# US 8,772,260 B2 · Methods for inhibiting expression of connective tissue growth factor

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- Number: US 8,772,260 B2
- Document ID: US8772260B2
- Status: Granted
- Kind: B2
- Application number: 13/584,573
- Filed: 2012-08-13
- Published: 2013-07-25
- Granted: 2014-07-08
- Earliest claimed: 2008-08-25
- Assignees: Isis Pharmaceuticals, Inc.; Excaliard Pharmaceuticals, Inc.
- Applicants: Nicholas M. Dean; J. Gordon Foulkes; Niall O'Donnell; C. Frank Bennett; Susan M. Frier
- Inventors: Nicholas M. Dean; J. Gordon Foulkes; Niall O'Donnell; C. Frank Bennett; Susan M. Frier
- Web page: https://patentgrep.com/patent/US8772260B2

## CPC

- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- 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 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/02: for peripheral neuropathies
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)}
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2320/30: Special therapeutic applications
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention provides compounds which comprise modified oligonucleotides capable of inhibitory expression of connective tissue factor and composition containing same as well as methods of treating hyperprolific disorders and fibrotic diseases, and of reducing scarring resulting from wound healing using such compounds.

## Claims

### Claim 1

A method of treating hypertrophic scarring, comprising administering to a subject in need of treatment for hypertrophic scarring a therapeutically effective amount of a composition comprising a compound which comprises a modified oligonucleotide consisting of 12-30 linked nucleosides, at least a 12 nucleobase sequence portion of which is present within the nucleobase sequence set forth in SEQ ID NO: 39, wherein the modified oligonucleotide comprises:
(a) a gap segment consisting of linked deoxynucleosides;
(b) a 5′ wing segment consisting of linked modified nucleosides; and
(c) a 3′ wing segment consisting of linked modified nucleosides;
wherein the gap segment is positioned between the 5 wing segment and the 3′ wing segment, and wherein each modified nucleoside within each wing segment comprises a modified sugar.

### Claim 2 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide comprises:
(a) a gap segment consisting of thirteen linked deoxynucleosides;
(b) a 5′ wing segment consisting of two linked modified nucleosides; and
(c) a 3′ wing segment consisting of five linked modified nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each modified nucleoside within each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphothioate linkage.

### Claim 3 (depends on 1)

The method of claim 1, wherein in the modified oligonucleotide at least one internucleoside linkage is modified.

### Claim 4 (depends on 3)

The method of claim 3, wherein each modified internucleoside linkage is a phosphorothioate linkage.

### Claim 5 (depends on 3)

The method of claim 3, wherein each of the remaining internucleoside linkages is a phosphodiester linkage.

### Claim 6 (depends on 4)

The method of claim 4, wherein each of the internucleoside linkages is a phosphorothioate linkage.

### Claim 7 (depends on 1)

The method of claim 1, wherein in the modified oligonucleotide the modified sugar is a 2′-O-methoxyethyl sugar.

### Claim 8 (depends on 1)

The method of claim 1, wherein in the modified oligonucleotide at least one nucleobase is modified.

### Claim 9 (depends on 1)

The method of claim 1, wherein in the modified oligonucleotide at least one cytosine nucleobase is modified.

### Claim 10 (depends on 9)

The method of claim 9, wherein each modified cytosine nucleobase is a 5′-methylcytosine.

### Claim 11 (depends on 10)

The method of claim 10, wherein each cytosine within the nucleobase sequence of said modified oligonucleotide is a 5′-methylcytosine.

### Claim 12 (depends on 1)

The method of claim 1, wherein said composition is administered topically.

### Claim 13 (depends on 1)

The method of claim 1, wherein said composition is administered subcutaneously.

### Claim 14 (depends on 1)

The method of claim 1, wherein said composition is administered intradermally.

### Claim 15 (depends on 1)

The method of claim 1, wherein said composition is administered locally into fibrotic tissue.

### Claim 16 (depends on 1)

The method of claim 1, wherein the hypertrophic scarring results from dermal wound healing.

### Claim 17 (depends on 16)

The method of claim 16, wherein the wound is selected from the group consisting of skin breakage, surgical incision and burn.

### Claim 18 (depends on 1)

The method of claim 1, wherein after treatment said subject experiences an improvement in scar severity at least by an amount selected from the group consisting of 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 99%.

### Claim 19

A method of treating hypertrophic scarring, comprising administering to a subject in need of treatment for hypertrophic scarring a therapeutically effective amount of a composition comprising a compound which comprises a modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence as recited in SEQ ID NO 39, wherein the modified oligonucleotide comprises:
(a) a gap segment consisting of thirteen linked deoxynucleosides;
(b) a 5′ wing segment consisting of two linked modified nucleosides; and
(c) a 3′ wing segment consisting of five linked modified nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment,
wherein each modified nucleoside within each wing segment comprises a 2′-O-methoxyethyl sugar,
wherein each internucleoside linkage is a phosphorothioate linkage, and
wherein each cytosine nucleobase is a 5′-methylcytosine.

### Claim 20

A method of treating hypertrophic scarring, comprising administering to a subject in need of treatment for hypertrophic scarring a therapeutically effective amount of a composition comprising an antisense oligonucleotide consisting of the nucleotide sequence of SEQ ID NO:39, said antisense oligonucleotide further characterized as having, from 5′ to 3′ direction,
a 5′ wing segment consisting of two nucleotides, a gap segment consisting of 13 nucleotides, and a 3′ wing segment consisting of five nucleotides,
wherein each nucleotide of said 5′ and 3′ wing segments comprises a 2′-O-methoxyethyl sugar,
wherein each nucleotide of said gap segment comprises a deoxyribose sugar,
wherein each cytosine base of said antisense oligonucleotide is a 5′-methylcytosine, and
wherein the internucleotide linkages between each nucleotide of said antisense oligonucleotide are phosphorothioate linkages.

### Claim 21 (depends on 20)

The method of claim 20, wherein said composition is administered topically.

### Claim 22 (depends on 20)

The method of claim 20, wherein said composition is administered subcutaneously.

### Claim 23 (depends on 20)

The method of claim 20, wherein said composition is administered intradermally.

### Claim 24 (depends on 20)

The method of claim 20, wherein said composition is administered locally into fibrotic tissue.

### Claim 25 (depends on 20)

The method of claim 20, wherein the hypertrophic scarring results from dermal wound healing.

### Claim 26 (depends on 25)

The method of claim 25, wherein the wound is selected from the group consisting of skin breakage, surgical incision and burn.

### Claim 27 (depends on 20)

The method of claim 20, wherein after treatment said subject experiences an improvement in scar severity at least by an amount selected from the group consisting of 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 99%.