# US 2019/0167816 A1 · Methods for preventing or treating fibrotic diseases

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- Number: US 2019/0167816 A1
- Document ID: US20190167816A1
- Status: Published application
- Kind: A1
- Application number: 16/263,406
- Filed: 2019-01-31
- Published: 2019-06-06
- Earliest claimed: 2016-08-01
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Gino Cortopassi; Alexey Tomilov; Natalie Torok; XiaoSong Jiang
- Web page: https://patentgrep.com/patent/US20190167816A1

## CPC

- A61K 48/0066: {Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid}
- A61K 31/122: having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4706: 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/711: Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 48/0008: {characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition}
- A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/531: Stem-loop; Hairpin
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention provides methods for preventing or treating a fibrotic disease in a subject. In some embodiments, the fibrotic disease is fatty liver disease, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis. In particular aspects, the methods comprise administering an inhibitor of Shc gene expression to achieve genetic suppression of Shc activity in the subject. In other aspects, the methods comprise administering a peptide, peptoid, or peptide-peptoid hybrid inhibitor of Shc to achieve pharmacological suppression of Shc protein activity in the subject.

## Claims

### Claim 1

A method for preventing or treating a fibrotic disease in a subject, the method comprising administering to the subject an effective amount of an inhibitor of Shc gene expression to achieve genetic suppression of Shc activity in the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the fibrotic disease is selected from the group consisting of fibrotic liver disease, pulmonary fibrosis, cardiac fibrosis, and cystic fibrosis.

### Claim 3 (depends on 1)

The method of claim 1, wherein the inhibitor of Shc gene expression comprises DNA, RNA, a nuclease, or a combination thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the inhibitor of Shc gene expression is administered to perform RNA interference, antisense therapy, CRISPR genome editing, a virus-mediated knockdown, or a combination thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the inhibitor of Shc gene expression is administered before the subject exhibits any symptoms of the fibrotic disease.

### Claim 6 (depends on 1)

The method of claim 1, wherein the subject exhibits one or more symptoms of the fibrotic disease.

### Claim 7 (depends on 6)

The method of claim 6, wherein the administration of the inhibitor of Shc gene expression ameliorates at least one of the one or more symptoms.

### Claim 8 (depends on 1)

The method of claim 1, wherein the suppression of Shc activity in the subject is transient.

### Claim 9 (depends on 1)

The method of claim 1, wherein the level of one or more biomarkers indicative of the fibrotic disease is abnormal.

### Claim 10 (depends on 9)

The method of claim 9, wherein the one or more biomarkers indicative of the fibrotic disease is selected from the group consisting of alpha-smooth muscle actin (αSMA), procollagen α1 (procol1), transforming growth factor-β (TGFβ), monocyte chemoattractant protein-1 (MCP1), interleukin-1β(IL-1b), tumor necrosis factor alpha (TNFα), connective tissue growth factor (CTGF), and platelet derived growth factor receptor beta (PDGFRβ).

### Claim 11 (depends on 1)

The method of claim 1, wherein the level of one or more biomarkers indicative of liver disease is abnormal.

### Claim 12 (depends on 11)

The method of claim 11, wherein the one or more biomarkers indicative of liver disease is selected from the group consisting of aspartate aminotransferase (AST), alanine aminotransferase (ALT), the ratio of AST to ALT, gamma-glutamyl transferase (GGT), the aspartate to platelet ratio index (APRI), alkaline phosphatase (AP), bilirubin, and ferritin.

### Claim 13 (depends on 9)

The method of claim 9, wherein the level of the one or more biomarkers is measured before administration of the inhibitor of Shc gene expression.

### Claim 14 (depends on 9)

The method of claim 9, wherein administration of the inhibitor of Shc gene expression results in the level of at least one of the one or more biomarkers returning to a control level.

### Claim 15

A method for preventing or treating a fibrotic disease in a subject, the method comprising administering to the subject an effective amount of a peptide inhibitor of Shc, a peptoid inhibitor of Shc, a peptide-peptoid hybrid inhibitor of Shc, or a combination thereof to achieve pharmacological suppression of Shc protein activity in the subject.

### Claim 16 (depends on 15)

The method of claim 15, wherein the fibrotic disease is selected from the group consisting of fibrotic liver disease, pulmonary fibrosis, cardiac fibrosis, and cystic fibrosis.

### Claim 17 (depends on 15)

The method of claim 15, wherein the peptide inhibitor, peptoid inhibitor, peptide-peptoid hybrid inhibitor, or combination thereof is administered before the subject exhibits any symptoms of the fibrotic disease.

### Claim 18 (depends on 15)

The method of claim 15, wherein the subject exhibits one or more symptoms of the fibrotic disease.

### Claim 19 (depends on 18)

The method of claim 18, wherein the administration of the peptide inhibitor, peptoid inhibitor, peptide-peptoid hybrid inhibitor, or combination thereof ameliorates at least one of the one or more symptoms.

### Claim 20 (depends on 15)

The method of claim 15, wherein the level of one or more biomarkers indicative of the fibrotic disease is abnormal.

### Claim 21 (depends on 20)

The method of claim 20, wherein the one or more biomarkers of the fibrotic disease is selected from the group consisting of alpha-smooth muscle actin (αSMA), procollagen α1 (procol1), transforming growth factor-β (TGFβ), monocyte chemoattractant protein-1 (MCPJ), interleukin-1β (IL-1b), tumor necrosis factor alpha (TNFα), connective tissue growth factor (CTGF), and platelet derived growth factor receptor beta (PDGFRβ).

### Claim 22 (depends on 15)

The method of claim 15, wherein the level of one or more biomarkers indicative of liver disease is abnormal.

### Claim 23 (depends on 22)

The method of claim 22, wherein the one or more biomarkers indicative of liver disease is selected from the group consisting of aspartate aminotransferase (AST), alanine aminotransferase (ALT), the ratio of AST to ALT, gamma-glutamyl transferase (GGT), the aspartate to platelet ratio index (APRI), alkaline phosphatase (AP), bilirubin, and ferritin.

### Claim 24 (depends on 20)

The method of claim 20, wherein the level of the one or more biomarkers is measured before administration of the peptide inhibitor, peptoid inhibitor, peptide-peptoid hybrid inhibitor, or combination thereof.

### Claim 25 (depends on 20)

The method of claim 20, wherein the administration of the peptide inhibitor, peptoid inhibitor, peptide-peptoid hybrid inhibitor, or combination thereof results in the level of at least one of the one or more biomarkers returning to a control level.

### Claim 26 (depends on 11)

The method of claim 11, wherein the level of the one or more biomarkers is measured before administration of the inhibitor of Shc gene expression.

### Claim 27 (depends on 11)

The method of claim 11, wherein administration of the inhibitor of Shc gene expression results in the level of at least one of the one or more biomarkers returning to a control level.

### Claim 28 (depends on 22)

The method of claim 22, wherein the level of the one or more biomarkers is measured before administration of the peptide inhibitor, peptoid inhibitor, peptide-peptoid hybrid inhibitor, or combination thereof.

### Claim 29 (depends on 22)

The method of claim 22, wherein the administration of the peptide inhibitor, peptoid inhibitor, peptide-peptoid hybrid inhibitor, or combination thereof results in the level of at least one of the one or more biomarkers returning to a control level.