof.

- 32 - The method of any one of claims 1-15, wherein the cholestatic disease is treated or prevented by improving cholesterol secretion out of the liver in the subject in need thereof. A method of treating or preventing liver injury due to protein accumulation in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. The method of claim 17, wherein the protein accumulation is cleared via autophagy. The method of claim 17 or 18, wherein the protein is a misfolded protein. The method of any one of claims 17-19, wherein the liver injury is due to alpha 1- antitrypsin deficiency. The method of claim 20, wherein the liver disease associated with alpha 1 -antitrypsin deficiency include inflammation. The method of claim 20, wherein the liver disease associated with alpha 1 -antitrypsin deficiency include decreases in platelets. A method of improving autophagy in a subj ect in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. The method of claim 23, wherein the autophagy eliminates accumulated protein in the liver. The method of claim 24, wherein the protein is a misfolded protein. A method of treating or preventing a viral infection-induced liver injury in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxy steroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. The method of claim 26, wherein the viral infection is SARS-Cov-2. The method of claim 26, wherein the viral infection is hepatitis A. The method of claim 26, wherein the viral infection is hepatitis B. The method of claim 26, wherein the viral infection is hepatitis C. The method of any one of claims 26-30, wherein the viral infection is associated with a dysregulated liver inflammatory response.

- 33 - The method of any one of claims 26-31, wherein the administration results in lowering the levels of immune response activation genes. The method of any one of claims 26-32, wherein the administration results in decreased inflammation. The method of any one of claims 26-33, wherein the subject in need thereof has elevated levels of alanine aminotransferase (ALT). The method of any one of claims 26-34, wherein the subject in need thereof has elevated levels of aspartate aminotransferase (AST). The method of any one of claims 26-35, wherein the subject in need thereof has decreased levels of albumin. A method of decreasing the severity of inflammation in a subject with a viral infection, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. A method of decreasing the severity of acute immune response in a subject with a viral infection, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. The method of claim 37 or 38, wherein the viral infection is SARS-Cov-2. The method of claim 37 or 38, wherein the viral infection is hepatitis A. The method of claim 37 or 38, wherein the viral infection is hepatitis B. The method of claim 37 or 38, wherein the viral infection is hepatitis C. The method of any one of claims 37-42, wherein the viral infection is associated with a dysregulated liver inflammatory response. The method of any one of claims 37-43, wherein the administration results in lowering the levels of immune response activation genes. The method of any one of claims 37-44, wherein the administration results in decreased inflammation. The method of any one of claims 37-45, wherein the subject in need thereof has elevated levels of alanine aminotransferase (ALT). The method of any one of claims 37-46, wherein the subject in need thereof has elevated levels of aspartate aminotransferase (AST). The method of any one of claims 37-47, wherein the subject in need thereof has decreased levels of albumin. A method of treating or preventing a malignancy selected from hepatocellular carcinoma (HCC), cholangioadenoma, cholangiocarcinoma, gallbladder adenocarcinoma, and malignancy of bile duct, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. The method of claim 49, wherein the malignancy is hepatocellular carcinoma (HCC). The method of claim 49, wherein the malignancy is cholangioadenoma. The method of claim 49, wherein the malignancy is cholangiocarcinoma. The method of claim 49, wherein the malignancy is gallbladder adenocarcinoma. The method of any one of claims 49-53, wherein the HSD17B13 receptor is expressed in the peritumoral space. A method of treating or preventing hemochromatosis in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. The method of claim 55, wherein the hemochromatosis is primary hemochromatosis. The method of claim 55, wherein the hemochromatosis is secondary hemochromatosis. The method of claim 55, wherein the hemochromatosis is caused by a liver disease. The method of claim 55, wherein the hemochromatosis is drug-induced hemochromatosi s . A method of treating or preventing lysosomal acid lipase deficiency (LAL-D) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. The method of claim 60, wherein the lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene. The method of claim 60, wherein the lysosomal acid lipase deficiency (LAL-D) causes Wolman disease. The method of claim 60, wherein the lysosomal acid lipase deficiency (LAL-D) causes Cholesteryl ester storage disease. The method of claim 60, wherein the lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene. The method of claim 60, wherein the lysosomal acid lipase deficiency (LAL-D) causes a buildup of fatty substances in the body's cells and tissues. The method of any one of claims 1-65, wherein the HSD17B13 inhibitor is a small molecule compound. The method of any one of claims 1-65, wherein the HSD17B13 inhibitor i

The method of any one of claims 1-65, wherein the HSD17B13 inhibitor comprises an estradiol mimetic, an anti-HSD17B13 antibody or antibody fragment, an oligonucleotide directed against an HSD17B13 encoding oligonucleotide, an antisense oligonucleotide, an RNAi, or an siRNA. The method of any of one of claims 1-68, wherein the subject is a mammal. The method of claim 69, wherein the subject is a human.