# US 9,750,718 B2 · Methods of treating hepatic fibrosis and associated diseases by regulating Rev-ERB activity

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,750,718 B2
- Document ID: US9750718B2
- Status: Granted
- Kind: B2
- Application number: 14/651,413
- Filed: 2013-12-12
- Published: 2015-11-19
- Granted: 2017-09-05
- Earliest claimed: 2012-12-12
- Assignees: The Charlotte-Mecklenburg Hospital Authority
- Applicants: The Charlotte-Mecklenburg Hospital Authority
- Inventors: Ting Li; Laura Schrum
- Web page: https://patentgrep.com/patent/US9750718B2

## CPC

- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/381: having five-membered rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 47/643: {Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention is directed to compositions and associated methods for treatment, prevention, amelioration, and/or delaying the onset of hepatic fibrosis and/or associated diseases. The methods preferably involve regulating at least one of Rev-erbα expression, activity, and subcellular localization. In particular, certain embodiments of the present invention relate to compositions and methods of using a Rev-erb-modulating agent (REMA) for the treatment or prevention of hepatic fibrosis and/or associated diseases. Preferably, the amount of a REMA administered comprises a quantity sufficient to modulate at least one of Rev-erbα expression, activity, and subcellular localization and reduce the activation of hepatic stellate cells (HSCs).

## Claims

### Claim 1

A method of treating, ameliorating, or delaying the onset of liver fibrosis and related pathologies in a mammal in need thereof, the method comprising:
providing a composition comprising a therapeutically effective amount of one or more Rev-erb-modulating agents (REMAs), the one or more REMAs being selected from the group consisting of 1,1-Dimethylethyl N-[(4-chlorophenyl)methyl]-N-[(5-nitro-2-thienyl)methyl])glycinate; N-Benzyl-N-(4-chlorobenzyl)-1-(5-nitrothiophen-2-yl)methanamine; N-Benzyl-N-(3,4-dichlorobenzyl)-1-(5-nitrothiophen-2-yl)methanamine; 2-((4-chlorobenzyl)((5-nitrothiophen-2-yl)methyl)amino)-N,N-dimethylacetamide; SR9009; SR9011; and combinations thereof; and
administering the composition to the mammal, the therapeutically effective amount comprising a quantity sufficient to modulate at least one of Rev-erbα expression, activity, and subcellular localization in at least a portion of the mammal's hepatic stellate cells (HSCs),
wherein the one or more REMAs is contained in a vector selected from the group consisting of a plasmid, cosmid, phagemid, or virus.

### Claim 2 (depends on 1)

The method of claim 1, wherein the one or more REMAs: modulates Rev-erbα activity or subcellular localization in at least a portion of the mammal's HSCs, increases Rev-erbα nuclear activity and/or nuclear localization, decreases Rev-erbα cytoplasmic activity and/or cytoplasmic localization, or combinations thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the modulation is direct.

### Claim 4 (depends on 1)

The method of claim 1, wherein the one or more REMAs comprises at least one synthetic ligand or small molecule.

### Claim 5 (depends on 1)

The method of claim 1, wherein the one or more REMAs comprises at least one natural REMA.

### Claim 6 (depends on 1)

The method of claim 1, wherein the one or more REMAs comprises an enzyme, an antibody, a protein, or combination thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein at least one of the one or more REMAs is linked to a carrier/targeting moiety.

### Claim 8 (depends on 7)

The method of claim 7, wherein the carrier/targeting moiety is mannose-6-phosphate modified human serum albumin.

### Claim 9 (depends on 1)

The method of claim 1, wherein the related pathologies comprise cirrhosis, HCC, neuronal diseases, cardiovascular diseases, or combinations thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein a therapeutically effective amount of the one or more REMAs comprises an amount sufficient to halt activation of HSCs.

### Claim 11 (depends on 1)

The method of claim 1, wherein a therapeutically effective amount of the one or more REMAs comprises an amount sufficient to revert at least a portion of any activated HSCs into a quiescent phenotype.

### Claim 12 (depends on 1)

The method of claim 1, wherein the one or more REMAs modulates expression, activity, and/or subcellular localization of at least one Rev-erb in addition to Rev-erbα in at least a portion of the mammal's HSCs.

### Claim 13 (depends on 12)

The method of claim 12, wherein the at least one Rev-erb in addition to Rev-erba is Rev-erbβ.

### Claim 14 (depends on 1)

The method of claim 1, wherein the mammal also suffers from at least one of viral hepatitis, autoimmune hepatitis, hepatic cirrhosis, acute alcoholic hepatitis, schistosomiasis, primary biliary cirrhosis, acute and fulminant hepatitis, congenital hepatic fibrosis, peliosis hepatitis, veno-occlusive disease, Budd-Chiari syndrome, vitamin A toxicity, Sclerosing cholangitis, non-alcoholic steatophepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, a metabolic liver disease, Wilson's disease, and hemochromatosis.

### Claim 15 (depends on 1)

The method of claim 1, wherein the mammal does not suffer from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatophepatitis (NASH), obesity, a metabolic disease, or autoimmune hepatitis.

### Claim 16 (depends on 1)

The method of claim 1, wherein Rev-Erba expression is modulated by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, and/or Rev-erbα nuclear localization is increased to at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.

### Claim 17 (depends on 1)

The method of claim 1, wherein the mammal is a human.

### Claim 18 (depends on 1)

The method of claim 1, wherein the step of administering the composition comprises oral, intravenous, intraperitoneal, intramuscular, transdermal, subcutaneous, topical, or sublingual administration.

### Claim 19 (depends on 1)

The method of claim 1, wherein the composition comprises a pharmaceutically acceptable carrier.

### Claim 20 (depends on 19)

The method of claim 19, wherein the composition is provided in the form of a liquid injectable composition, tablet, capsule, liquid oral composition, loaded nanoparticle, or transdermal patch.

### Claim 21 (depends on 19)

The method of claim 19, wherein the pharmaceutically acceptable carrier comprises a virus, liposome, polymer, or combinations thereof.

### Claim 22 (depends on 1)

The method of claim 1, further comprising the step of perfusing the composition comprising the one or more REMAs through a targeted tissue of the mammal.

### Claim 23 (depends on 22)

The method of claim 22, wherein the targeted tissue comprises at least a portion of the HSCs of the mammal.

### Claim 24 (depends on 1)

The method of claim 1, further comprising administering a non-REMA therapeutic agent either at the same time or at a different time as administering the composition comprising the one or more REMAs, wherein the non-REMA therapeutic agent is an anti-viral agent, miR-19b, an angiotensin II receptor antagonist, or a vasodilating medicament.

### Claim 25

A pharmaceutical composition, comprising: a therapeutically effective amount of one or more Rev-erb-modulating agents (REMA) and at least one pharmaceutically acceptable carrier, wherein administration of said one or more REMA to a mammal modulates Rev-erbα expression, activity, and/or subcellular location in at least a portion of the mammal's hepatic stellate cells (HSCs) wherein the one or more REMA comprises 1,1-Dimethylethyl N-[(4-chlorophenyl)methyl]-N-[(5-nitro-2-thienyl)methyl])glycinate; N-Benzyl-N-(4-chlorobenzyl)-I-(5-nitrothiophen-2-yl)methanamine; N-Benzyl-N-(3,4-dichlorobenzyl)-I-(5-nitrothiophen-2-yl)methanamine; 2-((4-chlorobenzyl)((5-nitrothiophen-2-yl)methyl)amino)-N,N-dimethylacetamide; SR9009; SR9011; or combinations thereof, wherein the one or more REMAs is contained in a vector selected from the group consisting of a plasmid, cosmid, phagemid, or virus.

### Claim 26 (depends on 25)

The composition of claim 25, wherein said therapeutically effective amount of said one or more REMA comprises a quantity sufficient to modulate at least one of Rev-Erbα expression in a mammal, halt activation of HSCs in a mammal, or revert at least a portion of any activated HSCs into a quiescent phenotype in a mammal.

### Claim 27 (depends on 25)

The composition of claim 25, wherein the one or more REMA is linked to a carrier/targeting moiety.

### Claim 28 (depends on 25)

The composition of claim 25, wherein the composition is provided in a form selected from a liquid injectable composition, a tablet, a capsule, loaded nanoparticle, an orally administrable liquid, or a transdermal patch.