# US 2014/0193825 A1 · Modulation of angiopoietin-like 3 expression

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

- Number: US 2014/0193825 A1
- Document ID: US20140193825A1
- Status: Published application
- Kind: A1
- Application number: 14/149,715
- Filed: 2014-01-07
- Published: 2014-07-10
- Earliest claimed: 2010-01-08
- Assignees: Isis Pharmaceuticals, Inc.
- Applicants: Isis Pharmaceuticals, Inc.
- Inventors: Rosanne M. Crooke; Mark J. Graham; Richard Lee; Kenneth W. Dobie
- Web page: https://patentgrep.com/patent/US20140193825A1

## 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 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- C12Q 1/6883: for diseases caused by alterations of genetic material
- G01N 33/5023: {on expression patterns}
- 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 2320/30: Special therapeutic applications
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/158: Expression markers
- 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
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Provided herein are methods, compounds, and compositions for reducing expression of an ANGPTL3 mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for reducing plasma lipids, plasma glucose and atherosclerotic plaques in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate any one or more of cardiovascular disease or metabolic disease, or a symptom thereof.

## Claims

### Claim 1

An antisense compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to ANGPTL3, wherein the antisense compound reduces expression of ANGPTL3 by at least 40%.

### Claim 2 (depends on 1)

The antisense compound of claim 1, wherein the modified oligonucleotide has a nucleobase sequence at least 90%, at least 95% or 100% complementary to any of SEQ ID NOs: 1-5 as measured over the entirety of said modified oligonucleotide.

### Claim 3 (depends on 1)

The antisense compound of claim 1, wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of a sequence recited in any one of SEQ ID NOs: 34, 37-38, 40-43, 45, 50-55, 57-64, 67, 69-75, 77-78, 81-83, 85, 87, 90, 92-103, 105-107, 109-110, 113-115, 117-123, 126-146, 148-160, 162-180.

### Claim 4 (depends on 1)

The antisense compound of claim 1, wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage.

### Claim 5 (depends on 4)

The antisense compound of claim 4, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 6 (depends on 1)

The antisense compound of claim 1, wherein at least one nucleoside of said modified oligonucleotide comprises a modified sugar.

### Claim 7 (depends on 6)

The antisense compound of claim 6, wherein at least one modified sugar is a bicyclic sugar.

### Claim 8 (depends on 6)

The antisense compound of claim 6, wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a (4′-CH(CH3)—O-2′) BNA, a (4′-CH2—O-2′) BNA, or a 4′-(CH2)n—O-2′ bridge, wherein n is 1 or 2.

### Claim 9 (depends on 1)

The antisense compound of claim 1, wherein at least one nucleoside of said modified oligonucleotide comprises a modified nucleobase.

### Claim 10 (depends on 9)

The antisense compound of claim 9, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 11 (depends on 1)

The antisense compound of claim 1, wherein the modified oligonucleotide consists of 20 linked nucleosides.

### Claim 12 (depends on 1)

The antisense compound of claim 1, wherein the modified oligonucleotide comprises:
a) a gap segment consisting of linked deoxynucleosides;
b) a 5′ wing segment consisting of linked nucleosides;
c) 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 13 (depends on 1)

The antisense compound of claim 1, wherein the antisense compound reduces ANGPTL3 expression in an animal and thereby:
a) reduces apoC-III expression levels;
b) reduces triglyceride levels;
c) reduces cholesterol levels;
d) reduces LDL levels;
e) reduces glucose levels;
f) improves insulin sensitivity; and/or
g) ameliorates a metabolic or cardiovascular disease.

### Claim 14

An assay for identifying an antisense compound that inhibits ANGPTL3 comprising:
a) contacting cells with an antisense compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to ANGPTL3;
b) measuring an amount of ANGPTL3 produced by the cells contacted by the antisense compound targeting ANGPTL3; and
c) comparing the amount of ANGPTL3 produced from the cells contacted with the antisense compound targeting ANGPTL3 to an amount of ANGPTL3 produced by cells not contacted with the antisense compound targeting ANGPTL3;
wherein a reduction in ANGPTL3 production by the cells contacted by the antisense compound targeting ANGPTL3 compared to the production of ANGPTL3 produced by cells not contacted by the antisense compound targeting ANGPTL3 identifies the antisense compound that inhibits ANGPTL3.

### Claim 15

A kit for decreasing ANGPTL3 wherein the kit comprises: a) an antisense compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to ANGPTL3, wherein the antisense compound reduces expression of ANGPTL3 by at least 40%, and b) a label.

### Claim 16 (depends on 14)

The kit of claim 14, wherein the kit further comprises a second agent.