# US 2012/0083522 A1 · Modulation of inflammatory responses by factor xi

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- Number: US 2012/0083522 A1
- Document ID: US20120083522A1
- Status: Published application
- Kind: A1
- Application number: 13/262,904
- Filed: 2010-04-15
- Published: 2012-04-05
- Earliest claimed: 2009-04-15
- Assignees: Isis Pharmaceuitcals, inc.
- Inventors: Brett P. Monia; Jeffrey R. Crosby; Robert A. MacLeod; Susan M. Freier
- Web page: https://patentgrep.com/patent/US20120083522A1

## 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)}
- A61K 31/7115: Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
- A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/06: Antiasthmatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/10: Antimycotics
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- 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
- C12Y 304/21027: Coagulation factor XIa (3.4.21.27)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- C12Y: ENZYMES

## Abstract

Disclosed herein are antisense compounds and methods for modulating Factor XI and modulating an inflammatory disease, disorder or condition in an individual in need thereof. Inflammatory diseases in an individual such as arthritis and colitis can be ameliorated or prevented with the administration of antisense compounds targeted to Factor XI.

## Claims

### Claim 1

A method for modulating an inflammatory response by administering a compound to an animal, wherein the compound comprises a Factor XI modulator and whereby the inflammatory response is modulated in the animal.

### Claim 2 (depends on 1)

The method of claim 1, wherein the Factor XI modulator is a modified oligonucleotide targeting Factor XI.

### Claim 3

A method for ameliorating or reducing the risk of an inflammatory disease, disorder or condition in an animal, or for treating an animal at risk for an inflammatory disease, disorder or condition, comprising administering a compound targeting Factor XI to the animal, wherein the compound administered to the animal ameliorates or reduces the risk of the inflammatory disease, disorder or condition in the animal, or treats the animal at risk for the inflammatory disease, disorder or condition.

### Claim 4

(canceled)

### Claim 5

A method for inhibiting Factor XI expression in an animal suffering from an inflammatory disease, disorder or condition, comprising administering a compound targeting Factor XI to the animal, wherein the compound administered to the animal inhibits Factor XI expression in the animal suffering from the inflammatory disease, disorder or condition.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The method of claim 1, wherein Factor XI has a sequence as shown in SEQ ID NO: 1 or SEQ ID NO: 2.

### Claim 8 (depends on 3)

The method of claim 3, wherein the compound targeting Factor XI is a modified oligonucleotide.

### Claim 9 (depends on 8)

The method of claim 8, wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence selected from among the nucleobase sequences recited in SEQ ID NOs: 15-269.

### Claim 10 (depends on 9)

The method of claim 9, wherein the nucleobase sequence of the modified oligonucleotide is 80% complementary to a nucleobase sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 6 or SEQ ID NO: 274.

### Claim 11 (depends on 8)

The method of claim 8, wherein the modified oligonucleotide consists of a single-stranded modified oligonucleotide.

### Claim 12 (depends on 8)

The method of claim 8, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides or wherein the modified oligonucleotide consists of 20 linked nucleosides.

### Claim 13

(canceled)

### Claim 14 (depends on 12)

The method of claim 12, wherein at least one internucleoside linkage is a modified internucleoside linkage, wherein at least one nucleoside comprises a modified sugar and/or wherein at least one nucleoside comprises a modified nucleobase.

### Claim 15 (depends on 14)

The method of claim 14, wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 16

(canceled)

### Claim 17 (depends on 14)

The method of claim 14, wherein at least one modified sugar is a bicyclic sugar or a 2′-O-methoxyethyl.

### Claim at position 18

-19. (canceled)

### Claim 20 (depends on 14)

The method of claim 14, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 21 (depends on 8)

The method of claim 8, 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 immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

### Claim 22 (depends on 8)

The method of claim 8, wherein the modified oligonucleotide comprises:
(a) a gap segment consisting of ten linked deoxynucleosides;
(b) a 5′ wing segment consisting of five linked nucleosides;
(c) a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.

### Claim at position 22

-28. (canceled)

### Claim 29 (depends on 1)

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

### Claim 30 (depends on 3)

The method of claim 3, wherein the inflammatory disease is arthritis, colitis, diabetes, sepsis, allergic inflammation, asthma, immunoproliferative disease, antiphospholipid syndrome or graft-related disorder, and/or an autoimmune disease.

### Claim 31

(canceled)

### Claim 32 (depends on 30)

The method of claim 30, wherein the arthritis is selected from rheumatoid arthritis, juvenile rheumatoid arthritis, arthritis uratica, gout, chronic polyarthritis, periarthritis humeroscapularis, cervical arthritis, lumbosacral arthritis, osteoarthritis, psoriatic arthritis, enteropathic arthritis and ankylosing spondylitis and wherein the colitis is selected from ulcerative colitis, Inflammatory Bowel Disease (IBD) and Crohn's Disease.

### Claim 33

(canceled)

### Claim 34 (depends on 3)

The method of claim 3, wherein the inflammatory disease disorder or condition is Th1 mediated and/or Th2 mediated.

### Claim 35 (depends on 34)

The method of claim 34, wherein a marker for the Th1 mediated and/or Th2 mediated inflammatory disease, disorder or condition is decreased.

### Claim 36 (depends on 35)

The method of claim 35, wherein the marker for Th1 is any of the cytokines IL-1, IL-6, INF-γ, TNF-α or KC.

### Claim at position 31

-38. (canceled)

### Claim 39 (depends on 35)

The method of claim 35, wherein the marker for Th2 is any of IL-4, IL-5, eosinophil infiltration or mucus production.

### Claim at position 33

-41. (canceled)

### Claim 42 (depends on 1)

The method of claim 1, further comprising a second agent.

### Claim 43

(canceled)

### Claim 44 (depends on 1)

The method of claim 1, wherein the compound is a salt form.

### Claim 45 (depends on 1)

The method of claim 1, further comprising a pharmaceutically acceptable carrier or diluent.

### Claim at position 38

-49. (canceled)