# US 2021/0277401 A1 · Compositions and Methods for Modulating PKK Expression

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- Number: US 2021/0277401 A1
- Document ID: US20210277401A1
- Status: Published application
- Kind: A1
- Application number: 15/929,573
- Filed: 2020-05-11
- Published: 2021-09-09
- Earliest claimed: 2014-05-01
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Thazha P. Prakash; Punit P. Seth; Eric E. Swayze; Susan M. Freier; Huynh-Hoa Bui
- Web page: https://patentgrep.com/patent/US20210277401A1

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/10: Antioedematous agents; Diuretics
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- 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 2310/315: Phosphorothioates
- C12N 2310/322: 2'-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 2310/345: having at least two different backbone modifications
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/351: Conjugate
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

Disclosed herein are antisense compounds and methods for decreasing PKK mRNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate PKK-associated diseases, disorders, and conditions.

## Claims

### Claim at position 1

-219. (canceled)

### Claim 220

A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and has a nucleobase sequence comprising at least 8 consecutive nucleobases of a nucleobase sequence selected from SEQ ID NOs: 346, 382, 931, 1111, 1117, 1393, 1401, 1817, 1876, 1886, 1940, 1947, 2008, 2018, and 2031.

### Claim 221 (depends on 220)

The compound of claim 220, wherein the nucleobase sequence comprises at least 15 consecutive nucleobases of a nucleobase sequence selected from SEQ ID NOs: 346, 382, 931, 1111, 1117, 1393, 1401, 1817, 1876, 1886, 1940, 1947, 2008, 2018, and 2031.

### Claim 222 (depends on 220)

The compound of claim 220, wherein the conjugate group comprises three N-acetylgalactosamine groups.

### Claim 223 (depends on 220)

The compound of claim 220, wherein the conjugate group is:

### Claim 224 (depends on 223)

The compound of claim 223, consisting of the modified oligonucleotide and the conjugate group.

### Claim 225 (depends on 220)

The compound of claim 220, wherein the modified oligonucleotide consists of 20 linked nucleosides.

### Claim 226 (depends on 220)

The compound of claim 220, wherein the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 10.

### Claim 227 (depends on 220)

The compound of claim 220, wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.

### Claim 228 (depends on 220)

The compound of claim 220, wherein each cytosine of the modified oligonucleotide is a 5′-methylcytosine.

### Claim 229 (depends on 220)

The compound of claim 220, wherein the modified oligonucleotide is single-stranded.

### Claim 230 (depends on 220)

The compound of claim 220, wherein the modified oligonucleotide comprises at least one 2′-O-methoxyethyl nucleoside, 2′-O-methyl nucleoside, constrained ethyl nucleoside, LNA nucleoside, and/or 3′-fluoro-HNA nucleoside.

### Claim 231 (depends on 220)

The compound of claim 220, wherein the modified oligonucleotide is a gapmer.

### Claim 232 (depends on 231)

The compound of claim 231, wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 5 linked nucleosides; and
a 3′ wing segment consisting of 5 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 233 (depends on 220)

The compound of claim 220, wherein the compound is in the form of a salt.

### Claim 234 (depends on 220)

A pharmaceutical composition comprising the compound of claim 220 and a pharmaceutically acceptable carrier or diluent.

### Claim 235 (depends on 234)

The pharmaceutical composition of claim 234, wherein the pharmaceutically acceptable carrier or diluent is phosphate buffered saline (PBS).

### Claim 236 (depends on 235)

The pharmaceutical composition of claim 235, wherein the pharmaceutical composition consists essentially of the compound and PBS.

### Claim 237 (depends on 220)

A method comprising administering the compound of claim 220 to a subject in need thereof.

### Claim 238 (depends on 237)

The method of claim 237, wherein administering the compound prevents, treats, or ameliorates a PKK associated disease, disorder or condition.

### Claim 239 (depends on 238)

The method of claim 238, wherein the PKK associated disease, disorder or condition is hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct.