ADAR-inhibitor compositions and uses thereof

Abstract

Provided herein are ADAR-inhibitor compositions and their uses in modulating energy homeostasis.

Description

ADAR-INHIBITOR COMPOSITIONS AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority of U.S. Provisional Patent Application serial number 63 / 688,668, filed August 29, 2024, and U.S. Provisional Patent Application serial number 63 / 640,137, filed April 29, 2024, the entire content of each of which is incorporated herein by reference.BACKGROUND

[0002] Energy homeostasis refers to the equilibrium between food intake and energy expenditure and, due to its impact on survival and propagation, is a closely regulated function. Dysregulation of energy homeostasis can lead to induction of metabolic disorders. Obesity, a complex metabolic disorder that may result from inherited, physiological, and environmental factors, as well as their combination with diet, physical activity, and exercise choices, is one of the most common pathological phenotypes of humans in generally affluent society. Resulting from chronic disequilibrium between energy uptake and expenditure obesity associates with type II diabetes, cardiovascular disease, and hypertension. The neuroendocrine hormones leptin and ghrelin act as reciprocal regulators of energy homeostasis. Leptin, produced by adipocytes, informs the hypothalamus about the state of fat stores and indirectly regulates appetite and energy expenditure. Ghrelin, produced by enteroendocrine cells of the gastrointestinal tract, particularly the stomach, informs the hypothalamus about the state of food being broken down in the stomach. Other hormones or peptides involved in energy homeostasis include, but are not limited to, glucagon-like peptide- 1 (GLP-1), cholecystokinin (CCK), and peptide YY aka peptide tyrosine tyrosine (PYY). Furthermore, disequilibrated energy homeostasis, e.g., particularly a fasting state, can reduce reproductive function or fertility in mammals. But challenges remain. For example, therapeutic interventions for weight loss include glucagon-like peptide 1 (GLP-1) mimics, but these treatments include challenging side effects such as nausea, vomiting, diarrhea, or constipation. Furthermore, although weight loss reduces obesity-related comorbidities, concomitant bone loss typically occurs with weight loss, seen as decreased bone mineral density (BMD) and increased bone turnover. Low BMD is associated with increased risk of fractures, and mortality rates increase following any fractures, particularly hip and vertebral fractures, but also other major fractures. Weight loss-induced bone loss is a particular concern in older adults. However, bone loss following weight loss has been shown not only in older adults, but also after gastric bypass, and after long-term calorie restriction in younger adultswith and without obesity. Thus, weight loss-induced bone loss likely carries a risk across the lifespan, and identifying treatments that induce clinically relevant weight loss while minimizing bone loss is essential in long-term obesity management (Jensen et aL, JAMA Netw Open. 2024;7(6) :e2416775).SUMMARY

[0003] Provided herein are improved treatments for modulating energy homeostasis, e.g., compositions comprising ADAR inhibitors and uses thereof.DETAILED DESCRIPTION

[0004] It has been discovered that adenosine deaminase acting on RNA (ADAR, e.g., ADAR1, e.g., ADARlpl50) enzyme inhibition (e.g., inhibition of ADAR by Compound A, pladienolide B, or fedratinib, or a pharmaceutically acceptable salt thereof) modulates energy homeostasis. Through its deaminase activity, ADAR edits adenosine to inosine in double-stranded RNA thereby affecting the transcriptome and ultimately affecting protein expression. While inhibition of ADAR function has been suggested as a therapeutic strategy outside of energy homeostasis, there are no FDA-approved inhibitors of ADAR for any therapeutic indication.

[0005] Provided herein are compositions comprising ADAR inhibitors and uses thereof in modulating energy homeostasis. In some embodiments, the compositions comprising ADAR inhibitor(s) may be in particle form as described herein, e.g., lipid nanoparticles comprising an ADAR inhibitor, or a combination thereof, laden therein. Without being bound by theory, ADARlpl50 inhibition used as described herein, unlike GLP agonists, may protect against potential side effects such as cancer because it overcomes immune checkpoint inhibitor resistance and prevents malignant regeneration fueled by ADAR1 editing of Let-7 primary microRNA, editing induced STAT3 splicing, and beta-catenin activation through inhibition of ARID1B, GLI1 editing that prevents SUFU inhibitor binding, and MDM2 3'UTR editing that stabilizes the transcript and promotes TP53 inhibition.

[0006] Thus, in some embodiments, provided herein are ADAR inhibitors for use in reducing high fat diet (HFD) related obesity in a subject in need thereof, or for use in the preparation of a medicament for such reducing.

[0007] In other embodiments, provided herein are ADAR inhibitors for use in reducing high fat diet (HFD) related insulin-resistance in a subject in need thereof, or for use in the preparation of a medicament for such reducing.

[0008] In still other embodiments, provided herein are ADAR inhibitors for use in reducing secretion of ghrelin by GHSR-la receptor positive cells in the gastric fundus in a subject in need thereof, or for use in the preparation of a medicament for such reducing.

[0009] In other embodiments, provided herein are ADAR inhibitors for use in reducing secretion of ghrelin by epsilon cells in the pancreas in a subject in need thereof, or for use in the preparation of a medicament for such reducing.

[0010] In still other embodiments, provided herein are ADAR inhibitors for use in reducing secretion of YY peptide production in a subject in need thereof, or for use in the preparation of a medicament for such reducing.

[0011] In some embodiments, provided herein are ADAR inhibitors for use in the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease or other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia, or gastric ulcers in a subject in need thereof, or for use in the preparation of a medicament for such treatment or prevention.

[0012] In other embodiments, provided herein are ADAR inhibitors for use in delaying or preventing disease progression in type 2 diabetes in a subject in need thereof, or for use in the preparation of a medicament for such delaying or preventing.

[0013] In still other embodiments, provided herein are ADAR inhibitors for use in decreasing food intake, decreasing [3-cell apoptosis, increasing (3-cell function and 3-cell mass, or for restoring glucose sensitivity to p-cells, in a subject in need thereof, or for use in the preparation of a medicament for such decreasing, increasing, or restoring.

[0014] In some other embodiments, provided herein are ADAR inhibitors for use in decreasing excess body weight, optionally including maintaining weight reduction long term, in a subject in need thereof, or for use in the preparation of a medicament for such decreasing.

[0015] In some embodiments, provided herein are ADAR inhibitors for use in chronic weight management in a subject in need thereof, or for use in the preparation of a medicament for such management.

[0016] In some embodiments, provided herein are ADAR inhibitors for use in improving glycemic control in a subject in need thereof, or for use in the preparation of a medicament for such improving.

[0017] In some embodiments, provided herein are ADAR inhibitors for use in modulating energy homeostasis in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such modulating.

[0018] In some embodiments, provided herein are ADAR inhibitors for use in modulating (e.g., decreasing) food intake in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such modulating.

[0019] In some embodiments, provided herein are ADAR inhibitors for use in reducing body fat, cholesterol, or triglycerides, or a combination thereof, in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

[0020] In some embodiments, provided herein are ADAR inhibitors for use in muscle preservation in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject in need thereof.

[0021] In some embodiments, provided herein are ADAR inhibitors for use in treating obesity in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such treating.

[0022] In some embodiments, provided herein are ADAR inhibitors for use in reducing body weight in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such reducing.

[0023] In some embodiments, provided herein are ADAR inhibitors for use in treating type II diabetes in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such treating.

[0024] In some embodiments, provided herein are ADAR inhibitors for use in promoting leptin production (e.g., leptin gene expression) in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such promoting.

[0025] In some embodiments, provided herein are ADAR inhibitors for use in increasing thermogenesis in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such increasing.

[0026] In some embodiments, provided herein are ADAR inhibitors for use in increasing metabolic rate in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such increasing.

[0027] In some embodiments, provided herein are ADAR inhibitors for use in reducing ghrelin production (e.g., ghrelin gene expression) in a subject need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such reducing.

[0028] In some embodiments, provided herein are ADAR inhibitors for use in promoting peptide YY production (e.g., PYY gene expression) in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such promoting.

[0029] In some embodiments, provided herein are ADAR inhibitors for use in restoring fertility in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject, or for use in the preparation of a medicament for such restoring, the subject experiencing infertility.

[0030] In some embodiments, the ADAR inhibitor referred to herein comprises: a first ADAR inhibitor selected from shADARl (e.g., in a plasmid, a viral vector, or a bacterial vector), Compound A, fedratinib, a pladienolide (e.g., pladienolide B), raltegravir, dolutegravir, AVA-ADR-001, ZYS-1 (Fludarabine-CI, CAS No. : 2734853-80-4), cladribine, 8- azaadenosine, pentostatin, EHNA hydrochloride (CAS No. : 58337-38-5), AMPD2 inhibitor 1 (CAS. No.: 2139356-35-5), hibifolin, coformycin, FR221647 (CAS No. : 256461-28-6), FR234938 (CAS No. : 256461-79-7), or AMPD2 inhibitor 2 (CAS No.: 3026893-31-9), or a pharmaceutically acceptable salt thereof; and optionally a second ADAR inhibitor, different from the first, selected from shADARl (e.g., in a plasmid, a viral vector, or a bacterial vector), raltegravir, dolutegravir, pladienolide B, Compound A, fedratinib, AVA-ADR-001, ZYS-1, cladribine, 8-azaadenosine, pentostatin, EHNA hydrochloride, AMPD2 inhibitor 1, hibifolin, coformycin, FR221647, FR234938, or AMPD2 inhibitor 2, or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the ADAR inhibitor referred to herein is selected from one or more of Compound A, fedratinib, pladienolide B, raltegravir, or dolutegravir, or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the ADAR inhibitor referred to herein includes a short hairpin RNA (shRNA) to silence ADAR1 expression via RNA interference (RNAi). In some embodiments, the shRNA is included in a plasmid, a viral vector, or a bacterial vector.

[0033] In some embodiments of the uses or treatments herein, the subject experiences a reduction in body weight (e.g., a statistically significant reduction).

[0034] In some embodiments of the uses or treatments herein, the subject experiences a reduction in body weight without a concurrent reduction in food intake.

[0035] In some embodiments of the uses or treatments herein, the subject experiences a reduction in food intake without a concurrent reduction in body weight.

[0036] In some embodiments of the uses or treatments herein, the subject does not experience nausea, vomiting, diarrhea, or constipation resulting from the administration of the ADAR inhibitor. In some embodiments of the uses or treatments herein, the subject does not experience muscle loss resulting from the administration of the ADAR inhibitor.

[0037] In some embodiments of the uses or treatments herein, the effect of the ADAR inhibitor is measurable at 2, 4, 8, or 12 weeks from initial administration of the ADAR inhibitor.

[0038] In some embodiments of the uses or methods of treatment herein, the subject has an initial body mass index of about 27 to about 30 kg / m2(overweight) or at least 30 kg / m2(obesity).

[0039] In some embodiments of the uses or methods of treatment herein, the subject experiences a reduction in body mass index of at least 3 kg / m2during or following use or treatment (e.g., during the time-course of the treatment regimen) as compared to prior to such use or treatment.

[0040] In some embodiments of the uses or methods of treatment herein, the subject experiences a maintenance or improvement of the subject's bone mineral density during or following use or treatment as compared to prior to such use or treatment. For example, in some embodiments, the subject experiences no statistically significant loss of their bone mineral density during or following use or treatment (e.g., during the time-course of the treatment regimen) as compared to prior to such use or treatment. In other embodiments, the subject experiences a statistically significant increase of their bone mineral density during or following use or treatment (e.g., during the time-course of the treatment regimen) as compared to prior to such use or treatment.

[0041] The uses described herein may be used in combination with one another.Definitions

[0042] Certain terms, whether used alone or as part of a phrase or another term, are defined below.

[0043] The articles "a" and "an" refer to one or to more than one of the grammatical object of the article.

[0044] Numerical values relating to measurements are subject to measurement errors that place limits on their accuracy. For this reason, all numerical values provided herein, unless otherwise indicated, are to be understood as being modified by the term "about." Accordingly, the last decimal place of a numerical value provided herein indicates its degree of accuracy. Where no other error margins are given, the maximum margin is ascertained by applying the rounding-off convention to the last decimal place or last significant digit when a decimal is not present in the given numerical value.

[0045] The term "amelioration" means a lessening of severity of at least one indicator of a condition or disease, such as a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of indicators may be determined by subjective or objective measures which are known to those skilled in the art.

[0046] The term "composition" refers to a mixture of at least two or more components.

[0047] The terms "effective amount" and "therapeutically effective amount" refer to an amount of therapeutic compound, such as an ADAR inhibitor herein, administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect. In general, the therapeutically effective amount can be estimated initially either in cell culture assays or in mammalian animal models, for example, in non-human primates, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in non-human subjects and human subjects.

[0048] The term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid filler, solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting at least one compound described herein within or to the patient such that the compound may perform its intended function. A given carrier must be "acceptable" in the sense of being compatible with the other ingredients of a particular formulation, including the compounds described herein, and not injurious to the patient. Otheringredients that may be included in the pharmaceutical compositions described herein are known in the art and described, for example, in "Remington's Pharmaceutical Sciences" (Genaro (Ed.), Mack Publishing Co., 1985), the entire content of which is incorporated herein by reference.

[0049] The term "pharmaceutical composition" refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0050] The terms "treatment" or "treating" refer to the application of one or more specific procedures used for the amelioration of a disease. A "prophylactic" treatment, refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset.

[0051] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the described subject matter and does not pose a limitation on the scope of the subject matter otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to practicing the described subject matter.

[0052] Groupings of alternative elements or embodiments of this disclosure are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. Furthermore, a recited member of a group may be included in, or excluded from, another recited group for reasons of convenience or patentability. When any such inclusion or exclusion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0053] References have been made to patents and printed publications throughout this specification, each of which are individually incorporated herein by reference in their entirety.

[0054] It is to be understood that the embodiments of this disclosure are illustrative. Accordingly, the present disclosure is not limited to that precisely as shown and described.Compositions

[0055] Provided herein are compositions comprising one or more ADAR inhibitor for use or treatment as described herein. In some embodiments, the compositions may be pharmaceutical compositions further comprising a pharmaceutically acceptable carrier. In some embodiments, the one or more ADAR inhibitor may be selected from ADAR1 inhibitors. In some embodiments, the ADAR inhibitor is an inhibitor of ADAR1 pl50 isoform present in cytoplasm. In some embodiments, the ADAR inhibitor is selected from pladienolides (including pladienolides A, B, C, D, E, F, and G), Compound A, Compound B, fedratinib, AVA-ADR-001, ZYS-1, cladribine, 8-azaadenosine, pentostatin, EHNA hydrochloride, AMPD2 inhibitor 1, hibifolin, coformycin, FR221647, FR234938, or AMPD2 inhibitor 2, shADARl (e.g., in a plasmid, a viral vector, or a bacterial vector), or a pharmaceutically acceptable salt thereof. In some embodiments, the ADAR inhibitor is selected from one or more of raltegravir, dolutegravir, pladienolide B, Compound A, or fedratinib, or a pharmaceutically acceptable salt thereof. The compounds herein are commercially available or are prepared according to previously described synthetic procedures. For example, Compound A has been described, including in WO 2021 / 026273 Al and US 10,675,267 B2, which are incorporated herein by reference. Compound A has also been synthesized as described by Chan et al. (Cell Reports Physical Science, 2020, 1, 12, 100277); Compound B is similarly prepared.Compound A

[0056] Pladienolide B has been synthesized previously, at least, as described, for example, by Rhoades et al. (Journal of the American Chemical Society 2021 143 (13), 4915-4920 DOI: 10.1021 / jacs.lc01135). Pladienolides A, C, D, E, F, and G are similarly prepared.Pladienolide B

[0057] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified using appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

[0058] Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources or are prepared using procedures described herein.

[0059] In some embodiments, the ADAR inhibitor compounds herein may be isotopically-labeled compounds (e.g., isotopically-labeled ADAR inhibitor), which are identical to those recited in the formulae herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number abundance different from the atomic mass or mass number abundance usually found in nature. Examples of isotopes suitable for inclusion in the compounds of herein include, without limitation, hydrogen, carbon, nitrogen,oxygen, and fluorine, such as, but not limited to2H,3H,13C,14C,15N,17O,18O, and18F, respectively. Other isotopes are contemplated herein, for example those of P, Cl, I, etc. Substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in the compounds herein arenC,13N,15O, and18F. Compounds herein that are isotopically-labeled can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using appropriate isotopically-labeled reagents or starting materials in place of non-isotopically-labeled reagents or starting materials. Thus, in some embodiments, provided herein are compounds of the formulae herein, wherein at least one atom is replaced by its corresponding atom having an atomic mass or mass number abundance different from the atomic mass or mass number abundance usually found in nature. For example, the compounds have one or more H (e.g.,1H) substituted, independently, with2H or3H. In some embodiments, one or more C is substituted, independently, with13C or14C. In some embodiments, one or more N is substituted with15N. In some embodiments, one or more 0 is substituted, independently, with17O or18O. In some embodiments, one or more F is substituted, independently, with18F.

[0060] In some embodiments, the ADAR inhibitor is included in a composition comprising a lipid nanoparticle or complex, which may be used to deliver the ADAR inhibitor to a cell. In some embodiments, LNPs or LCs may be prepared at ambient temperature by combining lipid, ADAR inhibitor, and aqueous vehicle by passing a mixture of the combined components back and forth between two tip-to-tip connected syringes to homogeneity or a target LNP or LC particle size. Thus, in some embodiments, provided herein are compositions comprising a lipid nanoparticle (LNP) or lipid complex (LC), wherein the LNP or LC optionally includes an internal volume that is laden with an internal composition comprising an ADAR inhibitor or a combination thereof. In some embodiments, the ADAR inhibitor or a combination thereof comprise at least 50% of the volume of the internal volume of the LNP or LC. In some embodiments, the ADAR inhibitor or a combination thereof comprise about 50% or more by weight of the LNP or LC. In some embodiments, the LNP or LC further comprises an exterior surface having an antibody specific for epsilon cells or an antibody specific for calreticulin. In some embodiments, the LNP or LC is in an aqueous composition.

[0061] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pladienolide A or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0062] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pladienolide B or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0063] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pladienolide A or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0064] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pladienolide C or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0065] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pladienolide D or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0066] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pladienolide E or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0067] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pladienolide F or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0068] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pladienolide G or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0069] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; Compound A or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0070] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; Compound B or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0071] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; fedratinib or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0072] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; AVA-ADR-001 or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0073] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; ZYS-1 or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0074] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; cladribine or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0075] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; 8-azaadenosine or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0076] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; pentostatin or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0077] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; EHNA hydrochloride or a pharmaceuticallyacceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0078] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; AMPD2 inhibitor 1 or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0079] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; hibifolin or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0080] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; coformycin or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0081] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; FR221647 or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0082] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; FR234938 or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0083] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; AMPD2 inhibitor 2 or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0084] In some embodiments, the compositions herein comprise an aqueous vehicle and an LNP or LC, wherein the LNP or LC comprises: a lipid; shADARl (e.g., in a plasmid, a viral vector, or a bacterial vector) or a pharmaceutically acceptable salt thereof; and an antibody specific for epsilon cells or an antibody specific for calreticulin.

[0085] In some embodiments, provided herein are packaged compounds, packaged compositions, or packaged pharmaceutical compositions, comprising a container holding a therapeutically effective amount of an ADAR inhibitor described herein, such as, but not limited to, fedratinib, Compound A, or pladienolide B, or a pharmaceutically acceptable saltthereof, or the like, and instructions for using the compound in accordance with one or more of the methods provided herein.

[0086] The present compounds or compositions, and associated materials, can be finished as a commercial product by the usual steps performed in the present field, for example by appropriate sterilization and packaging steps. For example, the material can be treated by UV / vis irradiation (200-500 nm), for example using photo-initiators with different absorption wavelengths (e.g. Irgacure 184, 2959), preferably water-soluble initiators (e.g. Irgacure 2959). Such irradiation is usually performed for an irradiation time of 1-60 min, but longer irradiation times may be applied, depending on the specific method. The material according to the present disclosure can be finally sterile-wrapped so as to retain sterility until use and packaged (e.g. by the addition of specific product information leaflets) into suitable containers (boxes, etc.).

[0087] According to further embodiments, the present compounds can also be provided in kit form combined with other components necessary for administration of the material to the patient. For example, disclosed kits, such as for use in the treatment of cancer, can further comprise, for example, administration materials.

[0088] The kits are designed in various forms based on the specific deficiencies they are designed to treat.

[0089] The compounds or compositions provided herein may be prepared and placed in a container for storage at ambient or elevated temperature. When the compound or composition is stored in a polyolefin plastic container as compared to a polyvinyl chloride plastic container, discoloration of the compound or composition, or sorption of the compound with the surface of the container, may be reduced, whether dissolved or suspended in a liquid composition (e.g., an aqueous or organic liquid solution), or as a solid. Without wishing to be bound by theory, the container may reduce exposure of the container's contents to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UV B light) or about 320-380 nm (UV A light)). Some containers also include the capacity to reduce exposure of the container's contents to infrared light, or also include a second component with such a capacity. The containers that may be used include those made from a polyolefin such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or a combination thereof, especially polyethylene, polypropylene, or a combination thereof. In some embodiments, the container is a glass container. The container may further be disposed within a second container, for example, a paper, cardboard, paperboard, metallicfilm, or foil, or a combination thereof, container to further reduce exposure of the container's contents to UV, visible, or infrared light. The compounds or compositions provided herein may need storage lasting up to, or longer than, three months; in some cases, up to, or longer than one year. The containers may be in any form suitable to contain the contents, for example, a bag, a bottle, or a box.Methods

[0090] Provided herein are uses of ADAR inhibitors related to energy homeostasis.

[0091] In some embodiments, provided herein are methods of modulating energy homeostasis in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of modulating energy homeostasis in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of modulating energy homeostasis in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of modulating energy homeostasis in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0092] In some embodiments, provided herein are methods of modulating (e.g., decreasing) food intake in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of modulating (e.g., decreasing) food intake in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of modulating (e.g., decreasing) food intake in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of modulating (e.g., decreasing) food intake in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0093] In some embodiments, provided herein are methods of treating obesity in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to thesubject. In some embodiments, provided herein are methods of treating obesity in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of treating obesity in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of treating obesity in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0094] In some embodiments, provided herein are methods of reducing body weight in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of reducing body weight in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of reducing body weight in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of reducing body weight in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0095] In some embodiments, provided herein are methods of reducing food intake in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, a reduction in food intake may reduce body fat in the subject. In further embodiments, provided herein are methods of reducing body fat (e.g., visceral fat, subcutaneous fat, white fat, brown fat, or beige fat), cholesterol, or triglycerides, or a combination thereof, in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. Also provided herein are methods for muscle preservation in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject in need thereof. Also provided herein are methods for bone density preservation in a subject (e.g., a subject who has undergone weight loss) in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject in need thereof.

[0096] In some embodiments, provided herein are methods of treating type II diabetes in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of treating type II diabetes in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of treating type II diabetes in need thereof, comprising administration of an effective amount of Compound A to the subject.In some embodiments, provided herein are methods of treating type II diabetes in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0097] In some embodiments, provided herein are methods of promoting leptin production (e.g., leptin gene expression) in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of promoting leptin production (e.g., leptin gene expression) in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of promoting leptin production (e.g., leptin gene expression) in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of promoting leptin production (e.g., leptin gene expression) in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0098] In some embodiments, provided herein are methods of increasing thermogenesis in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of increasing thermogenesis in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of increasing thermogenesis in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of increasing thermogenesis in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0099] In some embodiments, provided herein are methods of increasing metabolic rate in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of increasing metabolic rate in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of increasing metabolic rate in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of increasing metabolic rate in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0100] In some embodiments, provided herein are methods of reducing ghrelin production (e.g., ghrelin gene expression) in a subject need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of reducing ghrelin production (e.g., ghrelin gene expression) in a subject need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of reducing ghrelin production (e.g., ghrelin gene expression) in a subject need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of reducing ghrelin production (e.g., ghrelin gene expression) in a subject need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0101] In some embodiments, provided herein are methods of promoting peptide YY production (e.g., PYY gene expression) in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of promoting peptide YY production (e.g., PYY gene expression) in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of promoting peptide YY production (e.g., PYY gene expression) in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of promoting peptide YY production (e.g., PYY gene expression) in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0102] In some embodiments, provided herein are methods of restoring fertility in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject. In some embodiments, provided herein are methods of restoring fertility in a subject in need thereof, comprising administration of an effective amount of pladienolide B to the subject. In some embodiments, provided herein are methods of restoring fertility in a subject in need thereof, comprising administration of an effective amount of Compound A to the subject. In some embodiments, provided herein are methods of restoring fertility in a subject in need thereof, comprising administration of an effective amount of fedratinib or a pharmaceutically acceptable salt thereof to the subject.

[0103] In some embodiments, the ADAR inhibitor is selected from one of, or a combination of two or more of, raltegravir, dolutegravir, a pladienolide, Compound A, fedratinib, AVA-ADR- 001, ZYS-1, cladribine, 8-azaadenosine, pentostatin, EHNA hydrochloride, AMPD2 inhibitor 1,hibifolin, coformycin, FR221647, FR234938, or AMPD2 inhibitor 2, or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the ADAR inhibitor comprises: a first ADAR inhibitor selected from a pladienolide, Compound A, fedratinib, AVA-ADR-001, ZYS-1, cladribine, 8- azaadenosine, pentostatin, EHNA hydrochloride, AMPD2 inhibitor 1, hibifolin, coformycin, FR221647, FR234938, or AMPD2 inhibitor 2, or a pharmaceutically acceptable salt thereof; and optionally a second ADAR inhibitor, different from the first, selected from pladienolide B, Compound A, fedratinib, AVA-ADR-001, ZYS-1, cladribine, 8-azaadenosine, pentostatin, EHNA hydrochloride, AMPD2 inhibitor 1, hibifolin, coformycin, FR221647, FR234938, or AMPD2 inhibitor 2, or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments of the methods herein, the ADAR inhibitor is administered in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent, which may be an ADAR inhibitor, is selected from fedratinib, 8-aza-adenosine, raltegravir, or dolutegravir.

[0106] In some embodiments of the methods herein, the subject experiences a reduction in body weight. In some embodiments, the subject experiences a reduction in body weight without a concurrent reduction in food intake.

[0107] In some embodiments of the methods herein, the subject does not experience nausea, vomiting, diarrhea, or constipation (e.g., clinically relevant experience or statistically significant) resulting from the administration of the ADAR inhibitor.

[0108] In some embodiments of the methods herein, the ADAR inhibitor administration is administration of a pharmaceutical composition comprising the ADAR inhibitor and a pharmaceutically acceptable carrier.

[0109] In some embodiments of the methods herein, administration of the ADAR inhibitor is oral, nasal, suppository, intravenous, intramuscular, intraperitoneal, or subcutaneous administration.

[0110] In some embodiments, an ADAR inhibitor described herein is administered at a dose of between about 1 mg / kg to about 40 mg / kg. In some embodiments, an ADAR inhibitor is administered in a dose of between about 1 mg / kg to about 20 mg / kg. In some embodiments, an ADAR inhibitor is administered in a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, orabout 20 mg / kg. By way of example only, a 2 mg / kg dose administered to a human who weighs 60 kg is a dose of 120 mg. In some embodiments, an ADAR inhibitor described herein may reduce food intake, while not affecting body weight and / or not causing muscle loss. In such embodiments, the reduced food intake may lead to a reduction in body fat and / or body weight over time. In some embodiments, an ADAR inhibitor described herein is administered orally.

[0111] In some embodiments, reference herein to upregulation of a gene also refers to increased expression of the product of the gene. Similarly, reference herein to downregulation of a gene refers also to reduced expression of the product of the gene.

[0112] In some embodiments of the methods herein, the methods are performed in a cell. In some embodiments, the cell is in vitro. In some embodiments, the cell is in vivo, e.g., in a subject, e.g., in a mammalian subject, e.g., a human subject.

[0113] Accordingly, actual dosage levels of the active ingredients (e.g. Compound A, Compound B, Pladienolide B, and the like) prepared as described herein, the compositions, or the pharmaceutical compositions provided herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0114] In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and like factors well-known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0115] Routes of administration of include, without limitation, oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. In some embodiments, the oral or nasal route of administration is an oral inhalational or nasal inhalational route of administration. The compounds for use as described herein may be formulated for administration by any suitable route to achieve the method being applied.

[0116] Reference to ADAR inhibitor herein may be taken also as reference to a composition described herein comprising the ADAR inhibitor.EXAMPLES

[0117] The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure as described herein.Example 1: PYY Upregulation.

[0118] A subject is administered a pharmaceutical composition comprising about 25 to about 400 mg of an ADAR inhibitor once daily, which results in upregulation of PYY, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 2: Leptin Upregulation.

[0119] A subject is administered a pharmaceutical composition comprising about 25 to about 400 mg of an ADAR inhibitor once daily, which results in upregulation of leptin, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 3: Ghrelin Downregulation.

[0120] A subject is administered a pharmaceutical composition comprising about 25 to about 400 mg of an ADAR inhibitor once daily, which results in downregulation of ghrelin, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 4: CCK Upregulation.

[0121] A subject is administered a pharmaceutical composition comprising about 25 to about 400 mg of an ADAR inhibitor once daily, which results in upregulation of CCK, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 5: PYY Upregulation.

[0122] A subject is administered a pharmaceutical composition comprising about 25 to about 400 mg of an ADAR inhibitor once daily, which results in upregulation of GLP-1, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 6: Intravenous administration of ADAR Inhibitor.

[0123] Sprague Dawley rats are administered a single and biweekly bolus injection of a pharmaceutical composition comprising 1, 3, 5, and 8 mg / kg / day of Compound A. Quantifiable concentrations of Compound A in blood is observed at about 30-60 minutes post-dose. A ti / 2 of approximately 30 minutes was observed. Surprisingly, despite the short halflife of Compound A, therapeutic effects of the methods herein are observable, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 7: Oral administration of ADAR Inhibitor.

[0124] One or more subjects are administered a single and daily tablet of a pharmaceutical composition comprising about 400 mg of fedratinib or a pharmaceutically acceptable salt thereof. Therapeutic effects of the methods herein are observable, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 8: GLP1R Expression

[0125] The change in GLP1R expression based on ADAR over-expression is assayed following administration of an ADAR inhibitor (e.g., Compound A).Example 9: Reduction of Ghrelin Secretion.

[0126] Compound A is orally or intravenously administered to rats or mice for two weeks. Control used the same vehicle as administration of Compound A but without Compound A. Rats or mice were fed high fat diet in both groups (Compound A group or control group). The animals administered Compound A experienced a statistically significant reduction in ghrelin secretion (e.g., by GHSR-la receptor positive cells in the gastric fundus or epsilon cells in the pancreas) when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 10: Increase of YY Peptide Secretion.

[0127] Compound A is orally or intravenously administered to rats or mice for two weeks. Control used the same vehicle as administration of Compound A but without Compound A. Rats or mice were fed high fat diet in both groups (Compound A group or control group). The animals administered Compound A experienced a statistically significant increase in YY peptide secretion when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 11: Reduction of Weight Gain.

[0128] Compound A is orally or intravenously administered to rats or mice for two weeks. Control used the same vehicle as administration of Compound A but without Compound A. Rats or mice were fed high fat diet in both groups (Compound A group or control group). The animals administered Compound A experienced a statistically significant reduction in weightgain when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 12: Reduction of Ghrelin Secretion.

[0129] Fedratinib is orally or intravenously administered to rats or mice. Control used the same vehicle as administration of Fedratinib but without Fedratinib. Rats or mice were fed high fat diet in both groups (Fedratinib group or control group). The animals administered Fedratinib experienced a statistically significant reduction in ghrelin secretion (e.g., by GHSR- la receptor positive cells in the gastric fundus or epsilon cells in the pancreas) when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 13: Increase of YY Peptide Secretion.

[0130] Fedratinib is orally or intravenously administered to rats or mice. Control used the same vehicle as administration of Fedratinib but without Fedratinib. Rats or mice were fed high fat diet in both groups (Fedratinib group or control group). The animals administered Fedratinib experienced a statistically significant increase in YY peptide secretion when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 14: Reduction of Weight Gain.

[0131] Fedratinib is orally or intravenously administered to rats or mice for two weeks. Control used the same vehicle as administration of Fedratinib but without Fedratinib. Rats or mice were fed high fat diet in both groups (Fedratinib group or control group). The animals administered Fedratinib experienced a statistically significant reduction in weight gain when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 15: Reduction of Weight.

[0132] Compound A is orally or intravenously administered to rats or mice for two weeks. Control used the same vehicle as administration of Compound A but without Compound A. Rats or mice were fed high fat diet in both groups (Compound A group or control group). The animals administered Compound A experienced a statistically significant reduction in weight when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 16: Reduction of Weight.

[0133] Fed rati n i b is orally or intravenously administered to rats or mice for two weeks. Control used the same vehicle as administration of Fedratinib but without Fedratinib. Rats or mice were fed high fat diet in both groups (Fedratinib group or control group). The animals administered Fedratinib experienced a statistically significant reduction in weight when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 17: Bone Mineral Density Change.

[0134] Compound A is orally or intravenously administered to rats or mice for two weeks. Control used the same vehicle as administration of Compound A but without Compound A. Rats or mice were fed high fat diet in both groups (Compound A group or control group). The animals administered Compound A experienced a statistically significant maintenance or improvement in bone mineral density when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.Example 18: Modulation of GLP1R Expression.

[0135] The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in glucose homeostasis and food intake. Compound A is orally or intravenously administered to rats or mice for two weeks. Control used the same vehicle as administration of Compound A but without Compound A. Rats or mice were fed high fat diet in both groups (Compound A group or control group). The animals administered Compound A experienced a statistically significant change (e.g., increase) in GLP1R expression when compared to vehicle alone, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration. GLP1R expression is assayed, for example, as described in Ast, J., Nasteska, D., Fine, N.H.F. et al. Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling. Nat Commun 14, 301 (2023) or using68Ga- NODAGA-exendin-4, a radioligand specifically targeting GLP1R, as described in Stahle et al. Evaluation of glucagon-like peptide-1 receptor expression in nondiabetic and diabetic atherosclerotic mice using PET tracer 68Ga-NODAGA-exendin-4. Am J Physiol Endocrinol Metab 320: E989-E998, 2021, or with another suitable method of quantifying GLP1R expression. The increased expression of GLP1R leads to decreased appetite, contributing to weight loss.Example 19: Reduction in food intake.

[0136] (A) Rat Study: Sprague Dawley rats (27 males and 27 females) were divided into 5 groups. Rats received twice weekly intravenous bolus injections of vehicle, 1 mg / kg / dayCompound A, 3 mg / kg / day Compound A, 5 mg / kg / day Compound A, or 8 mg / kg / day Compound A (Groups 1, 2, 3, 4, and 5, respectively). The rats were monitored from Day 1 to Day 12, and a period of recovery extended to Day 26.

[0137] Dose dependent changes in food consumption at > 5 mg / kg in males and at 8 mg / kg in females were observed. Overall decreases in food consumption were observed in males (-8.80%, p < 0.01) at 5 mg / kg, in males (-15.75%, p < 0.01) at 8 mg / kg, and in females (-18.97%, p < 0.01) at 8 mg / kg. These decreases in food consumption did not impact overall body weight.

[0138] Overall decreases in weight between Day 1 and Day 12 were observed in males at 5 mg / kg (-2.13%, p < 0.05), in males at 8 mg / kg (-12.36%, p < 0.01) relative to controls. Recovery in body weight gains were observed in males at 8 mg / kg (1.60%, p < 0.05) between Day 19 and 26.

[0139] (B) Rabbit Study: Rabbits (24 males and 24 females) were divided into 5 groups. Rabbits received twice weekly intravenous bolus injections of vehicle, 1 mg / kg / day Compound A, 3 mg / kg / day Compound A, 10 mg / kg / day Compound A or 20 mg / kg / day Compound A (Groups 1, 2, 3, 4, and 5, respectively).

[0140] Overall (Day 1 to Day 12) decreases in food consumption were observed at >1 mg / kg in males (-4.03g to -14.90g) and at 1 mg / kg (-2.05g) and 10 mg / kg (-9.95g) in females relative to controls. During recovery, males still consumed less food than controls throughout recovery (-1.37g). No changes in body weights or body weight gains were observed during dosing or recovery.

Claims

CLAIMSWe claim:

1. A method of modulating energy homeostasis in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

2. A method of modulating (e.g., decreasing) food intake in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

3. A method of reducing body fat, cholesterol, or triglycerides, or a combination thereof, in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

4. A method of preserving muscle in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

5. A method of increasing GLP1R activity in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

6. A method of treating obesity in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

7. A method of reducing body weight in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

8. A method of treating type II diabetes in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

9. A method of promoting leptin production (e.g., leptin gene expression) in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

10. A method of increasing thermogenesis in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

11. A method of increasing metabolic rate in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

12. A method of reducing ghrelin production (e.g., ghrelin gene expression) in a subject need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

13. A method of promoting peptide YY production (e.g., PYY gene expression) in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

14. A method of restoring fertility in a subject in need thereof, comprising administration of an effective amount of an ADAR inhibitor to the subject.

15. The method of one of claims 1-14, wherein the ADAR inhibitor comprises: a first ADAR inhibitor selected from Compound A, fedratinib, a pladienolide (e.g., pladienolide B), raltegravir, dolutegravir, AVA-ADR-001, ZYS-1, cladribine, 8-azaadenosine, pentostatin, EHNA hydrochloride, AMPD2 inhibitor 1, hibifolin, coformycin, FR221647, FR234938, or AMPD2 inhibitor 2, or a pharmaceutically acceptable salt thereof; andoptionally a second ADAR inhibitor, different from the first, selected from raltegravir, dolutegravir, pladienolide B, Compound A, fedratinib, AVA-ADR-001, ZYS-1, cladribine, 8- azaadenosine, pentostatin, EHNA hydrochloride, AMPD2 inhibitor 1, hibifolin, coformycin, FR221647, FR234938, or AMPD2 inhibitor 2, or a pharmaceutically acceptable salt thereof.

16. The method of one of claims 1-14, wherein the ADAR inhibitor is selected from one or more of Compound A, fedratinib, pladienolide B, raltegravir, or dolutegravir, or a pharmaceutically acceptable salt thereof.

17. The method of one of claims 1-16, wherein the subject experiences a reduction in body weight, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.

18. The method of one of claims 1-16, wherein the subject experiences a reduction in body weight without a concurrent reduction in food intake, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.

19. The method of one of claims 1-18, wherein the subject experiences a reduction in food intake without a concurrent reduction in body weight, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration, or wherein the subject experiences an increase in expression of GLP1R from initial administration.

20. The method of one of claims 1-18, wherein the subject does not experience nausea, vomiting, diarrhea, or constipation resulting from the administration of the ADAR inhibitor, e.g. as measured at 2, 4, 8, or 12 weeks from initial administration.

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