# US 8,541,388 B2 · Methods for modulating expression of RBP4

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- Number: US 8,541,388 B2
- Document ID: US8541388B2
- Status: Granted
- Kind: B2
- Application number: 12/993,250
- Filed: 2009-05-21
- Published: 2011-05-26
- Granted: 2013-09-24
- Earliest claimed: 2008-05-22
- Assignees: Isis Pharmaceuticals, Inc.
- Applicants: Brett P. Monia; Xing-Xian Yu; Sanjay Bhanot
- Inventors: Brett P. Monia; Xing-Xian Yu; Sanjay Bhanot
- Web page: https://patentgrep.com/patent/US8541388B2

## CPC

- 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)}
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- 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: 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

Methods are provided for modulating RBP4 by administering a RBP4-specific modulator. Also provided are methods for treating cardiovascular and metabolic disorders in a subject or delaying or preventing risk factors thereof through the modulation of RBP4. The present invention is also directed to methods of decreasing lipid levels in a subject or for preventing or delaying the onset of a rise in lipid levels in a subject, comprising administering to said subject a RBP4-specific inhibitor.

## Claims

### Claim 1

A method of treating or ameliorating a cardiovascular disease in an animal diagnosed as having cardiovascular disease, comprising administering to the animal a therapeutically effective amount of a Retinol-Binding Protein 4 (RBP4) inhibitor, wherein the RBP4 inhibitor is a nucleic acid capable of inhibiting RBP4 by at least 24%, thereby treating or ameliorating the cardiovascular disease in the animal.

### Claim 2 (depends on 1)

The method of claim 1, wherein the cardiovascular disease is obesity, atherosclerosis, dyslipidemia, coronary heart disease, or a combination thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein the dyslipidemia is hyperlipidemia.

### Claim 4 (depends on 3)

The method of claim 3, wherein the hyperlipidemia is hypercholesterolemia.

### Claim 5 (depends on 1)

The method of claim 1, wherein the administering results in a reduction of cholesterol levels.

### Claim 6

A method of decreasing cholesterol levels in a human diagnosed as being in need of decreasing cholesterol levels comprising administering a Retinol-Binding Protein 4 (RBP4) inhibitor to the human diagnosed as being in need of decreasing cholesterol levels, wherein the RBP4 inhibitor is a nucleic acid capable of inhibiting RBP4 by at least 24%, thereby decreasing cholesterol levels in the human.

### Claim 7 (depends on 6)

The method of claim 6, wherein the nucleic acid is a modified oligonucleotide.

### Claim 8 (depends on 7)

The method of claim 7, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.

### Claim 9 (depends on 8)

The method of claim 8, wherein said modified oligonucleotide is a single-stranded oligonucleotide.

### Claim 10 (depends on 9)

The method of claim 9, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to human RBP4.

### Claim 11 (depends on 9)

The method of claim 9, wherein at least one internucleoside linkage is a modified internucleoside linkage.

### Claim 12 (depends on 11)

The method of claim 11, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 13 (depends on 9)

The method of claim 9, wherein at least one nucleoside contains a modified sugar.

### Claim 14 (depends on 13)

The method of claim 13, wherein the modified sugar comprises a 2′-O-methoxyethyl sugar moiety.

### Claim 15 (depends on 13)

The method of claim 13, wherein the modified sugar is a bicyclic nucleic acid sugar moiety.

### Claim 16 (depends on 9)

The method of claim 9, wherein at least one nucleoside comprises a modified nucleobase.

### Claim 17 (depends on 15)

The method of claim 15, wherein the bicyclic nucleic acid sugar moiety comprises a 4′-CH(CH3)-O-2′ bridge.

### Claim 18 (depends on 1)

The method of claim 1, wherein the administering comprises parenteral administration.

### Claim 19 (depends on 18)

The method of claim 18, wherein the parenteral administration comprises subcutaneous or intravenous administration.

### Claim 20 (depends on 1)

The method of claim 1, comprising co-administering the RBP4 inhibitor and at least one additional therapy.

### Claim 21 (depends on 20)

The method of claim 20, wherein the RBP4 inhibitor and the additional therapy are administered concomitantly.

### Claim 22 (depends on 20)

The method of claim 20, wherein the RBP4 inhibitor and the additional therapy are administered in the same formulation.

### Claim 23

A method comprising identifying an animal having a cardiovascular disease and administering to said animal a therapeutically effective amount of a composition comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence complementary to SEQ ID NO: 1, 2, 3, 4, 5, 6 or 7 as measured over the entirety of said modified oligonucleotide, wherein the modified oligonucleotide is capable of inhibiting Retinol-Binding Protein 4 (RBP4) by at least 24%, thereby treating the cardiovascular disease.

### Claim 24 (depends on 16)

The method of claim 16, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 25 (depends on 9)

The method of claim 9, wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleotides;
a 5′ wing segment consisting of linked nucleosides; and
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, and wherein each nucleoside of each wing segment comprises a modified sugar.

### Claim 26 (depends on 25)

The method of claim 25, wherein the oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides; and
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine in said modified oligonucleotide is a 5-methylcytosine.

### Claim 27 (depends on 1)

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

### Claim 28 (depends on 23)

The method of claim 23, wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.

### Claim 29 (depends on 28)

The method of claim 28, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 30 (depends on 23)

The method of claim 23, wherein at least one nucleoside of the modified oligonucleotide contains a modified sugar.

### Claim 31 (depends on 30)

The method of claim 30, wherein the modified sugar comprises a 2′-O-methoxyethyl sugar moiety.

### Claim 32 (depends on 31)

The method of claim 31, wherein the modified sugar is a bicyclic nucleic acid sugar moiety.

### Claim 33 (depends on 32)

The method of claim 32, wherein the bicyclic nucleic acid sugar moiety comprises a 4′-CH(CH3)-O-2′ bridge.

### Claim 34 (depends on 23)

The method of claim 23, wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase.

### Claim 35 (depends on 1)

The method of claim 1, wherein the nucleic acid comprises a modification selected from the group consisting of a modified internucleoside linkage, a modified sugar moiety, and a modified nucleobase.