WO2025014777A1 - Inhibition of clic1 to treat obesity and heart failure - Google Patents

Abstract

The present disclosure provides methods for treating obesity-related heart failure in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor. The present disclosure also provides methods for treating weightrelated hypertension in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor.

Description

COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO INHIBITION OF CLIC1 TO TREAT OBESITY AND HEART FAILURE CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 63/512,514, filed on July 7, 2023, which is incorporated by reference herein in its entirety. TECHNICAL FIELD [0002] The present disclosure relates to methods for treating obesity-related heart failure and weight-related hypertension as well as other Clic1-related indications. BACKGROUND [0003] Excess adiposity (body fat) is a major risk factor for cardiovascular disease. Obesity is associated with an elevated risk of heart failure, which can be phenotypically classified as heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, or heart failure with mildly reduced ejection fraction. Excess adiposity, in the form of overweight or obesity, is also associated with an elevated risk of hypertension. [0004] Excess adiposity promotes changes in the myocardium and vasculature, as well as through comorbidities. For example, excess adipose tissue leads to higher blood volume, in part due to elevated renal sodium retention. Excess adipose tissue also leads to higher blood pressure (hypertension) due to activation of the renin-angiotensin- aldosterone and sympathetic nervous systems. Further, many overweight or obese individuals suffer from at least one comorbidity such as dyslipidemia, glucose intolerance, or diabetes mellitus. [0005] There is a need for new methods to treat obesity-related heart failure, weight- related hypertension, and other Clic1-related indications. SUMMARY [0006] The present disclosure provides methods for treating obesity-related heart failure, weight-related hypertension, and other Clic1-related indications in a subject, COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO wherein the method comprises administering a chloride intracellular channel 1 (Clic1) inhibitor. [0007] In some embodiments, the present disclosure provides methods for treating obesity-related heart failure in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor. In some embodiments, the obesity- related heart failure is obesity-related heart failure with preserved ejection fraction. In some embodiments, the obesity-related heart failure is obesity-related heart failure with reduced ejection fraction. In some embodiments, the obesity-related heart failure is obesity-related heart failure with mildly reduced ejection fraction. In some embodiments, the obesity-related heart failure is diabetic cardiomyopathy. [0008] In some embodiments, the present disclosure provides methods of treating weight-related hypertension in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor. [0009] In some embodiments, the present disclosure provides methods of treating uncomplicated obesity, inflammation, neurodegeneration, or cancer, comprising administering to the subject an effective amount of a Clic1 inhibitor. [0010] In some embodiments, the Clic1 inhibitor has an IC50 for Clic1 of about 0.1 μM to about 250 μM. In some embodiments, the Clic1 inhibitor has an IC50 for Clic1 of about 5 μM to about 25 μM. In some embodiments, the Clic1 inhibitor is an organic molecule with a molecular weight of less than 500 g/mol. [0011] In some embodiments, the Clic1 inhibitor is IAA94, indacrinone, IAA-23, DCPIB, DIOA, ethacrynic acid (EA), anthracene-9-carboxylic acid (A9C), 5-nitro-2- (3-phenylpropylamino)-benozoic acid (NPPB), TS-TM-calix[4]arene, DNDS, DIDS, or a combination thereof:

COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO

[0012] In some embodiments, the Clic1 inhibitor is A, B, C, D, or E, or a combination thereof, of Formula 1:

[0013] In some embodiments, the Clic1 inhibitor is (-) IAA94, (+) IAA94, (-) indacrinone, (+) indacrinone, (-) p-OH-indacrinone, (+) p-OH-indacrinone, (-) p- fluoroindacrinone, (+) p-fluoroindacrinone, or combination thereof: COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO (+) indacrinone, (-) indacrinone,

(-) p-OH- p- or

COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO [0015] In some embodiments, the Clic1 inhibitor is thereof.

[0016] In some embodiments, the Clic1 inhibitor is:

, or a stereoisomer thereof. [0017] In some embodiments, the Clic1 inhibitor is administered to the subject orally or parenterally. In some embodiments, the Clic1 inhibitor provides a Cmax ranging from about 2 μg/ml to about 100 μg/ml. [0018] In some embodiments, the effective amount of the Clic1 inhibitor is about 0.1 mg to about 1000 mg per day. In some embodiments, the effective amount of the Clic1 inhibitor is about 0.5 mg/kg to about 5 mg/kg mg per day. In some embodiments, the effective amount of the Clic1 inhibitor is about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, or about 5.0 mg/kg per day. [0019] In some embodiments, the Clic1 inhibitor comprises a racemic mixture of IAA94, a racemic mixture of indacrinone, or a racemic mixture of p-OH indacrinone, and is administered to the subject in an amount of at least 10 mg per day. In some embodiments, the Clic1 inhibitor is (-) IAA94, (-) indacrinone, or (-) p-OH indacrinone, and is administered to the subject in an amount of at least 5 mg per day. In some embodiments, the Clic1 inhibitor is (-) indacrinone. In some embodiments, the Clic1 COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO inhibitor is (+) IAA94, (+), indacrinone, or (+) p-OH indacrinone, and is administered to the subject in an amount of at least 5 mg per day. [0020] In some embodiments, the Clic1 inhibitor comprises a mixture comprises an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) IAA94, or an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) indacrinone, or an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) p-OH indacrinone. In some embodiments, the Clic1 inhibitor comprises a mixture comprising an enantiomeric excess of >90%, >92%, >95%, or >99% of (-) indacrinone. [0021] In some embodiments, the Clic1 inhibitor is administered once or twice per day. In some embodiments, the Clic1 inhibitor is administered for at least about 3 months, at least about 4 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, or at least about 24 months. [0022] In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an incretin or an incretin mimetic. In some embodiments, the incretin or incretin mimetic is a glucagon-like peptide receptor (GLP-1R) agonist, a glucose-dependent insulinotropic polypeptide receptor GIPR) agonist, an amylin receptor agonist, a GLP- 1R/GIPR dual agonist, or a combination thereof. In some embodiments, the GLP-1R agonist is semaglutide or liraglutide. In some embodiments, the GLP-1R/GIPR dual agonist is tirzepatide. In some embodiments, the GLP-1R/amylin receptor dual agonist is amycretin. In some embodiments, the additional therapeutic agent is a glucagon receptor (GcGR) agonist or a GLP-1R/GIPR/GcGR triple agonist. In some embodiments, the GLP-1R/GIPR/GcGR triple agonist is retatrutide. In some embodiments, the additional therapeutic agent is cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), oxyntomodulin (OXM), amylin, or a combination thereof. In some embodiments, the additional therapeutic agent is an anti-GIPR antibody. In some embodiments, the anti-GIPR antibody is conjugated to a GLP-1 analogue. [0023] In some embodiments, the Clic1 inhibitor is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an incretin COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO or an incretin mimetic. In some embodiments, the incretin or incretin mimetic is a GLP- 1R agonist, a GIPR agonist, an amylin receptor agonist, a GLP-1R/GIPR dual agonist, or a combination thereof. In some embodiments, the GLP-1R agonist is semaglutide or liraglutide. In some embodiments, the GLP-1R/GIPR dual agonist is tirzepatide. In some embodiments, the GLP-1R/amylin receptor dual agonist is amycretin. In some embodiments, the additional therapeutic agent is a GcGR agonist or a GLP- 1R/GIPR/GcGR triple agonist. In some embodiments, the GLP-1R/GIPR/GcGR triple agonist is retatrutide. In some embodiments, the additional therapeutic agent is cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), oxyntomodulin (OXM), amylin, or a combination thereof. In some embodiments, the additional therapeutic agent comprises an antibody. In some embodiments, the antibody is an anti-GIPR antibody. In some embodiments, the anti-GIPR antibody is conjugated to a GLP-1 analogue. [0024] In some embodiments, the method reduces the subject’s food intake by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after starting treatment. [0025] In some embodiments, the method reduces the subject’s body weight by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, or at least about 20%, at least about 25%, or at least about 30%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0026] In some embodiments, the method reduces the subject’s systolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least 17%, at least 20%, or at least 25% within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0027] In some embodiments, the method reduces the subject’s diastolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0028] In some embodiments, the method: (i) reduces the subject’s body weight by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 17%, at least about 20%, at least about 25%, or at least about 30%; (ii) reduces the subject’s systolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least 17%, at least 20%, or at least 25%; and (iii) reduces the subject’s diastolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%; within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO [0029] In some embodiments, the method causes diuresis in the subject, as measured in urinary volume in mL collected over the course of about 1 hour, about 2 hours, about 4 hours, about 8 hours, or about 24 hours, wherein the subject’s urinary volume is increased by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 140%, at least about 160%, at least about 180%, or at least about 200%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0030] In some embodiments, the method does not cause diuresis in the subject, as measured in urinary volume in mL collected over the course of about 1 hour, about 2 hours, about 4 hours, about 8 hours, or about 24 hours, wherein the subject’s urinary volume is increased by less than about 50%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0031] In some embodiments, the method leads to glucose control in the subject, as measured by one or more of the following: (i) blood glucose levels ranging from 70-130 mg/dL in a fasted state; or (ii) blood glucose levels ranging from 70-180 mg/dL in a fed state; or (iii) glycated hemoglobin (HBA1c) of less than about 7%. [0032] In some embodiments, the method increases the subject’s lean body mass by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10%. [0033] In some embodiments, the subject is a human. In some embodiments, the subject has a metabolic syndrome. In some embodiments, the subject has Type 2 diabetes. In some embodiments, the subject has experienced weight gain following treatment with an antipsychotic. In some embodiments, the antipsychotic is clozapine, olanzapine, quetiapine, risperidone, aripiprazole, or ziprasidone. In some embodiments, the subject has a binge eating disorder. In some embodiments, the subject has Prader Willi Syndrome. In some embodiments, the subject has pre-diabetes. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO BRIEF DESCRIPTION OF THE DRAWINGS [0034] FIGS. 1A-1D show IAA94-mediated inhibition of fasting-induced refeeding and binge eating. FIG. 1A shows a schematic of the fasting-induced refeeding experiment, in which mice were fasted for 23 hours, then administered either R(+)- IAA94 (50 mg/kg IP) or vehicle control (Veh) and re-fed. FIG. 1B shows food intake measured post-IAA94 or -vehicle treatment, for a period of 1 hour. *p < 0.05. FIG.1C shows a schematic of the binge eating experiment, in which mice were exposed to a high-fat diet (HFD) intermittently (I), compared with continuous access (C) to HFD, and were administered either R(+)-IAA94 or vehicle control 1 hour prior to the intermittent HFD exposure. Mice who received intermittent HFD received normal chow (NC) prior to HFD exposure. FIG. 1D shows food intake was measured from 1 hour post-IAA94 or -vehicle treatment, for a period of 2.5 hours. *p < 0.05, one-way ANOVA followed by Two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli with 0.05 FDR. [0035] FIGS. 2A-2B show that IAA94-mediated inhibition of binge eating is mediated by Clic1. Male (FIG 2A) WT mice and (FIG.2B) Clic1 KO mice were fasted for 23 hours and then injected once with R(+)-IAA94 (10mg/kg) or vehicle before being re-fed with normal chow. Then, food intake was measured 24 hours after re-feeding (n=9-10/group). *p < 0.05, two-way ANOVA. [0036] FIGS. 3A-3E show that IAA94 treatment reduces food intake and induces weight loss in one week. Obese WT mice were administered vehicle control (VEH, black bars with circles) or R(+)-IAA94 (gray bars with squares) and provided access to normal chow. FIG. 3A shows food intake per day, FIG. 3B shows change in body weight in grams (g), and (FIGS.3C-3E) show blood levels of insulin (ng/ml), glucose (mg/dl), and free fatty acids (FFAs, mmol/L) on day 7. * p< 0.05. [0037] FIGs. 4A-4D show that IAA94 treatment reduces food intake and induces weight loss over 3 weeks. Obese WT mice were administered vehicle control (VEH, black with circles) or R(+)-IAA94 at either a low dose (LD, 10mg/kg, light gray with squares) or a high dose (HD, 50mg/kg, dark gray with triangles) and provided access to normal chow. FIG 4A shows percent weight loss, FIG 4B shows change in body weight in grams (g), FIG 4C shows average daily food intake in grams, and FIG 4D shows energy expenditure in kcal/kg. * p< 0.05. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO [0038] FIGS. 5A-5H show the whole-body phenotype of a Clic1 knockout (KO) mouse. Food intake and body weight in normal chow fed mice were studied. FIGS. 5A-5H show average daily food intake in grams (FIG. 5A), body weight in grams (FIG. 5B), food intake in grams, in the context of a food novelty test in which mice were administered 45% HFD for 20 min per day (FIG. 5C), energy expenditure in kcal/kg (FIG. 5D), respiratory quotient (FIG. 5E), average percentage lean mass and fat mass (FIG. 5F), glucose tolerance in mg/dl (FIG. 5G), and glucose-stimulated insulin levels in ng/ml (FIG. 5H), for WT (white with circles) and Clic1 KO (black with squares) mice. FIGS. 5A-5F n=7-8/group, *p < 0.05 Students t-test. FIGS. 5G- 5H n=7/group, *p < 0.05, two-way ANOVA followed by Two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli with 0.05 FDR. [0039] FIGS.6A-6H show another study on chronic IAA94 treatment. Diet-induced obese mice (fed a high fat diet for 6 weeks) received daily injections of either i) vehicle (black with circles); ii) R(+)-IAA94 - 10 mg/kg (gray with squares); iii) R(+)-IAA94 - 50 mg/kg (dark gray with triangles pointing up); iv) the GLP-1 agonist Liraglutide (Lira, black with triangles pointing down); or v) combination of Lira + IAA94 (50 mg/kg, diagonal stripes with diamonds). Daily food intake and body weight were monitored. Sacrifices were performed after 23 days. FIGS. 6A-6C show the effect of IAA94, Lira, or IAA94 + Lira on average daily food intake in grams (FIG. 6A), body weight in grams (FIG.6b), and weight loss in grams (FIG.6C), respectively. Chronic treatment with IAA94 results in significant weight loss. At day 18, the most significant weight loss was seen in Lira + IAA94 (50 mg/kg), IAA94 (50 mg/kg), Lira, IAA94 (10 mg/kg), and vehicle respectively. FIGS. 6D-6H show the effect of IAA94, Lira, or IAA94 + Lira on energy expenditure in kcal/kg (FIG. 6D), activity as measured by distance traveled in meters (m) (FIG. 6E), respiratory quotient (FIG. 6F), glucose tolerance in mg/dl (FIG. 6G), and glucose area under the curve in mg/dl – min (FIG. 6H). Vehicle (n=9), IAA9450mg/kg (n= 8), IAA9410mg/kg (n=7), Lira (n=6), combo [IAA94 50mg/kg + Lira] (n=6). FIGS. 6A, 6C-6F, 6H *p< 0.05 One-way ANOVA followed by Two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli with 0.05 FDR. [0040] FIGS.7A-7C show that IAA94 treatment reduces food intake and weight gain in high-fat diet fed Magel2 KO mice with hyperphagia, a model of Prader Willi Syndrome. FIG. 7A shows average daily food intake in grams (g), FIG. 7B shows COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO weight change in grams, and FIG.7C shows epididymal white adipose tissue (eWAT) weight in grams, of Magel2 WT mice that were treated with either vehicle (black with circles) or R(+)-IAA94 (10 mg/kg, gray with squares) and null mice that were treated with either vehicle (white with triangles pointing up) or R(+)-IAA94 (10 mg/kg, white with triangles pointing down), n=4-5 per group. * p< 0.05 One-way ANOVA followed by Two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli with 0.05 FDR. [0041] FIGS.8A-8B show pharmacokinetic data following oral administration of R- indacrinone (30 mg/kg) or S- indacrinone (50 mg/kg) to mice. Serum levels of and R- indacrinone (FIG. 8A) and S-indacrinone (FIG. 8B) are shown. FIG. 8C shows the effect of R-indacrinone (30 mg/kg, black) and S-indacrinone (50 mg/kg, white) compared to R-IAA94 (50 mg/kg, light gray) and vehicle (dark gray) on food intake in mice fasted for 24 hours, administered compound or vehicle, and then re-fed. [0042] FIG. 9A shows weight loss in diet-induced obese mice administered R- indacrinone at a low dose (10 mg/kg) or medium dose (20 mg/kg), S-indacrinone at a high dose (50 mg/kg), or vehicle (VEH). FIGS.9B-9C show the dose-dependent effect of R-indacrinone on food intake in diet-induced obese mice. [0043] FIGS. 10A-10B show inguinal fat weight (FIG. 10A) and epididymal fat weight (FIG. 10B) in diet-induced obese mice that were administered a low dose (10 mg/kg) or medium dose (20 mg/kg) of R-indacrinone, a high-dose (50 mg/kg) of S- indacrinone, or vehicle (VEH). [0044] FIGS. 11A and 11B show percent weight loss (FIG. 11A) and food intake (FIG. 11B) in diet-induced obese mice administered R-indacrinone for 7 days then weighed daily after cessation of R-indacrinone administration. Food intake was measured for 24 hours during R-indacrinone treatment (R-Inda) and after cessation of treatment (Recovery). [0045] FIGS. 12A shows binding to Clic1 protein by R-indacrinone compared with S-indacrinone. FIGS. 12B and 12C show the diuretic activity of R-indacrinone compared to vehicle only (Veh), measured by urine output in grams (g) (FIG.12B) and by sodium (NA) excretion in mmol (FIG.12C) in Sprague-Dawley rats at 2 hours after administration of R-indacrinone or vehicle. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO DETAILED DESCRIPTION [0046] The present disclosure provides methods for treating obesity-related heart failure and weight-related hypertension in a subject, wherein the methods comprise administering a chloride intracellular channel 1 (Clic1) inhibitor. Definitions: [0047] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. [0048] All references cited herein are incorporated by reference to the same extent as if each individual publication, patent application, or patent, was specifically and individually indicated to be incorporated by reference. [0049] The term “a” or “an” refers to one or more of that entity, i.e., can refer to a plural referent. As such, the terms “a” or “an”, and “one or more” are used interchangeably herein. In addition, reference to “an element” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there is one and only one of the elements. [0050] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. [0051] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, or the method being employed to COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO determine the value, or the variation that exists among the samples being measured. In some embodiments, the term “about” means within 5% of the reported numerical value. When used in conjunction with a range or series of values, the term “about” applies to the endpoints of the range or each of the values enumerated in the series, unless otherwise indicated. [0052] A “subject” is a living animal, particularly a mammal, which can be treated with a pharmaceutical composition described herein. In some embodiments, the subject is a human. In some embodiments, the human subject is a human child, a human teenager, or a human adult. In some embodiments, the subject is a non-human animal, including research animals such as a mouse, a rat, a pig, a dog, a rabbit, a monkey or other non-human primate, or a goat. [0053] “Dose” as used herein refers to an amount of a formulation that is administered to a patient and contains a therapeutically effective amount of a Clic1 inhibitor. For example, a dose may be one tablet or one capsule containing a formulation disclosed herein. [0054] “Treating” and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, reduction in likelihood of the occurrence of symptoms and/or underlying cause, and improvement or remediation of damage. Thus, “treating” a patient with a therapeutic agent as provided herein includes inhibiting a particular condition, disease or disorder in a susceptible individual as well as treatment of a clinically symptomatic individual. The term “treat” can also include treatment of a cell in vitro or an animal model. [0055] As used herein, “therapeutically effective amount” refers to an amount that is effective to achieve the desired therapeutic result. A therapeutically effective amount of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the patient. [0056] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, molecular biology techniques), microbiology, biochemistry and immunology, which are within the scope of those of skill in the art. Such techniques are explained fully in the literature, such as, "Molecular Cloning: A Laboratory Manual", second edition (Sambrook et al., 1989); "Oligonucleotide COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO Synthesis" (M. J. Gait, ed., 1984); "Animal Cell Culture" (R. I. Freshney, ed., 1987); "Methods in Enzymology" (Academic Press, Inc.); "Handbook of Experimental Immunology" (D. M. Weir & C. C. Blackwell, eds.); "Gene Transfer Vectors for Mammalian Cells" (J. M. Miller & M. P. Calos, eds., 1987); "Current Protocols in Molecular Biology" (F. M. Ausubel et al., eds., 1987); "PCR: The Polymerase Chain Reaction", (Mullis et al., eds., 1994); and "Current Protocols in Immunology" (J. E. Coligan et al., eds., 1991), each of which is expressly incorporated by reference herein. [0057] Several aspects of the invention are described below with reference to example applications for illustration. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the invention. One having ordinary skill in the relevant art, however, will readily recognize that the invention can be practiced without one or more of the specific details or with other methods. The present invention is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and/or concurrently with other acts or events. Furthermore, not all illustrated acts or events are required to implement a methodology in accordance with the present invention. Excess adiposity and cardiovascular disease [0058] The present disclosure provides methods of treating obesity-related heart failure, comprising administering to the subject an effective amount of a Clic1 inhibitor. The present disclosure further provides methods of treating weight-related hypertension, comprising administering to the subject an effective amount of a Clic1 inhibitor. [0059] Excess adiposity (body fat), including excess weight and obesity, is a major risk factor for cardiovascular disease. As used herein, “excess weight or weight-related” refers to a condition in which the body mass index (BMI) of a subject is 25 to 30. As used herein “obesity” refers to a condition in which the BMI of a subject is at least 30. As used herein, “BMI” is defined as the body mass of a subject in kilograms (kg) divided by the square of the body height in meters (m) and is expressed in units of kg/m². [0060] Obesity is associated with an elevated risk of heart failure. As used herein, “heart failure” refers to any condition characterized by either (a) abnormally low COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO cardiac output in which the heart is unable to pump blood at an adequate rate or in adequate volume, or (b) relatively normal or only slightly reduced cardiac output, but abnormally high diastolic filling pressures. [0061] Heart failure can be phenotypically classified as heart failure with reduced ejection fraction or heart failure with preserved ejection fraction. As used herein “ejection fraction” refers to a measurement, expressed as a percentage, of how much blood the left ventricle pumps out with each contraction. As used herein, the term “preserved ejection fraction” is understood to mean an ejection fraction of at least about 50%. Heart failure with preserved ejection fraction is a form of heart failure with abnormally high diastolic filing pressures. In some embodiments, a preserved ejection fraction may be between about 50% and about 70%. As used herein, the term “reduced ejection fraction” is understood to mean an ejection fraction of less than about 40%. Heart failure with an ejection fraction of 40 to 50% is referred to as “mid-range,” “borderline,” or “mildly reduced” ejection fraction. In some embodiments, the obesity- related heart failure is heart failure with reduced rejection faction. In some embodiments, the obesity-related heart failure is heart failure with preserved rejection faction. In some embodiments, the obesity-related heart failure is heart failure with mildly reduced rejection faction. [0062] As used herein, the term “obesity-related heart failure” can also include heart failure with diabetic cardiomyopathy. Diabetic cardiomyopathy can be characterized by both heart failure with preserved ejection fraction and also heart failure with reduced ejection fraction. It is generally associated with obesity and type II diabetic related inflammation of the cardiac muscle tissue that leads to abnormal contractility and ventricular stiffness. This inflammation may be mediated by increased inflammasome activity, which can be reduced by Clic1 inhibition. [0063] Excess adiposity, in the form of excess weight or obesity, is also associated with an elevated risk of hypertension. As used herein, hypertension refers to systolic blood pressure ^130 mmௗHg and diastolic blood pressure ^80 mmௗHg. Excess adiposity promotes changes in the myocardium and vasculature, as well as through comorbidities. For example, excess adipose tissue leads to higher blood volume, in part due to elevated renal sodium retention. Excess adipose tissue also leads to higher blood pressure (hypertension) due to activation of the renin-angiotensin-aldosterone and sympathetic COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO nervous systems. Further, many obese individuals suffer from at least one comorbidity such as dyslipidemia, glucose intolerance, or diabetes mellitus. [0064] Disruptions to biological hunger and satiety cues have also been demonstrated in obesity. The hypothalamic arcuate nucleus (ARH) is critical for regulation of food intake and energy balance. Agouti-related peptide AgRP neurons and neuropeptide Y (NPY) neurons of the ARH are activated by signals associated with hunger (e.g., ghrelin) and inhibited by signals associated with satiety (e.g., leptin). The firing rate of NPY neurons in the ARH correlates well with feeding behavior, firing faster in food- deprived mice than in satiated animals. However, in diet-induced obesity, leptin fails to decrease food intake, due to a loss of sensitivity of the ARH neurons. The underlying mechanism for this loss of responsiveness appears to be that, in the context of diet- induced obesity, ARH NPY neurons have an increased firing rate and depolarized membrane potential similar to that of fasted non-obese animals (Baver et al. J. Neurosci.2014; 34:5486-5496). Further, in the context of diet-induced obesity, AgRP neurons show decreased responsiveness to ghrelin and to cholecystokinin, a hormone that inhibits AgRP neurons in response to dietary fat in non-obese subjects (Beutler et al. eLife. 2020; 9:e55909) as well as a loss of GABA-mediated inhibition (Korgan et al. bioRxiv. 2021. doi: 10.1101/2021.05.31.446473). Restoring the responsiveness of AgRP/NPY neurons to hunger and satiety cues, potentially by re-polarization of membrane potential, is a potential therapeutic target. [0065] The present disclosure further provides methods of treating uncomplicated obesity, inflammation, neurodegeneration, or cancer, comprising administering to the subject an effective amount of a Clic1 inhibitor. As used herein, “uncomplicated obesity” refers to obesity in a subject, wherein the subject does not also have hypertension or heart failure. [0066] In some aspects, the present disclosure provides a composition for use in treating or preventing a disease or disorder disclosed herein. In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0067] In some embodiments, the disease or disorder is obesity-related heart failure. In some embodiments, the obesity-related heart failure is obesity-related heart failure with preserved ejection fraction, reduced ejection fraction, or mildly reduced ejection COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO fraction. In some embodiments, the obesity-related heart failure is diabetic cardiomyopathy. In some embodiments, the disease or disorder is weight-related hypertension. In some embodiments, the disease or disorder is obesity, inflammation, neurodegeneration, or cancer. In some embodiments, the composition comprises a Clic1 inhibitor as disclosed herein. Chloride intracellular channel 1 (Clic1) Inhibitors [0068] In obesity, inhibition of NPY/AgRP neurons by GABA is impaired by chloride dysregulation. Clic1 increases intracellular chloride, which likely abolishes GABA inhibition. Notably, expression and membrane localization of Clic1 is increased in NPY/AgRP neurons in diet-induced obesity. Increasing chloride permeability can also depolarize the resting membrane potential, increasing nerve activity. [0069] Inhibition of Clic1 with indacrinone has a diuretic effect (Irvin JD Pharmacol Ther.1980: 28(3):376-383). During treatment with indacrinone for diuresis, a reduction in blood pressure and a modest effect on weight loss has been observed (Wilhelmensson CE, Br. J. Pharmac.1979: 8, 261-266). The (-) enantiomer of indacrinone has a larger diuretic and natriuretic effect than the (+) enantiomer. Lower doses of the (-) enantiomer in the 1-20 mg range can induce a strong diuretic effect (both natriuresis and water diuresis). The (+) enantiomer can inhibit Clic1 with a substantially weaker diuretic effect. In some embodiments to treat obesity-related heart failure or weight- related hypertension, it may be preferred to have different ratios of the two enantiomers, using the (-) enantiomer to produce diuresis and the (+) enantiomer to produce weight loss. For example, a method wherein the Clic1 inhibitor includes 1-40 mg of the (-) enantiomer and 100-500 mg of the (+) enantiomer may be preferred for treating obesity- related heart failure or weight-related hypertension, while an enantiomerically pure form of the (+) enantiomer may be preferred to treat uncomplicated obesity or other conditions impacted by Clic1 inhibition. [0070] The present disclosure provides inhibitors of Clic1 used in the methods of treating obesity-related heart failure described herein. The present disclosure additionally provides inhibitors of Clic1 used in the methods of treating weight-related hypertension described herein. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO [0071] In some embodiments, the Clic1 inhibitor has an IC50 for Clic1 of about 0.1 μM to about 250 μM. In some embodiments, the Clic1 inhibitor has an IC50 for Clic1 of about 5 μM to about 25 μM. In some embodiments, the Clic1 inhibitor has an IC50 for Clic1 of about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 11 μM, about 12 μM, about 13 μM, about 14 μM, about 15 μM, about 16 μM, about 17 μM, about 18 μM, about 19 μM, about 20 μM, about 21 μM, about 22 μM, about 23 μM, about 24 μM, or about 25 μM. [0072] In some embodiments, the Clic1 inhibitor is an organic molecule with a molecular weight of less than 500 g/mol. or

COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO [0074] In some embodiments, the Clic1 inhibitor is A, B, C, D, or E, or a combination thereof, of Formula 1:

[0075] In some embodiments, the Clic1 inhibitor comprises a racemic mixture of A, B, C, D, or E, or a combination thereof, of Formula 1. In some embodiments, the Clic1 inhibitor comprises a stereoisomer of A. In some embodiments, the Clic1 inhibitor comprises a racemic mixture of A. In some embodiments, the Clic1 inhibitor comprises a stereoisomer of B. In some embodiments, the Clic1 inhibitor comprises a racemic mixture of B. In some embodiments, the Clic1 inhibitor comprises a stereoisomer of C. In some embodiments, the Clic1 inhibitor comprises a racemic mixture of C. In some embodiments, the Clic1 inhibitor comprises a stereoisomer of D. In some embodiments, the Clic1 inhibitor comprises a racemic mixture of D. In some embodiments, the Clic1 inhibitor comprises a stereoisomer of E. In some embodiments, the Clic1 inhibitor comprises a racemic mixture of E. [0076] In some embodiments, the Clic1 inhibitor comprises (+) IAA94, (-) IAA94, (-)indacrinone,

COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO

p- (-) p-OH- indacrinone, (+) p-fluoroindacrinone, or (-) p- fluoroindacrinone. In some embodiments, the Clic1 inhibitor comprises (-) indacrinone. In some embodiments, the Clic1 inhibitor comprises (+) indacrinone. In some embodiments, the Clic1 inhibitor comprises (-) indacrinone and (+) indacrinone. In some embodiments, the Clic1 inhibitor comprises (-) p-OH-indacrinone. In some embodiments, the Clic1 inhibitor comprises (+) p-OH-indacrinone. In some embodiments, the Clic1 inhibitor comprises (-) p-OH-indacrinone and (+) p-OH- indacrinone. In some embodiments, the Clic1 inhibitor comprises (+) p- fluoroindacrinone. In some embodiments, the Clic1 inhibitor comprises (-) p- fluoroindacrinone. In some embodiments, the Clic1 inhibitor comprises (-) p- fluoroindacrinone and (+) p-fluoroindacrinone. [0077] In some embodiments, the Clic1 inhibitor is a compound of Formula 4, 12, or17, as defined below and described in Woltersdorf 1977 J. Med. Chem. (20)11:1400-

In some embodiments wherein the Clic1 inhibitor is a compound of Formula 4, X¹ = Cl, Me, or H; X² = Cl or Me; R = Me, H, Et, n-Pr, i-Pr, n-Bu, s-Bu, t-Bu, or c-C₅H₉; and R² = H or Me. In some embodiments wherein the Clic1 inhibitor is a compound of Formula 4, X¹; X²; R; and R² are defined according to Table 1. Exemplary embodiments of the Clic1 inhibitor that is a compound of Formula 4 include, but are not limited to, 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n, 4o, 4p, 4q, 4r, 4s, and 4t, as defined in Table 1. In some embodiments, the Clic1 inhibitor that is a compound of Formula 4 comprises a stereoisomer of 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n, 4o, 4p, COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 4q, 4r, 4s, or 4t. In some embodiments, the Clic1 inhibitor includes one or more racemic mixtures thereof. Table 1. Embodiments of Clic1 Inhibitors of Formula 4

[0079] In some embodiments, the Clic1 inhibitor is a compound of Formula 12 or 17. In some embodiments wherein the Clic1 inhibitor is a compound of Formula 12 or 17, X¹ = Cl or Me; X² = Cl; R = Me, Et, i-Pr, c-C₅H₉, or —(CH₂)₄—, or —(CH₂)₅—; R¹ = Me, n-Pr, Et, CH₂C₆H₅, CH₂CH=CH, —(CH₂)₄—, or —(CH₂)₅—; and R² = H. In some embodiments wherein the Clic1 inhibitor is a compound of Formula 12 or 17, X¹; X²; R; R¹; and R² are defined according to Table 2. Exemplary embodiments of the Clic1 inhibitor that is a compound of Formula 12 or 17 include, but are not limited to, 12a, 12b, 12c, 12d, 12e, 12f, 12g, 12h, 12i, 17a, and 17b, as defined in Table 2. In some embodiments, the Clic1 inhibitor that is a compound of Formula 12 or 17 comprises a stereoisomer of 12a, 12b, 12c, 12d, 12e, 12f, 12g, 12h, 12i, 17a, or 17b. In some embodiments, the Clic1 inhibitor includes one or more racemic mixtures thereof. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO Table 2. Embodiments of Clic1 Inhibitors of Formula 12 or 17

[0080] In some embodiments, the Clic1 inhibitor comprises

or a stereoisomer thereof. In some embodiments, the Clic1 inhibitor comprises the (-) enantiomer thereof. In some embodiments the Clic1 inhibitor comprises the (+) enantiomer thereof. In some embodiments, the Clic1 inhibitor comprises a racemic mixture thereof. In some embodiments, the Clic1 inhibitor comprises a mixture comprising an enantiomeric excess of the (-) enantiomer of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99%. [0081] In some embodiments, the Clic1 inhibitor comprises ,

[0082] or a stereoisomer thereof. In some embodiments, the Clic1 inhibitor comprises the (-) enantiomer thereof. In some embodiments the Clic1 inhibitor comprises the (+) enantiomer thereof. In some embodiments, the Clic1 inhibitor is indacrinone. In some COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO embodiments, the Clic1 inhibitor is (-) indacrinone. In some embodiments, the Clic1 inhibitor is (+) indacrinone. The (R) enantiomer of indacrinone is equivalent to the (-) enantiomer, and the terms “R-indacrinone” and “(-) indacrinone” are used interchangeably herein. The (S) enantiomer of indacrinone is equivalent to the (+) enantiomer, and the terms “S-indacrinone” and “(+) indacrinone” are used interchangeably herein. In some embodiments, the Clic1 inhibitor comprises a racemic mixture thereof. In some embodiments, the Clic1 inhibitor comprises a mixture comprising an enantiomeric excess of the (-) enantiomer of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99%. In some embodiments, the Clic1 inhibitor comprises a mixture comprising an enantiomeric excess of (-) indacrinone of >90%, >92%, >95%, or >99% of (-) indacrinone. [0083] In some embodiments, the Clic1 inhibitor comprises a combination of one or more of the Clic1 inhibitors described herein. Methods of Treatment [0084] As noted above, the present disclosure provides a method of treating obesity- related heart failure in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor. As noted above, the present disclosure also provides a method of treating weight-related hypertension in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor. In some embodiments, the present disclosure provides said method wherein the Clic1 inhibitor is administered to the subject orally or parenterally. In some embodiments, the method comprises administering the Clic1 inhibitor orally. In some embodiments, the method comprises administering the Clic1 inhibitor parenterally, e.g., intravenously, rectally, or by injection. In some embodiments, the method comprises the Clic1 inhibitor locally, e.g., topically or intramuscularly. In some embodiments, the method comprises administering the Clic1 inhibitor to target tissues. The skilled artisan can determine an appropriate site and route of administration based on factors including, but not limited to, the disease or condition being treated. [0085] The dose and dosage regimen may depend upon a variety of factors readily determined by a physician, such as the nature of the disease or condition, the characteristics of the subject, and the subject's history. In some embodiments, the effective amount of the Clic1 inhibitor is about 0.1 mg to about 1000 mg per day. In COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO certain embodiments the effective amount of the Clic1 inhibitor is about is about 5 mg to about 20 mg per day. In other embodiments, the effective amount of the Clic1 inhibitor is about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg per day. In some embodiments, the effective amount of the Clic1 inhibitor is about 0.5 mg/kg to about 5 mg/kg mg per day. In some embodiments, the effective amount of the Clic1 inhibitor is about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, or about 5.0 mg/kg per day. [0086] In some embodiments, the Clic1 inhibitor comprises a racemic mixture of IAA94, a racemic mixture of indacrinone, or a racemic mixture of p-OH indacrinone and is administered to the subject in an amount of at least 10 mg per day. In some embodiments, the Clic1 inhibitor is (-) IAA94, (-) indacrinone, or (-) p-OH indacrinone and is administered to the subject in an amount of at least 5 mg per day. In some embodiments, the Clic1 inhibitor is (-) indacrinone and is administered to the subject in an amount of at least 5 mg per day. In some embodiments, the Clic1 inhibitor comprises a mixture comprising an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) IAA94, or an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) indacrinone, or an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) p-OH indacrinone, and is administered to the subject in an amount of at least 5 mg per day. In some embodiments, the Clic1 inhibitor comprises a mixture comprising an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92% >95%, or >99% of (+) IAA94, or an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (+) indacrinone, or an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (+) p-OH indacrinone, and is administered to the subject in an amount of at least 5 mg per day. [0087] In some embodiments, the methods comprise administering a Clic1 inhibitor, wherein the Clic1 inhibitor is administered once or twice per day. The skilled artisan COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO can determine an appropriate dosage regimen based on factors including, but not limited to, the nature of the disease or condition, the characteristics of the subject, and the subject's history. [0088] In some embodiments, the Clic1 inhibitor is administered for at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, or at least about 24 months. The skilled artisan can determine an appropriate duration of treatment based on factors including, but not limited to, the nature of the disease or condition, the characteristics of the subject, and the subject's history. Additional Therapeutic Agents [0089] The present disclosure further provides methods of treating obesity-related heart failure and weight-related hypertension, as described herein, wherein the method further comprises providing to the subject an additional therapeutic agent. [0090] In some embodiments, the additional therapeutic agent is an incretin or an incretin mimetic. Incretins are gut hormones that are secreted after ingestion of food. Examples of incretins include, but are not limited to, glucagon-like peptide 1 (GLP-1) agonist and glucose-dependent insulinotropic polypeptide (GIP). [0091] The receptors for GLP-1 and GIP as well as glucagon are members of the family of 7-transmembrane-spanning, heterotrimeric G-protein coupled receptors. They are structurally related to each other and share not only a significant level of sequence identity but have also similar mechanisms of ligand recognition and intracellular signaling pathways. Similarly, the peptides GLP-1, GIP, and glucagon share regions of high sequence identity/similarity. [0092] The receptors for GLP-1 and GIP can also be bound by drugs classified as incretin mimetics. Examples of incretin mimetics include, but are not limited to, GLP- 1 receptor (GLP-1R) agonists and GIP receptor (GIPR) agonists. In some embodiments, the incretin or incretin mimetic is a GLP-1R agonist, a GIPR agonist, an amylin receptor agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/amylin receptor dual agonist, or a combination thereof. Examples of GLP-1R agonists include, but are not limited to, liraglutide, albiglutide, exenatide, lixisenatide, albiglutide, dulaglutide, and COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO semaglutide. In some embodiments, the GLP-1R agonist is semaglutide or liraglutide. In some embodiments, the GLP-1R/GIPR dual agonist is tirzepatide. In some embodiments, the GLP-1R/amylin receptor dual agonist is amycretin. [0093] In some embodiments, the additional therapeutic agent is a glucagon receptor (GcGR) agonist or a GLP-1R/GIPR/GcGR triple agonist. In some embodiments, the GLP-1R/GIPR/GcGR triple agonist is retatrutide. In some embodiments, the additional therapeutic agent is cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), oxyntomodulin (OXM), amylin, or a combination thereof. [0094] In some embodiments, the additional therapeutic agent comprises an antibody. In some embodiments, the antibody is an anti-GIPR antibody. In some embodiments, the anti-GIPR antibody is conjugated to a GLP-1 analogue. Pharmaceutical Compositions [0095] In some embodiments, the Clic1 inhibitor is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. The Clic1 inhibitor, alone or in combination with one or more additional therapeutic agents, can be combined with one or more pharmaceutically acceptable carriers, diluents, excipients, and reagents useful in preparing a formulation that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for mammalian, e.g., human or primate, use. [0096] Examples of carriers, diluents and excipients include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Solutions or suspensions used for the formulations can include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial compounds such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating compounds such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates; detergents such as Tween 20 to prevent aggregation; and compounds for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. In particular embodiments, the pharmaceutical compositions are sterile. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO [0097] Pharmaceutical compositions may further include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). In some embodiments, the composition is sterile and may be fluid such that it can be drawn into a syringe or delivered to a subject from a syringe. The carrier can be, e.g., a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In certain embodiments, the pharmaceutical composition is stable under the conditions of manufacture and storage and is preserved against the contaminating action of microorganisms such as bacteria and fungi. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the internal compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. [0098] Sterile solutions can be prepared by incorporating the Clic1 inhibitor in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the therapeutic agent plus any additional desired ingredient from a previously sterile- filtered solution thereof. [0099] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an incretin or an incretin mimetic. In some embodiments, the incretin or incretin mimic is a GLP-1R agonist, a GIPR agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/amylin COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO receptor dual agonist, or a combination thereof. In some embodiments, the GLP-1R agonist comprises semaglutide or liraglutide. In some embodiments, the GLP-1R/GIPR dual agonist comprises tirzepatide. In some embodiments, the GLP-1R/amylin receptor dual agonist is amycretin. In some embodiments, the additional therapeutic agent is a GcGR agonist or a GLP-1R/GIPR/GcG GcGR triple agonist. In some embodiments, the GLP-1R/GIPR/GcGR triple agonist is retatrutide. In some embodiments, the additional therapeutic agent is cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), oxyntomodulin (OXM), amylin, or a combination thereof. In some embodiments, the additional therapeutic agent comprises an antibody. In some embodiments, the antibody is an anti-GIPR antibody. In some embodiments, the anti-GIPR antibody is conjugated to a GLP-1 analogue. [0100] The skilled artisan can determine suitable components and relative amounts thereof pharmaceutically acceptable carriers, diluents, excipients, and or additional reagents for preparation of a pharmaceutical composition of the one or more Clic1 inhibitors. Effects Following Treatment [0101] Subjects with obesity-related heart failure often also have associated diseases, conditions, or symptoms including, but not limited to, hyperglycemia and/or impaired glucose control, and retention of sodium and water. Subjects with weight-related hypertension may also have associated diseases, conditions, or symptoms including, but not limited to, hyperglycemia and/or impaired glucose control, and retention of sodium and water. [0102] As noted above, the present disclosure provides methods of treating obesity- related heart failure and methods of treating weight-related hypertension in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor. In some embodiments, the subject, having received the method of treatment, will have therapeutic outcomes including, but not limited to, reduced food intake, weight loss, reduced blood pressure, reduction of glycemic index and/or improved glucose control, and diuresis. [0103] In some embodiments, the method reduces the subject’s food intake by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after starting treatment. In some embodiments, reduced food intake is measured over the course of about 30 minutes, about 45 minutes, 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 18 hours, or about 24 hours. In some embodiments, food intake is measured during a single meal that is about 30 minutes, about 45 minutes, or about 60 minutes. In some embodiments, food intake is measured while the subject is allowed food ad libitum. [0104] In some embodiments, the method reduces the subject’s body weight by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 17%, at least about 20%, at least about 25%, or at least about 30% within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0105] In some embodiments, the method reduces the subject’s systolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least 17%, at least 20%, or at least 25% within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment [0106] In some embodiments, the method reduces the subject’s diastolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0107] In some embodiments, the method of treatment has at least three therapeutic effects. In some embodiments, the method of treatment reduces the subject’s body weight, systolic blood pressure, and diastolic blood pressure. In some embodiments, the method: (i) reduces the subject’s body weight by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 17%, at least about 20%, at least about 25%, or at least about 30%; (ii) reduces the subject’s systolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least 17%, at least 20%, or at least 25%; and (iii) reduces the subject’s diastolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%; within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0108] In some embodiments, the method of treatment that has at least two therapeutic effects. In some embodiments, the method of treatment leads to at least two of the therapeutic effects (i), (ii), and (iii). In some embodiments, the method reduces the subject’s body weight as in (i) and systolic blood pressure as in (ii). In some embodiments, the method reduces the subject’s body weight as in (i) and diastolic blood COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO pressure as in (iii). In some embodiments, the method reduces the subject’s systolic blood pressure as in (ii) and diastolic blood pressure as in (iii). [0109] In some embodiments, the method leads to diuresis in the subject, as measured by urinary volume in mL. In some embodiments, urine volume of the subject is increased by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 140%, at least about 160%, at least about 180%, or at least about 200%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. In some embodiments, urinary volume is measured over the course of about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 18 hours, or about 24 hours. [0110] In some embodiments, the method leads to diuresis in the subject, as measured by urinary excretion of sodium (Na+) in mEq per day. In some embodiments, urinary excretion of sodium by the subject is increased by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 140%, at least about 160%, at least about 180%, or at least about 200%. In some embodiments, urinary excretion of sodium by the subject is measured over the course of about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 18 hours, or about 24 hours. In some embodiments, urinary excretion of sodium by the subject is measured at about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0111] In some embodiments, the method leads to improved glucose control in the subject, as measured by fasting blood glucose in mg/dL. In some embodiments, improved glucose control in the subject comprises blood glucose ranging from 70-130 mg/dL in a fasted state. In some embodiments, improved glucose control in the subject comprises fasting blood glucose that is reduced by at least about 1 mg/dL, at least about 2 mg/dL, at least about 3 mg/dL, at least about 4 mg/dL, at least about 5 mg/dL, at least about 6 mg/dL, at least about 7 mg/dL, at least about 8 mg/dL, at least about 9 mg/dL, at least about 10mg/dL, at least about 12 mg/dL, at least about 15 mg/dL, at least about COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 17 mg/dL, or at least about 20 mg/dL, compared to that measured before starting treatment. In some embodiments, the improvement of glucose control of the subject is measured at about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0112] In some embodiments, the method leads to improved glucose control in the subject, as measured by blood glucose in a fed state, in mg/dL. In some embodiments, improved glucose control in the subject comprises blood glucose ranging from 70-180 mg/dL in a fed state. In some embodiments, improved glucose control in the subject comprises blood glucose, in a fed state, that is reduced by at least about 1 mg/dL, at least about 2 mg/dL, at least about 3 mg/dL, at least about 4 mg/dL, at least about 5 mg/dL, at least about 6 mg/dL, at least about 7 mg/dL, at least about 8 mg/dL, at least about 9 mg/dL, at least about 10mg/dL, at least about 12 mg/dL, at least about 15 mg/dL, at least about 17 mg/dL, or at least about 20 mg/dL, compared to that measured before starting treatment. In some embodiments, the improvement of glucose control of the subject is measured at about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0113] In some embodiments, the method leads to improved glucose control in the subject, as measured by glycated hemoglobin (HbA1c) test. In some embodiments, HbA1c is reduced by at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1.1%, at least about 1.2%, at least about 1.3%, at least about 1.4%, at least about 1.5%, at least about 1.7%, at least about 2.0%, at least about 2.5%, or at least about 3.0%. In some embodiments, the improvement of glucose control of the subject is measured at about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. [0114] In some embodiments, the method increases lean body mass by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10%. In some embodiments, the increase in lean body mass of the subject is measured at about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks after starting treatment. within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks after starting treatment. Indications for Treatment [0115] In some embodiments of the methods disclosed herein, the subject is a human. [0116] Subjects with obesity-related heart failure and subjects with weight-related hypertension may have one or more comorbid conditions or diseases. In some embodiments of the method, the subject has a metabolic syndrome, optionally Type 2 diabetes. In some embodiments of the method, the subject has diabetic cardiomyopathy. In some embodiments of the method, the subject has experienced weight gain following treatment with an antipsychotic, optionally clozapine, olanzapine, quetiapine, risperidone, aripiprazole, or ziprasidone. In some embodiments of the method, the subject has a binge eating disorder. In some embodiments of the method, the subject has Prader Willi Syndrome. In some embodiments of the method, the subject has pre-diabetes. EXAMPLES Example 1: Inhibition of Clic1 Reduces Food Intake after Fasting and During Binge Eating [0117] Inhibition of Clic1 reduces food intake in the context of fasting/re-feeding and binge eating. In the fasting and re-feeding model (Fig.1A), mice were injected with the Clic1 inhibitor R(+)-IAA94 (50mg/kg) or vehicle and then refed. IAA94 treatment decreased food intake over the course of 1 hour, as shown in Fig.1B. In the binge eating model (Fig. 1C), mice were exposed to a high-fat diet (HFD) intermittently (I), compared with continuous access (C) to HFD, and were administered either R(+)- IAA94 or vehicle control 1 hour prior to the intermittent HFD exposure. IAA94 reduced food intake over a period of 2.5 hours, as shown in Fig. 1D. These data are consistent with inhibition of Clic1 resulting in decreased food intake. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO [0118] In a Clic1 knockout mouse model (KO), IAA94 did not reduce food intake, which shows that IAA94-mediated inhibition of binge eating is mediated by Clic1. WT mice and Clic1 KO mice were fasted for 23 hours and then injected once with R(+)- IAA94 (10mg/kg) or vehicle (VEH) before being re-fed with normal chow. Unlike WT mice (Fig.2A), Clic1 KO mice (Fig.2B) treated with IAA94 did not have reduced food intake over the 24 hours after re-feeding. These data are consistent with the food-intake reducing effects of IAA94 being mediated by Clic1 inhibition. Example 2: Inhibition of Clic1 with R(+)-IAA94 Reduces Food Intake and Induces Weight Loss in Obese Individuals [0119] Inhibition of Clic1 reduces food intake and body weight in the context of obesity. Fig.3 shows an acute IAA94 treatment model in which obese WT mice were administered vehicle control (VEH) or R(+)-IAA94 and provided access to normal chow. IAA94 significantly reduced average food intake per day (Fig.3A), body weight (BW) in grams (Fig.3B), and blood levels of insulin in ng/ml (Fig.3C) on day 7. Blood glucose and free fatty acid levels were not significantly different between groups (Fig. 3D and 3E). These data are consistent with Clic1 inhibition reducing food intake and body weight in obese individuals. [0120] Fig.4 shows a longer-term IAA94 treatment model in which obese WT mice were administered vehicle or R(+)-IAA94 at either a low dose (LD, 10mg/kg) or a high dose (HD, 50mg/kg) and provided access to normal chow. Mice that received low-dose or high-dose IAA94 underwent weight loss, resulting in loss of about 17% of body weight (low -dose IAA94) and 27% of body weight (high-dose IAA94 by day 21 of treatment (Fig.4A). IAA94 (low-dose and high-dose) led to significantly reduced body weight in grams (Fig.4B). Food intake was also significantly reduced in mice receiving low-dose or high-dose IAA94 (Fig. 4C), despite approximately equal energy expenditure in all three groups (Fig.4D). These data are consistent with Clic1 inhibition reducing food intake and body weight in obese individuals. [0121] Fig. 5 shows the effect of Clic1 ablation on food intake and body weight. Normal WT and Clic1 knockout (KO) mice were provided normal chow ad libitum. Average daily food intake in grams (Fig.5A) and body weight (Fig.5B) were reduced in Clic1 KO mice, despite roughly equivalent energy expenditure (Fig. 5D) and respiratory quotient (Fig.5E) in both groups. Food intake was also lower for Clic1 KO COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO mice in the context of a food novelty test in which mice were administered 45% HFD for 20 min per day (Fig.5C). The average percentage lean mass was higher in ClicKO mice despite roughly equivalent average percentage fat mass (Fig. 5F). Clic1 KO did not appear to substantially affect glucose tolerance (Fig.5G); however, Clic1 KO mice demonstrated lower insulin following glucose stimulation (Fig. 5H), indicating improved insulin sensitivity. These data are consistent with Clic1 inhibition reducing food intake, body weight, and glucose-responsive insulin production. Example 3: Inhibition of Clic1 in Combination with GLP-1 Agonists Reduces Body Weight [0122] Fig. 6 shows the effect of chronic Clic1 inhibition through prolonged treatment with R(+)-IAA94, alone or in combination with a GLP-1 agonist (Liraglutide, or Lira). In diet-induced obese mice, Clic1 inhibition dose-dependently reduced food intake (Fig.6A) and body weight (Fig.6B), leading to dose-dependent weight loss (Fig. 6C). The effect of the high dose of IAA94 was roughly equivalent to that of GLP-1 agonist Lira, a known agent for inducing and maintaining weight loss in obese individuals. A combination of Lira and high-dose IAA94 had an additive effect on food intake, body weight, and weight loss. These effects were despite roughly equivalent energy expenditure (Fig.6D), activity as measured by distance traveled in meters (Fig. 6E), respiratory quotient (Fig. 6F), glucose tolerance in mg/dl (Fig. 6G), and glucose area under the curve (Fig.6H). These data are consistent with Clic1 inhibition reducing food intake and body weight in obese individuals to a degree commensurate with GLP- 1 agonist Lira, and having an additive effect when used in combination with Lira. Example 4: Inhibition of Clic1 in a Model of Prader-Willi Syndrome [0123] Fig. 7 shows the effect of Clic1 inhibition in a mouse model of Prader Willi syndrome. In Magel2 KO mice with hyperphagia, a known model of Prader Willi syndrome, in the absence of treatment, food intake, weight gain, and epididymal white adipose tissue (eWAT) weight were higher than that of WT mice. R(+)-IAA94 treatment reduced food intake (Fig. 7A) and prevented weight gain (Fig. 7B) in both WT and Magel2 KO mice. IAA94 also reduced eWAT weight in Magel2 KO mice (Fig. 7C). These data are consistent with Clic1 inhibition reducing food intake, preventing COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO weight gain, and reducing white adipose tissue mass in individuals with Prader-Willi syndrome. Example 5: Inhibition of Clic1 with S(+)-indacrinone in Obese Individuals [0124] S(+)-indacrinone is used to inhibit Clic1 in a diet-induced obese mouse model. The model involves WT mice fed a high-fat (60%) diet for 8 weeks. These diet-induced obese mice are then administered S(+)-indacrinone (5, 10, 20, and/or 40 mg/kg) or vehicle control. Food intake and body weight are measured for 21 days. It is expected that mice administered one or more of these S(+)-indacrinone dose regimens will show significantly reduced average food intake per day by day 21 of treatment (e.g., 5-10% reduction in food intake). It is also expected that mice administered one or more of these S(+)-indacrinone dose regimens will show significantly reduced body weight by day 21 of treatment (e.g., 5-30% reduction in body weight). These predicted results would be consistent with Clic1 inhibition reducing food intake and body weight in obese individuals. Example 6. Plasma Concentration of R-Indacrinone and S-Indacrinone Upon Administration [0125] Serum was collected from mice at various time points after oral administration of R-indacrinone (30 mg/kg) or S-indacrinone (50 mg/kg). Time points included 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours. Serum levels of R-indacrinone (FIG.8A) and S-indacrinone (FIG.8B) are shown. Example 7. Inhibition of Food Intake by R-Indacrinone and S-Indacrinone after Fasting [0126] Mice were fasted for 24 hours, then administered either R-indacrinone (30 mg/kg), S-indacrinone (50 mg/kg), R-IAA94 (50 mg/kg), or vehicle, one hour prior to re-feeding. Food intake was measured for 24 hours from the time of re-feeding in mice that received R-indacrinone (black circles), S-indacrinone (open circles), R-IAA94 (light gray circles), or vehicle (dark gray circles). Food intake is shown as percentage of food consumed compared to mice that received vehicle (FIG.8C). COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO Example 8: Inhibition of Clic1 with R-Indacrinone Reduces Food Intake and Induces Weight Loss in Obese Individuals [0127] Diet-induced obese WT mice were administered R-indacrinone at a low (10 mg/kg) or medium (20 mg/kg) dose, S-indacrinone at a high dose (50 mg/kg), or vehicle, and provided access to normal chow. Body weight and food intake were measured over time. FIG. 9A shows that 20 mg/kg R-indacrinone has a greater effect on weight loss than 50 mg/kg S-indacrinone. FIGS. 9B-9C show the effect of a low (10 mg/kg, FIG. 9B) or medium (20 mg/kg, FIG. 9C) dose of R-indacrinone on food intake in grams. [0128] Adiposity was assessed in diet-induced obese mice that received R- Indacrinone at a low (10 mg/kg) or medium (20 mg/kg) dose, S-indacrinone at a high dose (50 mg/kg), or vehicle (VEH) by measuring inguinal fat weight and epididymal fat weight. FIGS. 10A-10B show that 20 mg/kg R-indacrinone has a greater effect on reduction in inguinal fat weight (FIG.10A) and epididymal fat weight (FIG.10B) than 50 mg/kg S-indacrinone in diet-induced obese mice. Example 9: Reversal of Reduction in Food Intake and Body Weight Following Cessation of R-Indacrinone Administration [0129] Diet-induced WT mice were administered R-indacrinone (30 mg/kg) for seven days, then dosing of R-indacrinone was stopped. Body weight was measured daily during R-indacrinone treatment and following cessation of R-indacrinone dosing. Weight loss in the R-indacrinone treated mice was reversed following cessation of dosing (FIG. 11A). Food intake over 24 hours was measured during R-indacrinone treatment (R-Inda) and after cessation of administration of R-indacrinone (Recovery). Food intake increased after cessation of R-indacrinone dosing (FIG.11B). Example 10: Clic1 Binding Activity of R-Indacrinone and S-Indacrinone [0130] Binding of R-indacrinone and S-indacrinone to Clic1 protein was measured by one-dimensional (1D) saturation transfer difference (STD) NMR. Results are shown in (FIG.12A). Example 10: Diuretic Activity of R-Indacrinone COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO [0131] Diuretic activity of R-indacrinone was assessed in Sprague-Dawley rats by measuring urine output in grams (g) (FIG. 12B) and sodium (NA) excretion in mmol (FIG.12C) at 2 hours after administration of R-indacrinone or vehicle.

Claims

COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO CLAIMS 1. A method of treating obesity-related heart failure in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor. 2. A method of treating weight-related hypertension in a subject in need thereof, comprising administering to the subject an effective amount of a Clic1 inhibitor. 3. A method of treating uncomplicated obesity, inflammation, neurodegeneration, or cancer, comprising administering to the subject an effective amount of a Clic1 inhibitor. 4. The method of claim 1, wherein the obesity-related heart failure is obesity-related heart failure with preserved ejection fraction. 5. The method of claim 1, wherein the obesity-related heart failure is obesity-related heart failure with reduced ejection fraction. 6. The method of claim 1, wherein the obesity-related heart failure is obesity-related heart failure with mildly reduced ejection fraction. 7. The method of claim 1, wherein the obesity-related heart failure is diabetic cardiomyopathy. 8. The method of any of claims 1-7, wherein the Clic1 inhibitor has an IC50 for Clic1 of about 0.1 μM to about 250 μM. 9. The method of claim 8, wherein the Clic1 inhibitor has an IC50 for Clic1 of about 5 μM to about 25 μM. 10. The method of any of claims 1-9, wherein the Clic1 inhibitor is an organic molecule with a molecular weight of less than 500 g/mol. 11. The method of any of claims 1-10, wherein the Clic1 inhibitor is IAA94, indacrinone, IAA-23, DCPIB, DIOA, ethacrynic acid (EA), anthracene-9-carboxylic acid (A9C), 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), TS-TM- calix[4]arene, DNDS, DIDS, or a combination thereof: COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO

12. The method of any of claims 1-10, wherein the Clic1 inhibitor is A, B, C, D, or E, or a combination thereof, of Formula 1:

COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 13. The method of any of claims 1-10, wherein the Clic1 inhibitor is (-) IAA94, (+) IAA94, (-) indacrinone, (+) indacrinone, (-) p-OH-indacrinone, (+) p-OH-indacrinone, (-) p-fluoroindacrinone, (+) p-fluoroindacrinone, or combination thereof:

(-) p-OH-

indacrinone, (+) p-fluoroindacrinone, or

p- fluoroindacrinone. 14. The method of any of claims 1-10, wherein the Clic1 inhibitor is a compound of Formula 4, 12, or 17:

COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO

, or a stereoisomer thereof. 17. The method of any of claims 1-16, wherein the Clic1 inhibitor is administered to the subject orally or parenterally. 18. The method of any one of claims 1-17, wherein the Clic1 inhibitor provides a Cmax ranging from about 2 μg/ml to about 100 μg/ml. 19. The method of any of claims 1-18, wherein the effective amount of the Clic1 inhibitor is about 0.1 mg to about 1000 mg per day. 20. The method of any of claims 1-19, wherein the effective amount of the Clic1 inhibitor is about 0.5 mg/kg to about 5 mg/kg mg per day. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 21. The method of claim 20, wherein the effective amount of the Clic1 inhibitor is about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, or about 5.0 mg/kg per day. 22. The method of any of claims 1-21, wherein the Clic1 inhibitor comprises a racemic mixture of IAA94, a racemic mixture of indacrinone, or a racemic mixture of p-OH indacrinone, and is administered to the subject in an amount of at least 10 mg per day. 23. The method of any of claims 1-21, wherein the Clic1 inhibitor is (-) IAA94, (-) indacrinone, or (-) p-OH indacrinone, and is administered to the subject in an amount of at least 5 mg per day. 24. The method of claim 23, wherein the Clic1 inhibitor is (-) indacrinone. 25. The method of any of claims 1-21, wherein the Clic1 inhibitor is (+) IAA94, (+), indacrinone, or (+) p-OH indacrinone, and is administered to the subject in an amount of at least 5 mg per day. 26. The method of any of claims 1-21, wherein the Clic1 inhibitor comprises a mixture comprising an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) IAA94, or an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) indacrinone, or an enantiomeric excess of >55%, >60%, >70%, >80%, >90%, >92%, >95%, or >99% of (-) p-OH indacrinone. 27. The method of claim 26, wherein the Clic1 inhibitor comprises a mixture comprising an enantiomeric excess of >90%, >92%, >95%, or >99% of (-) indacrinone. 28. The method of any of claims 1-27, wherein the Clic1 inhibitor is administered once or twice per day. 29. The method of any of claims 1-28, wherein the Clic1 inhibitor is administered for at least about 3 months, at least about 4 months, at least about 6 months, at least about COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 9 months, at least about 12 months, at least about 15 months, at least about 18 months, or at least about 24 months. 30. The method of any of claims 1-29, wherein the method further comprises administering an additional therapeutic agent. 31. The method of claim 30, wherein the additional therapeutic agent is an incretin or an incretin mimetic. 32. The method of claim 31, wherein the incretin or incretin mimetic is a glucagon-like peptide receptor (GLP-1R) agonist, a glucose-dependent insulinotropic polypeptide receptor GIPR) agonist, an amylin receptor agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/amylin receptor dual agonist, or a combination thereof. 33. The method of claim 32, wherein the GLP-1R agonist is semaglutide or liraglutide. 34. The method of claim 32, wherein the GLP-1R/GIPR dual agonist is tirzepatide. 35. The method of claim 32, wherein the GLP-1R/amylin receptor dual agonist is amycretin. 36. The method of claim 30, wherein the additional therapeutic agent is a glucagon receptor (GcGR) agonist or a GLP-1R/GIPR/GcGR triple agonist. 37. The method of claim 36, wherein the GLP-1R/GIPR/GcGR triple agonist is retatrutide. 38. The method of claim 30, wherein the additional therapeutic agent is cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), oxyntomodulin (OXM), amylin, or a combination thereof. 39. The method of claim 30, wherein the additional therapeutic agent is an anti-GIPR antibody, optionally conjugated to a GLP-1 analogue. 40. The method of any of claims 1-39, wherein the Clic1 inhibitor is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. 41. The method of claim 40, wherein said pharmaceutical composition further comprises an additional therapeutic agent. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 42. The method of claim 41, wherein the additional therapeutic agent is an incretin or an incretin mimetic. 43. The method of claim 42, wherein the incretin or incretin mimetic is a GLP-1R agonist, a GIPR agonist, a GLP-1R/GIPR dual agonist, or a combination thereof. 44. The method of claim 43, wherein the GLP-1R agonist is semaglutide or liraglutide. 45. The method of claim 43, wherein the GLP-1R/GIPR dual agonist is tirzepatide. 46. The method of claim 41, wherein the additional therapeutic agent is a GcGR agonist or a GLP-1R/GIPR/GcGR triple agonist. 47. The method of claim 46, wherein the GLP-1R/GIPR/GcGR triple agonist is retatrutide 48. The method of claim 41, wherein the additional therapeutic agent is cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), oxyntomodulin (OXM), amylin, or a combination thereof. 49. The method of any of claims 1-48, wherein the method reduces the subject’s food intake by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after starting treatment. 50. The method of any of claims 1-49, wherein the method reduces the subject’s body weight at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 12%, at least about 15%, at least about 17%, or at least about 20%, at least about 25%, or at least about 30%, within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 51. The method of any of claims 1-50, wherein the method reduces the subject’s systolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least 17%, at least 20%, or at least 25% within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. 52. The method of any of claims 1-51, wherein the method reduces the subject’s diastolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. 53. The method of any one of claims 1-52, wherein the method: (i) reduces the subject’s body weight by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 17%, at least about 20%, at least about 25%, or at least about 30%; (ii) reduces the subject’s systolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least 17%, at least 20%, or at least 25%; and (iii) reduces the subject’s diastolic blood pressure, as measured in mmHg, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%; within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. 54. The method of any of claims 1-53, wherein the method causes diuresis in the subject, as measured in urinary volume in mL collected over the course of about 1 hour, about 2 hours, about 4 hours, about 8 hours, or about 24 hours, wherein the subject’s urinary volume is increased by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 140%, at least about 160%, at least about 180%, or at least about 200%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. 55. The method of any of claims 1-53, wherein the method does not cause diuresis in the subject, as measured in urinary volume in mL collected over the course of about 1 hour, about 2 hours, about 4 hours, about 8 hours, or about 24 hours, wherein the subject’s urinary volume is increased by less than about 50%, within about 2 weeks, about 3 weeks about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, or about 24 months after starting treatment. 56. The method of any of claims 1-55, wherein the method leads to glucose control in the subject, as measured by one or more of the following: (i) blood glucose levels ranging from 70-130 mg/dL in a fasted state; or (ii) blood glucose levels ranging from 70-180 mg/dL in a fed state; or (iii) glycated hemoglobin (HBA1c) of less than about 7%. COOLEY LLP ATTORNEY DOCKET NO.: 349489-2003 CLBO-001/01WO 57. The method of any of claims 1-56, wherein the method increases the subject’s lean body mass by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10%. 58. The method of any of claims 1-57, wherein the subject is a human. 59. The method of any of claims 1-58, wherein the subject has a metabolic syndrome. 60. The method of claim 59, wherein the subject has Type 2 diabetes. 61. The method of any of claims 1-58, wherein the subject has experienced weight gain following treatment with an antipsychotic. 62. The method of claim 61, wherein the antipsychotic is clozapine, olanzapine, quetiapine, risperidone, aripiprazole, or ziprasidone. 63. The method of any of claims 1-58, wherein the subject has a binge eating disorder. 64. The method of any of claims 1-58, wherein the subject has Prader Willi Syndrome. 65. The method of any of claims 1-58, wherein the subject has pre-diabetes.